Introduction ⬇
AHFS Class:
- Antineoplastic Agents 10:00
Generic Name(s):
Interferon alfa is a family of proteins and glycoproteins with antiviral, antineoplastic, and immunomodulating activities.2,8,47,70,255,259,261,456,648,714,717,740,906,1211,1240,1241,1339,1426,1464 Interferon alfa is available in the US as interferon alfa-2b2 and interferon alfa-n3.3 For information on interferon alfa-n3, see Interferon Alfa 8:18.20. Interferon alfa also is available covalently bound to monomethoxy polyethylene glycol (PEG) (i.e., peginterferon alfa).20,48,49 and Peginterferon Alfa 10:00.For information on peginterferon alfa, see Peginterferon Alfa 8:18.20
Uses ⬆ ⬇
Interferon alfa is used in the treatment of various cancers, including hairy cell leukemia, AIDS-related Kaposi's sarcoma, follicular non-Hodgkin's lymphoma, and melanoma.2
For information on use of interferon alfa in the treatment of various viral infections, see Interferon Alfa 8:18.20.
Hairy Cell Leukemia 
Interferon alfa (alfa-2a [no longer commercially available in the US], alfa-2b) is used for the treatment of hairy cell leukemia2,135,153,219,439,1620,1621,1623,1625,1627,1629,1635 (leukemic reticuloendotheliosis).171,1636 Results from a limited number of studies in which comparative efficacy was not a specific objective suggest that both interferon subtypes have similar efficacy in patients with this disease.122,137,141,174,239,246,248,1003
Therapy with interferon alfa produces complete response in 10% and clinically important tumor regression or disease stabilization (complete or partial responses; overall response) in approximately 80% of patients with hairy cell leukemia,122,123,124,125,126,127,128,129,131,132,134,135,136,138,141,142,143,170,175,178,181,182,191,193,199,202,219,220,237,239,243,248,249,250,252,253,260,266,278,439,1620,1624,1635,1636 including in previously untreated patients (i.e., those who have not undergone splenectomy) as well as in those with progressive disease in whom splenectomy has been performed.122,141,237,248,260,1004 The drug does not appear to be curative.123,125,126,134,136,141,142,171,174,182,202,219,250,252,273,1003,1154,1620,1621,1624,1627,1629,1635 Because of their apparent greater efficacy (i.e., higher complete response rate), cladribine or pentostatin is preferred for most patients with hairy cell leukemia who require treatment.439,1619,1620,1621,1622,1623,1624,1625,1627,1632,1637 (See Cladribine 10:00 and also see Pentostatin 10:00.) Because of the availability of effective drug therapies, splenectomy is becoming less important as a therapeutic option in patients with hairy cell leukemia.439,1621,1623,1627,1632,1636,1637 Additional studies and long-term follow-up are needed to elucidate optimal therapy for hairy cell leukemia.1620,1627,1632,1637
Reductions in splenomegaly and in the number of leukemic cells in peripheral blood generally are the initial signs of response to interferon alfa therapy in patients with hairy cell leukemia.122,124,133,134,136,138,141,171,173,191,199,202,239,243,246,248,1003,1006,1007,1620,1635 Interferon alfa also may decrease bone marrow hypercellularity and hairy cell infiltrates and result in substantial and sustained improvements in granulocyte and platelet counts in peripheral blood and hemoglobin concentrations.2,122,124,131,136,137,138,139,174,175,180,189,193,199,220,237,239,246,248,249,250,252,260,266,1620,1635 Most patients with hairy cell leukemia have at least one abnormality in their hematologic profile prior to interferon therapy,119,130,131,133,135,136,137,138,140,142,171,173,174,175,178,191,192,193,194,195,250,252,253 and response to the drug is characterized by complete or partial normalization of hematologic values, including hemoglobin concentration and granulocyte and platelet counts in peripheral blood and bone marrow.2,119,122,124,131,136,137,139,140,174,175,180,182,189,193,195,199,200,220,221,248,250,252,1620,1635 Patients who respond to interferon alfa therapy have an increased performance status, a decreased number of infections as granulocyte counts improve, and substantially reduced requirements for red blood cell and platelet transfusions.122,124,129,132,135,136,170,171,175,189,191,193,219,237 Clinical improvement in patients treated with interferon alfa may be apparent within the first month of therapy122,123,124,128,134,141,171,192,239,248,252,266 and usually is apparent within 6 months;131,191,202,239,246,248,1005,1549,1620,1635 however, up to 9-12 months or more of therapy may be required for clinical response.124,129,138,141,202,243
Clinical response to interferon alfa therapy in hairy cell leukemia generally is similar whether or not the patient has undergone splenectomy,2,122,129,134,136,174,181,186,237,260,1548 although limited data suggest that response may occur more rapidly in splenectomized patients.181,1545 In addition, some studies indicate that the incidence of complete remission may be greater in previously untreated patients than in splenectomized patients.134,138,141,248 Because of the availability of more effective agents such as cladribine and pentostatin, splenectomy is a less important therapeutic option in patients with hairy cell leukemia.439,1620,1621,1623,1627,1632,1636 Some clinicians suggest that splenectomy may be considered in patients who do not respond to therapy with cladribine, pentostatin, or interferon alfa or when massive splenomegaly or splenic rupture with pain and infection are present.1620 Although interferon alfa generally appears equally effective in patients with mild or severe disease,136,138,139,220,239,248,249,250,252 differences in response rate observed in these studies may have been related to initiation of interferon alfa therapy at an earlier clinical stage of the disease in previously untreated patients.138,141,248 In most patients with substantial splenomegaly, interferon alfa therapy reduces the spleen to normal or near-normal size136,202 and produces a reversal of the hematologic abnormalities in peripheral blood that result from hypersplenism.2,122,129,138,191,199,246 In some of these patients, interferon therapy may reverse hypersplenism which, if not reversed, could have necessitated splenectomy.2,129,135,136,186,202 In those patients who exhibit persistent splenomegaly despite interferon alfa therapy, splenectomy may be required.129,136 Limited evidence also suggests that the addition of interferon alfa to antimicrobial therapy in patients with hairy cell leukemia and unresponsive mycobacterial or fungal infections may result in microbiologic and/or clinical cure of the infection,192,193 apparently through restoration by interferon alfa of impaired immune function;122,137,175,192,193,248,253 therefore, some clinicians suggest that interferon may be particularly beneficial and preferable therapy in patients with hairy cell leukemia who have recurrent opportunistic infections.192,193,253,1548,1549
During the initial 1-3 months of interferon alfa therapy, marked depression in hematopoiesis may occur,2,128,129,134,138,171,173,239,248,250,252,1620 as evidenced by a substantial decrease in the monocyte, granulocyte, and polymorphonuclear leukocyte counts in peripheral blood;122,129,138,173,239,248,250,252 however, peripheral blood counts generally improve with continued therapy.2,122,124,129,171,237,239,252 It has not been established whether the initial transient decrease in circulating granulocytes observed in many patients may increase their risk of infection;248,318,376,461 however, individuals with hairy cell leukemia have required red blood cell and platelet transfusions during this period of transient myelosuppression.250,252 (See Cautions: Precautions and Contraindications.) Interferon alfa therapy does not appear to adversely affect hemoglobin concentration and platelet count in patients with normal pretreatment values of these parameters.137,173 Following this initial interferon-induced depression in hematopoiesis, peripheral hematologic parameters generally return to normal over several (e.g., 2-6) months, with platelet count usually returning first, followed by hemoglobin concentration and granulocyte and monocyte counts,2,122,124,129,134,135,136,141,171,175,239,243,248,250,252,1549 and these parameters may continue to improve throughout the initial 9-12 months of therapy.122,124,128,138,141,171,175
In addition to restoring peripheral blood counts to normal or near-normal values, interferon alfa produces substantial decreases in the leukemic cell index (the product of the percentages of bone marrow cellularity and leukemic cell infiltrates in the marrow).2,124,131,136,137,138,139,173,175,180,189,193,199,237,246,248,249,250,252,260,266,1620 While return of peripheral blood hematologic values to normal usually occurs after only 2-6 months of therapy,2,122,124,131,134,135,173,175,237,243,248,250,1549,1635 evidence suggests that prolonged (at least 9-12 months) therapy with interferon alfa generally is necessary to decrease leukemic cell infiltration in bone marrow;2,124,131,134,136,220,237,243,250,260 several patients categorized as having minor responses to interferon therapy reportedly have had a greater than 50% decrease in or complete clearing of leukemic cells in bone marrow despite persistence of neutropenia.239 Limited evidence suggests that interferon therapy produces a decrease in leukocyte counts in most patients who have leukocytosis prior to therapy.137,248
Interferon alfa may reverse the clinical and laboratory manifestations (e.g., splenomegaly, anemia and other cytopenias, leukemic infiltration)122,124,126,135,137,138,142,171,182,220,239,248 of hairy cell leukemia and has induced objective remissions that may persist for 2 years or longer (range: 0.5 months to longer than 2 years).123,126,129,176,182,193,202,248,250,1144,1549 During the first 3 months following discontinuance of interferon alfa therapy in patients with hairy cell leukemia, an increase in the percentage of leukemic infiltrates in bone marrow frequently is evident.125,171,182,250 However, this change represents a relative rather than an absolute increase in bone marrow leukemic cells related to the rapid exit of normal myeloid and erythroid precursors from the bone marrow following discontinuance of interferon alfa therapy.125,171,250 Although patients usually are not refractory to a second course of interferon alfa therapy,125,132,134,179,182,175,248,273 such therapy generally is not required unless the progressive increase in leukemic infiltrates in bone marrow is accompanied by one or more peripheral blood cytopenias.126,248,250 Deterioration in peripheral blood cell counts does not occur rapidly after discontinuance of interferon alfa therapy;125,126 however, within 7-12 months after completion of therapy, peripheral blood platelet and granulocyte counts may decrease to 60% of those achieved at the end of an initial course of therapy.125,176,248 A second course of interferon alfa therapy may be required 2-19 months after completion of the initial course because of this reduction in platelet and granulocyte counts,125,126,248,250 suggesting that maintenance therapy with interferon alfa may be necessary for prolonged remission in patients with hairy cell leukemia.122,125,132,141,171,179,182,202,246,251,1148,1152,1153,1154
Limited evidence suggests that response to interferon alfa therapy during long-term treatment of hairy cell leukemia may be dose related,132,179,180,243,252,1148,1154 although conflicting data have been reported.124,126,141,248,252,1003,1144,1148 In one study, most patients who received 1 million units/m2 of interferon alfa achieved normalization of hematologic values and a reduction in leukemic bone marrow infiltration but had delayed increases in granulocyte count relative to individuals treated with 2 or 4 million units/m2; a few patients achieved only partial responses despite prolonged therapy (i.e., for approximately 1 year).180 In another study, there was a relatively high incidence of disease progression in patients with hairy cell leukemia who were treated with very low (200,000 units/m2) dosages of interferon alfa, which is unusual in patients treated with standard dosages (e.g., 2 million units/m2) of the drug.124,132,182 Most patients whose disease progressed on this low-dose regimen demonstrated a hematologic response within 3 months of increasing the interferon alfa dosage to that of a standard regimen.179 While low-dose regimens of interferon alfa are not recommended for initial therapy or for relapse of hairy cell leukemia because of the risk of disease progression and associated neutropenia and thrombocytopenia, low-dose therapy with the drug may prove to be useful for maintenance in patients whose disease is in remission, but additional study and experience are needed.132,179,1548,1549,1620
Response to interferon alfa therapy may be monitored periodically (e.g., monthly) by determining peripheral blood hemoglobin concentration and platelet, granulocyte, and leukemic cell counts in peripheral blood and bone marrow and comparing these with baseline values.2 Although the manufacturer and some clinicians state that therapy should be discontinued if the patient does not respond within 6 months,2,219,1549 other clinicians suggest that therapy be continued for at least 12 months unless there is evidence of disease progression; onset of response has been noted as late as 9-12 months following initiation of treatment in some patients,124,130,141,202,220,248,250,1003,1007,1154 and limited evidence suggests that prolonged therapy (e.g., 12-18 months or longer) may improve the possibility of a response,2 including complete remission.130,137,181,200,249,1015,1549 However, it has not been established whether achieving complete remission offers any advantage in terms of performance status or survival.143,174,191,252,1015,1620 In addition, the possible advantage of prolonged maintenance therapy compared with more aggressive induction regimens requires further study.141,191,202,252,1548
The optimum duration of interferon alfa therapy for hairy cell leukemia has not been clearly established, although it appears that therapy should continue for at least 6 months.141,173,174,191,202,219,220,248,250,252,1620 Extending interferon alfa therapy up to a total duration of 18-24 months can maintain therapeutic response during treatment, but does not appear to influence the clinical course of the disease once interferon has been discontinued.125,129,136,141,182,248,1003,1144,1548,1549 Optimum duration of therapy cannot be defined until the biochemical and pharmacologic factors that predict prolonged survival have been identified.141,252 Bone marrow histology does not completely normalize in most patients following treatment with interferon alfa,122,123,129,131,132,134,136,142,171,175,182,221,239,250,252,1548,1620 and many (e.g., 20-50%) patients who respond to initial therapy relapse within 6-12 months after discontinuance of the drug.123,125,126,132,134,136,141,182,202,243,248,1003,1144,1152,1620 Although limited evidence suggests that early disease relapse following completion of treatment may be more common in patients with severe neutropenia or hyperleukocytosis at the time of diagnosis,176 other studies have not confirmed a correlation between these baseline hematologic findings and duration of remission.182 Limited data suggest that the best indicators of relapse following interferon alfa therapy in patients with hairy cell leukemia may be the neutrophil (leukocyte) alkaline phosphatase (NAP or LAP) score and the percentage of hairy cells in bone marrow.182,1006,1145,1154,1627 In one study, patients whose NAP score was less than 30 had the best prognosis (as measured by time from discontinuance of interferon therapy until further antileukemic therapy was needed); patients with greater than 30% leukemic cells in bone marrow had a poor prognosis, while an NAP score of 30 or greater and 30% or less leukemic cells in bone marrow was associated with an intermediate prognosis.182,1627 Further studies are needed to determine which clinical and/or laboratory indices are most useful in predicting relapse and the need for subsequent maintenance therapy following interferon therapy or splenectomy.176,182,1006,1009,1145,1154
Limited data are available on long-term survival in patients with hairy cell leukemia treated with interferon alfa.137,141,171,219,249,273,1152 The survival rate at 24-48 months for patients who respond to the drug ranges from approximately 87-94%,2,135,182,202,237,1145 while the corresponding survival rate for comparable controls treated with standard therapies, including antineoplastic agents (principally chlorambucil) or supportive care (e.g., transfusions), has ranged from approximately 35-75% at 14-40 months.2,135,237
AIDS-related Kaposi's Sarcoma
Interferon alfa (alfa-2a [no longer commercially available in the US], alfa-2b) is used for the palliative treatment of AIDS-related Kaposi's sarcoma in selected adults,2,152,153,204,206,210,378,440,1625,1647,1648 and is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this disease.1546 The likelihood of response to interferon alfa treatment is greater in patients without systemic symptoms who have limited lymphadenopathy and relatively intact immune systems as indicated by CD4+ T-cell counts.2,153,156,378,378,385,1549,1647 Patients who have constitutional (“B”) symptoms (e.g., fever, night sweats, weight loss) and/or who have a history of opportunistic infection at the time of diagnosis of Kaposi's sarcoma generally respond poorly to interferon.145,146,153,156,203,206,378,379,380,381,383,386,391,394,1549 For advanced AIDS-related Kaposi's sarcoma, a liposomal anthracycline (doxorubicin or daunorubicin) or paclitaxel are recommended as drugs of choice (see Uses: AIDS-related Kaposi's Sarcoma in Doxorubicin, Daunorubicin, , and Paclitaxel 10:00).440,1625
In contrast to the usual protracted, indolent course of the classic (e.g., Mediterranean) form of Kaposi's sarcoma,378,1386 Kaposi's sarcoma in patients with human immunodeficiency virus (HIV) infection often is rapidly progressive.145,148,210,378,381,383,386,1386 AIDS-related Kaposi's sarcoma may progress to multifocal, widespread lesions that involve the skin, oral mucosa, and lymph nodes as well as visceral organs such as the GI tract, lung, liver, and spleen;145,146,149,154,210,378,381,383,386,1051 such lesions often are numerous and may be cosmetically unattractive or disfiguring and accompanied by lymphedema.204,378,1549 All patients with AIDS-related Kaposi's sarcoma should be receiving highly active antiretroviral therapy; in some patients, initiation of antiretroviral therapy alone may result in tumor regression and resolution of lesions.190,440
Interferon alfa should not be used in patients with visceral AIDS-related Kaposi's sarcoma associated with rapidly progressive or life-threatening disease2,153,1549 since such patients require rapid cytoreduction, while the response to interferon generally is slow88,156,1549 and poor.2,145,153,154,155,156,203,204,378,381,383,384,385,386,387,388,389,1549 It has been suggested that disease progression theoretically could occur in such patients1549 secondary to interferon's immunosuppressive properties.5,8,255,256,630,637,732,733,734,735,768,769,770,771,775,776,777,810,813,814,1252,1549
Although response rates are variable, interferon alfa therapy is associated with clinically important tumor regression or disease stabilization145,146,148,149,153,154,155,156,203,204,208,210,378,379,380,381,383,385,386,1051 in a substantial proportion of patients with AIDS-related Kaposi's sarcoma who do not have a history of opportunistic infections or “B” symptoms; major (complete plus partial) responses occur in approximately 20-50% of such patients receiving high-dose (36-54 million units daily) therapy with the drug.153,154,155,204,208,378,379,380,381,383,385,394,395,1051 The variability in overall response rates may be explained in part by the relative severity of AIDS in patients in different studies,146 and response rates exceeding 50% may occur in patients with a relatively good prognosis.209
Antiretroviral effects of interferon alfa have been demonstrated in vitro72,156 and in vivo,155,156 and some studies have reported an apparent correlation between these effects (e.g., as evidenced by decreased viral shedding and p24 antigenemia) and clinical response to interferon therapy in patients with AIDS-related Kaposi's sarcoma.145,155,156,204,400 The antiviral effects of interferon alfa have been most prominent in patients with the most competent (in terms of baseline CD4+ T-cell counts) immune systems.145,155,204,400 However, the effects of interferon alfa on immune function are not clearly defined or consistent,145,146,148,154,155,206,378,381,383,385 since substantial improvement in immunologic status (as measured in vitro) has not been observed when the drug was used alone146,148,154,155,206,391 and progression of immunodeficiency has occurred in some patients during interferon alfa therapy.148,149,155,208 In responding patients with early AIDS and Kaposi's sarcoma, interferon alfa reportedly improved quality of life by inducing substantial tumor regression,155 and such patients also had a lower incidence of opportunistic infection than those not responding to such therapy.380,386,391 Interferon alfa has produced improvement at all disease sites (although not always concomitantly), including skin, lymph nodes, and GI tract,149,154,208,209,380,382,385,386 and Kaposi's lesions generally begin to regress within 4-8 weeks following initiation of therapy.145,209,378
Response to interferon alfa therapy appears to be related to multiple factors, including pretreatment immune status of the patient, presence of disease symptoms, and interferon dosage.145,146,148,153,154,155,156,203,204,208,381,383,400,1051 Patients with AIDS-related Kaposi's sarcoma who are most likely to respond to therapy with interferon alfa are those who have had no prior opportunistic infections and those with relatively normal CD4+ T-cell counts, limited lymphadenopathy, and no systemic manifestations (e.g., weight loss, fever, night sweats).145,153,154,155,156,203,204,378,381,383,384,385,386,387,388,389,394,400,460,1051 Evidence suggests that relative preservation of immune function may be required for interferon alfa to be active as an antitumor agent,156,378,460 and the severity of clinical manifestations in patients with AIDS-related Kaposi's sarcoma appears to be associated with the degree of immunologic impairment in these patients.155,156,378,386,460 Pretreatment determinations of immune function (as assessed by total lymphocyte count, CD4+ T-cell counts, and the ratio of CD8+ T-cells) frequently have been associated with clinical outcome and response to therapy.145,146,153,154,155,156,203,204,378,383,385,386,388,389,391,394 Patients with CD4+ T-cell counts exceeding 400/ mm3 appear to have the highest response rates (approximately 40-50%) to interferon alfa therapy;155,156 in some studies in which pretreatment levels of CD4+ T cells were not substantially higher in responding than in nonresponding patients,145,148,382,1549 therapy with interferon alfa was associated with a marked increase in the number of these T cells.145
Response of AIDS-related Kaposi's sarcoma to interferon alfa therapy also appears to be related to interferon dosage,154,156,203,206,380,381,385,386,1051 although some evidence that did not show a clear dose effect also has been reported;146 dosages of 20 million or more units/m2 daily appear to be associated with better and more rapid responses than low dosages (e.g., 1-3 million units/m2 daily).154,156,206,380,385,386,1051 Initial therapy with high dosages (e.g., 30-50 million units daily) of interferon alfa has produced major responses in approximately 40-45% of patients with less-advanced AIDS (e.g., patients with CD4+ T-cell counts exceeding 400/ mm3 who have not experienced severe opportunistic infections);153,154,155,206,380,381 comparable response rates with a somewhat reduced incidence of adverse effects have been achieved when interferon alfa therapy was initiated at a low dosage (e.g., 3 million units daily) and dosage was increased over several days to 36 million units daily.145 Interferon alfa dosages of less than 3 million units daily generally are not as effective as higher dosages in inducing tumor regression,154,156,206,380,381 while dosages exceeding 36 million units (up to a maximum of 54 million units) daily generally11,376,419 have been associated with an unacceptable degree of adverse effects. In one study, patients who responded to therapy with 36 million units of interferon alfa daily during the first month of treatment reportedly developed new lesions when the dosing frequency was decreased to 3 times weekly.208
Patients without detectable acid-labile, endogenous interferon activity in serum prior to treatment generally are more likely to respond to therapy with exogenously administered interferon alfa.146,154,205,208,209,381,383,385,386,391,393,394,1549 Initial response to interferon alfa therapy, but not the duration of response or survival, generally has been independent of the stage of Kaposi's sarcoma (as determined by the location and extent of tumor involvement).145,148,153,155,203,204,381,382,383 Some evidence indicates that the presence of visceral disease or extensive dissemination of the tumor is not necessarily an indicator of poor prognosis to therapy;208,380,386 however, not all sites respond equally (e.g., pulmonary disease may respond relatively poorly).381,1549 Limited data also suggest that response of cutaneous lesions to interferon alfa therapy in patients with AIDS-related Kaposi's sarcoma may depend on the cytologic and/or histochemical characteristics of the lesions.210 Papular and nodular lesions, which are composed principally of endothelial cells, usually undergo partial or complete regression with interferon alfa therapy, while flat hemorrhagic lesions consisting of pericytial cells generally remain unchanged.210
The optimum duration of therapy with interferon alfa in patients with AIDS-related Kaposi's sarcoma has not been determined.460 The median duration of response for patients receiving therapy with the drug has been approximately 7 months; however, complete and partial responses have persisted for longer than 3 years in some patients who received maintenance therapy for variable periods.145,154,208,378,380,394 Patients who were asymptomatic prior to treatment or who achieved a complete response with therapy generally had more rapid responses206 and longer durations of remission than symptomatic patients or those who achieved partial responses.154,206 Some clinicians suggest that unless an opportunistic infection or severe interferon-associated adverse effects occurs, consideration should be given to continuing interferon alfa therapy indefinitely, with appropriate dosage adjustment, provided a response or disease stabilization is observed;460,1549 however, the effect of such a regimen on duration of response has not been fully elucidated.460,1549 In one study, patients who received 6 months of maintenance therapy with interferon alfa after attaining complete responses (i.e., complete gross and histologic clearing of lesions) while on the drug were still disease free 5 months after cessation of maintenance therapy.148 Further long-term follow-up is needed to determine an optimum duration of interferon alfa therapy for patients with AIDS-related Kaposi's sarcoma.148,460,1549
No treatment, including interferon alfa, has been shown conclusively to alter the natural history of AIDS-related Kaposi's sarcoma, although responders generally survive longer than nonresponders and thus the drug appears to affect disease progression.151,378,380,383,385,386,391,1549 In one clinical study, patients who achieved a major (complete plus partial) response with high-dose (36-54 million units daily) interferon alfa therapy had a median survival exceeding 28 months, while nonresponders had a median survival of only 14 months.154,380 In another study in patients receiving an interferon alfa-2b dosage of 30 million units/m2 three times weekly, the median survival in responders and nonresponders reportedly was 22.6 and 9.7 months, respectively.2 Responding patients with a pretreatment CD4+ T-cell count exceeding 200 cells/ mm3 reportedly survived longer than responders who had lower baseline CD4+ T-cell counts and longer than nonresponders, regardless of their baseline CD4+ T-cell counts;2 median survival was approximately 31 months in patients who had CD4+ T-cell counts exceeding 200/ mm3 and only about 9 months in those who had CD4+ T-cell counts less than or equal to 200/ mm3.2 Some limited long-term follow-up data from patients with AIDS-related Kaposi's sarcoma treated with interferon alfa suggest that patients whose tumors regressed with interferon therapy had a substantial reduction in opportunistic infections and longer survival compared with nonresponders.154,380,460 However, whether these differences in response are attributable to interferon or are part of the natural history of AIDS-related Kaposi's sarcoma has not been determined.151,156,203,378,380,383,386,460 Limited placebo-controlled studies have not shown any effect of interferon alfa on survival in patients with AIDS-related Kaposi's sarcoma who have had at least one opportunistic infection, although therapy with the drug in such patients has not been extensively evaluated.155 Some clinicians suggest that cytotoxic antineoplastic therapy may be preferable to interferon alfa treatment in patients with a poor prognosis because antineoplastic therapy is possibly more effective and response more rapid, and there is no evidence that such therapy predisposes these patients to infection or that interferon alfa therapy is superior; in patients with a favorable prognosis, the efficacy of antineoplastic therapy appears to be comparable to that of interferon.151,1549 Controlled, comparative studies, in which clinical endpoints for survival and time to first opportunistic infection are well defined, and long-term follow-up of patients with early HIV infection and Kaposi's sarcoma are needed to determine whether interferon alfa or other therapies can produce meaningful improvements in survival and/or quality of life.155,156
Interferon alfa also has been used for the treatment of classic Mediterranean Kaposi's sarcoma†.1387,1549 In at least one patient with laryngeal involvement, the drug produced complete regression of these lesions.1387 However, there is a paucity of information regarding the efficacy of such therapy, and the advanced age of patients with this form of Kaposi's may limit their tolerance of the drug's adverse effects.1549 In addition, radiation therapy and/or conventional antineoplastic therapy generally are preferred when treatment is indicated in this form of Kaposi's.1549
Non-Hodgkin's and Cutaneous T-cell Lymphomas
Interferon alfa (alfa-2b) is labeled by the FDA for use in conjunction with anthracycline-containing combination chemotherapy for the treatment of clinically aggressive follicular non-Hodgkin's lymphoma in adults.2 Interferon alfa also has been used for the treatment of low-grade adult non-Hodgkin's lymphomas†11,254,257,299,300,302,305,341,342,343,346,347,348,350,1126,1383,1384,1625 and for the treatment of cutaneous T-cell lymphomas†.172,217,254,257,299,302,342,348,1109,1110,1111,1117,1118,1382,1385
Although other agents generally are preferred,442,1625 the safety and efficacy of interferon alfa-2b in conjunction with a combination chemotherapy regimen has been evaluated for initial treatment in patients with clinically aggressive, large-tumor-burden, stage III/IV follicular non-Hodgkin's lymphoma.2 In a randomized, controlled trial, 130 patients received CHVP chemotherapy alone and 135 patients received CHVP therapy and interferon alfa-2b (5 million units subcutaneously 3 times weekly) for 18 months.2 CHVP chemotherapy consisted of cyclophosphamide 600 mg/m2, doxorubicin 25 mg/m2, and teniposide 60 mg/m2 administered IV on day 1 with oral prednisone (40 mg/m2 daily on days 1-5).2 Treatment consisted of 6 CHVP cycles administered monthly, followed by an additional 6 cycles administered every 2 months for 1 year.2 Patients in both treatment groups received a total of 12 CHVP cycles over 18 months.2 The group receiving CHVP and interferon alfa-2b had longer progression-free survival than those receiving CHVP alone (2.9 years versus 1.5 years).2 After a median follow-up of 6.1 years, the median survival for patients treated with CHVP alone was 5.5 years while median survival for patients treated with CHVP and interferon alfa-2b had not been reached.2 In 3 other randomized, controlled studies, use of interferon alfa in conjunction with anthracycline-containing combination chemotherapy regimens was associated with prolonged progression-free survival.2 Differences in overall survival were not consistently observed.2
The manufacturer states that efficacy of interferon alfa-2b in the treatment of low-grade, low-tumor-burden follicular non-Hodgkin's lymphoma has not been determined.2 Interferon alfa given alone has produced objective clinical responses in approximately 40-60% of patients with low-grade lymphocytic adult non-Hodgkin's lymphomas†.11,254,257,299,300,302,305,341,342,343,346,347,348,350,1126,1383,1384 However, these diseases typically have a long, indolent course,346,347,1118,1121,1122,1123 and improved survival with available therapies, including interferon alfa, in low-grade adult lymphocytic lymphomas has not been documented.302,346,347,1118,1121,1122,1123 Interferon alfa generally appears to have little therapeutic value in intermediate- or high-grade adult non-Hodgkin's lymphomas†,11,259,305,343,346,347,348,1118,1121,1126,1383,1384 although occasional responses have been reported with high dosages of the drug.11,259,261,299,302,305,343,347,348,1118,1377,1383,1384 Features of B- and T-cell types that might predict response to interferon alfa in non-Hodgkin's lymphomas have not been identified,260,1377 and further study is warranted to determine which, if any, subpopulation of patients with higher-grade lymphomas is most likely to benefit from interferon alfa therapy.305
Responses to interferon alfa therapy in low-grade lymphocytic adult non-Hodgkin's lymphomas generally have been noted in patients with advanced disease who have received extensive prior treatment with regimens containing either anthracycline-derivative antineoplastic agents (e.g., doxorubicin) or radiation therapy;11,19,299,300,305,341,528,1376,1377 objective responses have been noted in approximately 40-50% of patients with advanced low-grade lymphocytic lymphoma refractory to standard treatment regimens,11,306,346,528,1123,1376,1377 with complete responses occurring in approximately 6-15% of patients.11,306,346,347,528,1376,1377 Whether interferon alfa can produce comparable responses in patients with early-stage, low-grade lymphocytic lymphoma who have not received prior therapy has not been established to date;11,299,305,341,343,346,348,1118 studies are ongoing.300,341,343 Evidence suggests that relatively low doses of interferon alfa (e.g., 2-3 million units/m2) may be as effective as but less toxic than the high doses (e.g., 50 million units/m2) initially used in the treatment of lymphocytic adult non-Hodgkin's lymphomas†;172,299,300,343,350,1123 however, limited data suggest that patients who experience disease relapse while receiving low doses of interferon alfa may not respond to subsequent therapy with higher doses of the drug.350,1549
Systemic therapy with interferon alfa has produced response rates of approximately 40-75% in patients with cutaneous T-cell lymphomas† (CTCL; e.g., mycosis fungoides, Sézary syndrome).172,217,254,257,299,302,342,346,348,1109,1110,1111,1117,1118,1382,1385 Such responses have been reported in patients who have failed to respond to topical or systemic therapy with other drugs89,217,306,344,346,1117,1118,1382 as well as in previously untreated patients;299,342,1109,1110,1118,1382,1385 many clinicians consider interferon alfa the most effective single-agent therapy for patients whose disease is refractory to standard treatment (topical mechlorethamine, psoralen plus UVA light, total electron-beam irradiation, antineoplastic agents) for these neoplasms.89,217,257,305,344,346,348,1549 In one study in a limited number of patients with advanced, refractory CTCL, objective responses lasting 3 to more than 36 months (median duration approximately 5 months) were noted in 45% of patients receiving interferon alfa in an initial dosage of 50 million units/m2 IM 3 times weekly.89,217,346,1111,1117 However, as with other non-Hodgkin's lymphomas, the optimum therapeutic regimen for interferon alfa in patients with CTCL has not been determined, and the effects of the drug on survival when given to patients with earlier stages of the disease and/or in combination with antineoplastic or other therapies are being evaluated.89,217,257,299,346,347,348 Large cutaneous lesions in patients with CTCL have undergone a substantial decrease in size during interferon alfa therapy,89,217,305 and extracutaneous responses (e.g., reductions in the size of palpable lymph nodes and in the number of circulating malignant cells)89,346,1118 have also occurred.89,305,346,347,1111,1118
Prognosis for patients with CTCL† depends on stage of the disease, type of skin lesion, and presence or absence of peripheral blood, lymph node, or visceral involvement;346 however, responses to interferon alfa appear to be unrelated to disease stage89,217,348,1111,1119,1120,1375 and/or prior therapy.89,217,346,348,1111,1119 Limited data suggest that response to interferon alfa may depend on dosage and scheduling of the drug.300,342,1375 Highest response rates reportedly occur with doses ranging from 6-50 million units.11,342,343,344,345,346,347,348,1123,1385 Among patients with CTCL, those with mycosis fungoides appear most responsive to interferon therapy.217,259,261,302,1385 Complete remissions with interferon alfa therapy have been reported in approximately 10-27% of patients with CTCL,89,257,305,346,348,361 generally in patients receiving high doses (e.g., 50 million units/m2).259,261
Preliminary evidence suggests that the combination of interferon alfa and phototherapy (psoralen plus UVA light irradiation) is effective and generally well tolerated in patients with CTCL†,299,361 although individuals with the more aggressive large-cell variant of the disease may be less likely to respond to this regimen.361 In one study, intralesional administration† of low doses of interferon alfa appeared to be more effective than a fivefold higher dose administered IM in patients with plaque-phase mycosis fungoides, suggesting that intralesional concentrations of the drug may be an important determinant of therapeutic response.1111,1116
Melanoma
Adjuvant Therapy
Interferon alfa (alfa-2a [no longer commercially available in the US], alfa-2b) is used as an adjunct to surgery (within 56 days of surgery)2 in adults with malignant melanoma who are disease free but at high risk for systemic recurrence.2,450,673,1527,1529,1652 Use of adjuvant therapy with interferon alfa following surgical resection prolongs disease-free but not overall survival in patients at high risk for recurrence of disease, particularly among patients with node-positive melanoma.673,1527,1529,1652
In a large randomized trial, patients receiving adjuvant therapy with interferon alfa-2b within 56 days of surgery for deep primary (T4) or regionally metastatic (N1) melanoma had prolonged disease-free and overall survival but experienced substantial toxicity compared with patients receiving surgery alone.1652 Patients with Breslow's classification greater than 4 mm, and those with any Breslow's classification with primary or recurrent lymph node involvement, were included in the study.2 Adjuvant therapy consisted of IV interferon alfa-2b 20 million units/m2 5 days per week for 4 weeks followed by maintenance therapy with 10 million units/m2 subcutaneously 3 days per week for 48 weeks.1652 Median overall survival of 3.82 or 2.78 years, respectively, was observed in patients receiving adjuvant interferon alfa therapy or undergoing surgery alone while median time to relapse was 1.72 or 0.98 years, respectively, with such treatment.2,1652 The estimated 5-year overall survival rate was 46 or 37% in patients receiving adjuvant therapy or undergoing surgery alone, respectively.2,1652 Although interpretation of the data is limited because stratification was performed to ensure balance rather than to make comparisons between the patient groups, subgroup analysis demonstrated benefit of adjuvant therapy with interferon alfa-2b only among patients with node-positive disease; the small number of patients with node-negative disease enrolled in the trial does not allow any meaningful conclusions regarding efficacy of adjuvant therapy with interferon alfa in this group.1519,1652 Toxicity was substantial with 67% of patients experiencing severe (grade 3) toxicity at some point during the year of treatment;1652 depending on the individual patient and the relative value placed on time spent with toxicity and survival time with relapsed disease, the quality-of-life-adjusted gain in survival time may or may not be significant in patients receiving adjuvant therapy with interferon alfa.1520
In a subsequent 3-arm randomized trial comparing adjuvant therapy with high-dose IV interferon alfa-2b (followed by maintenance therapy with subcutaneous interferon alfa-2b), adjuvant therapy with low-dose subcutaneous interferon alfa-2b, or observation following surgical resection of deep primary (T4) or primary or recurrent regionally metastatic (N1) melanoma, disease-free survival was prolonged in patients receiving high-dose interferon alfa versus observation; however, overall survival did not differ among the groups.1527 Results from another large trial in patients randomized to receive observation or adjuvant therapy with high-dose IM interferon alfa-2a (no longer commercially available in the US) 3 days a week for 12 weeks following surgery for primary melanomas greater than 1.69 mm in thickness with or without nodal involvement did not detect a difference in recurrence or survival rates, but subset analysis suggested a trend toward increased rate and duration of disease-free survival in patients with node-positive disease receiving adjuvant interferon alfa.1521 Use of adjuvant therapy with interferon alfa may be a reasonable option in selected patients (e.g., those with deep primary tumors or node-positive disease), but further study is needed to establish the role of adjuvant therapy with interferon alfa in patients with high-risk, localized melanoma.1451,1519,1521,1529
Metastatic Melanoma
Interferon alfa has been used alone for the treatment of metastatic melanoma† in selected patients.1446 Response rates averaging about 16% (with approximately 4% complete responses) have been reported in patients with metastatic melanoma receiving interferon alfa as a single agent administered daily or 3 times per week.859,1446
Monotherapy with IM interferon alfa dosages ranging from 10-20 million units/m2 3 times weekly340,1104,1105,1107 has been used in patients with metastatic melanoma. However, therapy with interferon alfa alone in tolerable dosages appears unlikely to alter survival in patients with this metastatic disease.337,339 The median duration of response following therapy with interferon alfa alone in patients with metastatic melanoma has been reported to be 5 months,339,408,1104,1106 but some patients have achieved complete responses lasting longer than 2-3 years.337,339,340,1104 A relatively prolonged course of interferon alfa therapy (i.e., approximately 3 months) may be required to produce responses in patients with metastatic melanoma.337,338
Prognostic factors that reliably identify patients with metastatic melanoma who are likely to respond favorably to interferon alfa therapy have not been identified to date.339 Most responses to interferon alfa monotherapy have occurred in patients with subcutaneous and small-volume disease.1447 However, long-term responses have been observed in patients with visceral- and nonvisceral-dominant disease, in previously treated and untreated patients, and in those treated with monotherapy or combination drug therapy.337,338,339,340,1104,1106 Limited data suggest that intralesional therapy with interferon alfa has clinical activity in patients with melanoma, but efficacy of the drug given by this route has not been compared with that of systemic interferon therapy.1108
Interferon alfa also has been used in combination therapy for the treatment of metastatic melanoma.1342,1343,1344,1345,1346,1347,1443,1444,1445,1530,1531,1532 Results from a small randomized trial suggested that the combination of interferon alfa and dacarbazine was superior to dacarbazine alone,1445 but other studies did not confirm these findings.1343,1443,1444 The addition of interferon alfa did not increase response rate or prolong survival in patients receiving high-dose IV aldesleukin1530 or continuous IV infusion aldesleukin and IV cisplatin1531 for the treatment of metastatic melanoma. The use of interferon alfa and aldesleukin in combination with conventional chemotherapeutic agents (e.g., cisplatin, dacarbazine) is being investigated for the treatment of metastatic melanoma.1342,1344,1345,1346,1347 A large randomized trial is under way to investigate the comparative efficacy and toxicity of concurrent biochemotherapy with interferon alfa-2b, aldesleukin, cisplatin, vinblastine, and dacarbazine versus combination chemotherapy with cisplatin, vinblastine, and dacarbazine.1347
Basal Cell and Squamous Cell Skin Cancers
Interferon alfa has been used effectively by intralesional injection in the treatment of basal cell carcinoma†.272,1466,1467,1468,1469,1470 The response of these lesions to interferon alfa therapy appears to be related to the dose and duration of therapy with the drug,1469 increasing with increasing total dose and duration.1468,1469 While response was poor in patients treated with intralesional injection of 0.9 million units 3 times weekly for 3 weeks in one study158 and in those treated with a single 10 million-unit dose of a long-acting (protamine zinc) interferon alfa injection in another study,1468 a good response was observed in other studies employing larger total doses and/or more prolonged therapy.272,1466,1467,1468,1469,1470 In a large, multicenter study, a histologic cure rate exceeding 80% was observed at 1 year in patients receiving intralesional therapy with 1.5 million units of interferon alfa 3 times weekly for 3 weeks.1470 A similar histologic cure rate was observed after 4 months in another study in which patients received intralesional interferon alfa therapy with a long-acting injection at a dosage of 10 million units once weekly for 3 weeks;1468 however, the risk of adverse effects appears to be increased with this regimen compared with the lower-dose, more frequently administered regimen employing the immediate-release injection.1468,1469 As with other (e.g., surgical) therapy, patients treated with intralesional interferon alfa therapy for basal cell carcinoma should be followed closely for evidence of residual cancer.1469 In addition, some clinicians caution that, pending further accumulation of data, the possibility that the lesions occasionally may be transformed into epidermoid cysts by interferon alfa therapy should be considered, since there may be some attendant risk of carcinoma reversion.1466 Although intralesional interferon alfa appears to be safe and effective in the treatment of basal cell carcinoma,272,1466,1467,1468,1469,1470 and offers the potential for improved cosmetic results and patient acceptance compared with surgical management of this cancer,272,1468,1469 the role of interferon therapy compared with other therapies (e.g., surgery, cryosurgery, curettage and electrodessication) remains to be more fully elucidated.1466,1469
Limited evidence also suggests that intralesional therapy with interferon alfa can produce clinical and/or histologic responses in patients with squamous cell carcinoma† or keratoacanthoma†.158 Clinical improvement also has been reported in a limited number of patients with actinic (solar) keratosis†, which either disappeared or showed histologic improvement with intralesional interferon alfa therapy.158,1471 However, experience with interferon alfa in the treatment of these skin disorders is less extensive than in the treatment of basal cell carcinoma, and further study is needed to determine the potential role of the drug in the treatment of these disorders.
Chronic Myelogenous Leukemia
Interferon alfa (alfa-2a [no longer commercially available in the US], alfa-2b†) is used for the treatment of adult-type (Philadelphia chromosome-positive) chronic myelogenous (myelocytic, myeloid) leukemia (CML)259,260,261,299,300,301,302,303,305,306,307,308,309,310,311,312,441,1029,1420,1479,1533,1594,1625,1638,1639,1640,1641,1642,1643,1644 in patients who are in the chronic phase of the disease1638,1639,1640 and who have been minimally pretreated (within 1 year of diagnosis).1638,1639,1640 In patients with CML, interferon alfa can produce complete or partial hematologic remissions and cytogenetic responses.1625,1638,1639,1640,1641,1642,1643,1644 Although the cytogenetic responses may be prolonged in some patients,301,305,307,308,309,310,311,312,1023,1024,1027,1479,1549,1594 further study and follow-up are needed to determine whether the drug can improve long-term survival in patients with this disease.300,301,302,303,304,305,307,309,310,1479,1594,1639 Limited data suggest that pediatric patients with adult-type CML (i.e., Philadelphia-positive disease) also may exhibit a good therapeutic response to interferon alfa similar to that achieved in adults;1539,1549 however, children with juvenile-type CML† (i.e., Philadelphia-negative disease) generally are unresponsive to chemotherapy or interferon alfa.1549 (See Pediatric Precautions.)
Complete hematologic remission, generally characterized by relative normalization of leukocyte and platelet counts, reduction in leukocyte alkaline phosphatase concentrations, marked reduction of splenomegaly, and decreased bone marrow cellularity,301,305,307,308,310,311,312,1420,1638 has been achieved in approximately 22-80% of patients receiving 2-5 million units/m2 of interferon alfa daily or 3 times weekly for prolonged periods (e.g., 1-3 years).259,261,299,302,305,306,307,308,310,311,312,1479,1594,1638,1639,1640,1641,1642,1644 A cytogenetic response (i.e., suppression of Philadelphia chromosome-positive cells) generally occurs in at least 10-70% of patients achieving complete hematologic remission with interferon alfa therapy.259,299,300,301,302,305,306,307,308,309,310,311,312,1023,1024,1027,1028,1029,1420,1479,1533,1535,1549,1594,1638,1639,1640,1642 Unlike the transient suppression of the Philadelphia chromosome generally observed with intensive cytotoxic antineoplastic therapy,307,310,312,1024,1031,1038,1534,1549,1639 interferon alfa has produced complete suppression of this chromosome for about 2-8 years or longer in some patients.301,305,307,308,309,310,311,312,1024,1027,1029,1533,1549,1594,1639 However, interferon-induced decreases in bone marrow cellularity and suppression of Philadelphia chromosome-positive cells are delayed compared with hematologic improvement,300,301,310,312,1023,1024,1029,1031 with median times to complete hematologic and cytogenetic remission reported in early studies as 3.4 and 9 months, respectively,310,312,1024,1479 but in more recent studies as 5-6.7 and greater than 18 months, respectively.1029,1479,1639,1640 In addition, while the ability of interferon alfa to suppress the malignant Philadelphia chromosome-positive clone and favor reemergence of a normal clone of marrow cells suggests that the drug is potentially curative,1479,1549,1639 only intensive chemotherapy, alone or combined with radiation therapy, followed by bone marrow transplantation has been shown to be curative to date.308,309,1045,1086,1142,1240,1326,1404,1479,1543,1549,1639
Hematologic and cytogenetic responses to interferon alfa therapy appear to be greatest in newly diagnosed, previously untreated patients with low- to intermediate-risk disease (i.e., low to moderately high leukocytosis, splenomegaly, and presence of the Philadelphia chromosome)299,301,310,1024,1027,1479,1639 who have early chronic-phase CML (i.e., those who are treated within 12 months of diagnosis);299,310,312,1479 response rates are approximately fourfold to sixfold higher in the early chronic phase compared with the accelerated and blast phases of the disease.260,299,310,312 In addition, limited data indicate that response rates to interferon alfa are increased in patients who are white and younger than 60 years of age.1639 Interferon alfa reportedly can control the thrombocytosis that may occur during the initial and/or accelerated phase of CML,301,305,307,1024,1025,1026,1027 but the drug generally has little or no long-term therapeutic effect in the accelerated or blast phase of the disease.301,310,312,1026,1028,1033,1479 However, some evidence indicates that interferon alfa-treated patients with CML who enter blast crisis frequently have a lymphoid blast phenotype, which in a subset of patients appears to be associated with greater response to subsequent antineoplastic therapy,312,1038,1039 rather than the more typical myeloid blast transformation.301,1024,1027 There is some evidence to suggest that response to interferon alfa in patients with CML also may be dose related,301,310,312,1028,1034,1639 as evidenced in one study by a higher response rate in patients receiving 5 million versus 2 million units/m2 three times weekly;310,1028 some clinicians suggest an interferon alfa dosage of 5 million units/m2 given daily.1639 However, additional study is needed to determine the optimum dosage of interferon alfa in the treatment of CML.299,309,1549,1638,1644
Results of a randomized, multicenter, controlled study in newly diagnosed or minimally treated patients (those who received less than 100 mg of busulfan or less than 50 g of hydroxyurea) with CML demonstrate a longer median survival in patients receiving interferon alfa (44% of patients receiving interferon alfa also received intermittent single-drug chemotherapy) versus those receiving conventional therapy with antineoplastic agents (e.g., hydroxyurea, busulfan).1638 Median survival of 69-72 or 52-55 months, respectively, was reportedly observed in patients receiving interferon alfa or conventional chemotherapy while overall hematologic response rate was 60% (40% had complete response) or 70% (30% had complete response) in patients receiving interferon alfa or conventional chemotherapy, respectively.1638 Usually, cytogenetic responses were only observed in patients who had complete hematologic remissions, and longer survival was observed in patients with cytogenetic response.1638,1639,1640 In addition, the time of disease progression from chronic to blastic phase was 69-72 or 45-46 months in patients receiving interferon alfa or conventional chemotherapy, respectively.1638
Concomitant administration of interferon alfa-2b† with cytarabine has been associated with increased survival in patients with CML.1659,1660 Results of a randomized controlled study in previously untreated patients with CML demonstrate a longer survival in patients receiving interferon alfa-2b (5 million units/m2 given subcutaneously daily) in combination with cytarabine (20 mg/m2 daily for 10 days given subcutaneously 2 weeks after initiation of interferon alfa-2b therapy and monthly thereafter) versus those receiving interferon alfa-2b without cytarabine; patients from both groups also received hydroxyurea 50 mg/kg daily until a complete hematologic remission was achieved.1659 After 3 years, median survival rate of about 86 or 79%, respectively, reportedly was observed in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine while overall hematologic response rate was 66 or 55% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively.1659,1660 Major cytogenetic response rate after 12 months was 41 or 24% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively.1659,1660 Longer survival was observed in patients with cytogenetic response.1659 Some patients underwent allogeneic or autologous bone marrow transplantation, and the 2-year survival rate after allogeneic bone marrow transplantation was 56 or 59% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively, while 2-year survival rate after autologous bone marrow transplantation was 61 or 68% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively.1659 Patients who did not have complete hematologic or major cytogenetic responses within 6 or 12 months, respectively, were allowed to cross over to combined treatment with interferon alfa-2b and cytarabine.1659,1661,1662 Among patients who received initial therapy with interferon alfa-2b without cytarabine, but then crossed over to receive combined treatment with interferon alfa-2b and cytarabine, complete and partial responses of 2 and 6%, respectively, were observed.1659,1662
Further studies and follow-up of previously untreated patients receiving interferon alfa for CML are needed to determine whether the drug alters the natural course of the disease.300,301,302,303,305,307,1028,1594,1638 However, results of several studies indicate that patients with CML who achieve a complete hematologic and cytogenetic response to interferon alfa therapy have a substantially longer survival rate than those who have partial or no response;312,1639,1640,1642,1643,1644 complete elimination of malignant cells in peripheral blood and bone marrow (as determined by Southern blot and polymerase chain reaction analyses) has been reported following prolonged therapy with the drug.301,308,1027,1040 Longer survival usually is associated with slower progression to the blastic phase.1638,1641
Renal Cell Carcinoma
Overview
Interferon alfa, alone or in combination therapy, is used for the treatment of metastatic renal cell carcinoma† in selected patients.443,715,1625,1694,1697 There is no generally accepted standard drug therapy for metastatic renal cell carcinoma.1694,1752 Because of the poor response to systemic therapy, surgical resection often is included in the management of metastatic renal cell carcinoma.443,1697 (See Uses: Renal Cell Cancer, in Aldesleukin 10:00 for an overview of therapy for metastatic renal cell carcinoma.)
Various forms of systemic drug therapy, including cytotoxic agents, hormonal agents, and biologic agents (e.g., interferon alfa, aldesleukin, antiangiogenic and other targeted therapy), have been studied in patients with metastatic renal cell carcinoma.443,1694,1697 Response rates with cytotoxic chemotherapy generally have been poor (10% or less) for any regimen that has been studied in adequate numbers of patients with metastatic renal cell carcinoma.443,1694,1697,1752 Evidence suggests that the incidence of tumor regression associated with interferon alfa therapy is similar to or possibly greater than that associated with conventional hormonal or antineoplastic drug therapy for this disease, and that adverse effects associated with interferon therapy may be less debilitating than those associated with these therapies.331,335,336,753,923,1462,1549 Results of studies with hormonal therapy (e.g., medroxyprogesterone acetate, tamoxifen) has been studied in the treatment of metastatic renal cell carcinoma, results have been disappointing, and these agents are no longer used.1694,1696,1752
Immunotherapy with interferon alfa or aldesleukin is used for the systemic treatment of metastatic renal cell carcinoma despite low response rates.443,1694,1696,1697,1698 Interferon alfa produces objective responses in only 5-30% (overall about 10-15%)334,443,617,715,1462,1694,1697,1699,1700 of patients with metastatic disease†, and complete responses are uncommon (about 1%).225,1094,1462,1697,1700 The overall response rates associated with either interferon alfa or aldesleukin monotherapy appear to be similar (10-15 versus 15%, respectively), but evidence suggests that the incidence of complete or durable response is lesser with interferon alfa than with aldesleukin (1 versus 5%).443,1694,1696,1697,1699,1700,1752 In addition, a survival benefit has been associated with interferon-alfa-containing regimens in patients with metastatic renal cell carcinoma1707,1709 whereas such data are lacking for aldesleukin.1752 Results of large randomized trials1707,1709 and analysis of pooled data1699 from several randomized studies indicate that interferon alfa, used alone or in combination, modestly increases response rates and prolongs survival in patients with metastatic renal cell carcinoma compared with conventional antineoplastic or hormonal agents.
Whether higher response rates or more durable responses are observed in patients with metastatic renal cell carcinoma receiving immunotherapy with cytokines, such as interferon alfa, than in those receiving supportive care only has not been fully established.1701,1702,1752 Results from a randomized, placebo-controlled trial showed no benefit in overall response rate, rate of durable complete response, time to disease progression, or duration of survival with use of the cytokine interferon gamma-1b for metastatic renal cell carcinoma.1703 Most of the evidence for the use of interferon alfa in the treatment of metastatic renal cell carcinoma is based on results from noncomparative, phase II studies;1698,1701,1703,1708 interferon alfa has not been studied in placebo-controlled trials,1710 and evidence from randomized trials comparing interferon alfa monotherapy or interferon alfa-containing regimens with other agents is limited.1698,1701,1702,1703,1707,1709,1710,1711
Because the prognosis for patients with metastatic renal cell carcinoma is poor and conventional cytokine therapy has minimal activity with substantial toxicity, all patients with this cancer should be considered for inclusion in clinical trials at the time of diagnosis.443,1694,1695,1697,1700,1701,1709,1752 Supportive care (e.g., adequate analgesia for pain management, surgery for solitary brain metastasis or spinal cord compression, radiation therapy for palliation of metastases, particularly painful bone metastases) remains a mainstay of therapy for patients with metastatic renal cell cancer.1694,1695,1750,1752
The use of interferon alfa as adjuvant therapy for completely resected, locally advanced renal cell carcinoma did not improve survival or reduce the risk of relapse.1695,1704,1705 No systemic therapy has been shown to reduce the risk of relapse or prolong survival in patients with localized renal cell carcinoma at high risk of recurrence;1694,1695,1697,1704,1705,1706 preliminary results from a small randomized trial suggest that adjuvant therapy with ex vivo activated T cells (ALT) and high-dose cimetidine delays disease recurrence.1751
Monotherapy for Metastatic Renal Cell Carcinoma
Most evidence for the use of interferon alfa as a single agent for the treatment of metastatic renal cell carcinoma is based on uncontrolled phase II studies.1698,1701,1703,1708 Evidence from controlled, comparative studies evaluating the efficacy of interferon alfa as a single agent versus other agents in the treatment of metastatic renal cell carcinoma is limited.1698,1707
Although evidence suggests that the incidence of complete or durable response is lesser with interferon alfa (1 versus 5%), the overall response rates associated with either interferon alfa or aldesleukin monotherapy appear to be similar (10-15 versus 15%, respectively).443,1694,1696,1697,1699,1700,1752 In addition, interferon alfa therapy is less toxic than high-dose aldesleukin therapy,1698,1700,1752 and 2 large randomized trials have demonstrated a survival benefit for interferon-alfa-containing regimens in patients with metastatic renal cell carcinoma1707,1709
Combination Therapy for Metastatic Renal Cell Carcinoma
Interferon alfa has been used in various combination regimens with other agents including biologic response modifiers (e.g., aldesleukin),1696,1698,1712,1713,1714,1715,1716,1717,1718,1719,17,20,1721,1722,1723,1724,1725,1726,1727,1743 and/or conventional chemotherapeutic agents (e.g., fluorouracil, vinblastine)1700,1709,1714,1729,1730,1731,1732,1733,1734,1735,1736,1737,1738,1740,1741,1742 for the treatment of metastatic renal cell carcinoma. According to analysis of pooled data1699 from several randomized studies, higher overall response rate (14 versus 8%) and prolonged survival were observed for regimens containing interferon alfa compared with antineoplastic or hormonal regimens for the treatment of metastatic renal cell carcinoma.1699
Interferon alfa has been used in combination with aldesleukin for the treatment of metastatic renal cell carcinoma.1696,1698,1712,1713,1714,1715,1716,1717,1718,1719,17,20,1721,1722,1723,1724,1725,1726,1727 A collective response rate of about 20% (5% complete responses, 15% partial responses), similar to the overall response rate of 15% observed with aldesleukin monotherapy1696,1715 has been observed in patients with metastatic renal cell carcinoma receiving interferon alfa in combination with aldesleukin.1698,1712,1713,1714,1715,1716,1717,1718,1719,17,20,1721,1722,1723,1724,1725,1726,1727
A retrospective analysis indicates that similar efficacy and less toxicity are observed in patients receiving subcutaneous interferon alfa and subcutaneous aldesleukin compared with continuous IV infusion of aldesleukin alone for advanced renal cell carcinoma.1712 In a large, randomized trial, patients with metastatic renal cell carcinoma receiving subcutaneous interferon alfa-2a (no longer commercially available in the US) combined with continuous IV infusion of aldesleukin had a higher response rate and higher rate of event-free survival at 1 year but no difference in overall survival compared with those receiving either agent alone; less toxicity was observed in patients receiving interferon alfa than in those receiving aldesleukin, either alone or in combination therapy.1698 The low response rates observed for monotherapy with interferon alfa or aldesleukin in this trial may have contributed to the differences observed in comparison with the combination therapy.1717,1728,1752
Limited evidence from a randomized, phase II trial suggests that the addition of interferon alfa-2b to a high-dose, intermittent IV infusion regimen of aldesleukin did not improve response rate, and incidence of complete response and duration of response appeared to be more favorable for patients receiving high-dose aldesleukin monotherapy for advanced renal cell carcinoma.1719 At a median follow-up of 72 months in another randomized phase II trial, median duration of response was longer (53 versus 14 months) and the rate of progression-free survival at 3 years was higher (13 versus 3%) for patients receiving high-dose IV aldesleukin alone compared with those receiving IV interferon alfa-2b and high-dose IV aldesleukin.1729 Another phase II randomized trial indicates that toxicity is greater but overall survival is not improved when subcutaneous interferon alfa is added to a regimen of subcutaneous aldesleukin.1718 In a randomized trial, no survival difference was observed in patients receiving subcutaneous interferon alfa, subcutaneous aldesleukin, and oral tamoxifen versus oral tamoxifen alone.1702
Interferon alfa, with or without aldesleukin, also has been used in combination with conventional chemotherapeutic agents (e.g., fluorouracil, vinblastine) for the treatment of metastatic renal cell carcinoma.1700,1709,1714,1729,1730,1731,1732,1733,1734,1735,1736,1737,1738,1740,1741,1742
In a phase III randomized trial, median survival was prolonged (16.9 versus 9.4 months) and response rate was higher (16.5 versus 2.5%) but grade 4 toxicity was more frequent (18 versus 2%) in patients receiving subcutaneous interferon alfa-2a (no longer commercially available in the US) and IV vinblastine than in those receiving IV vinblastine alone.1709 The role of vinblastine in combination with interferon alfa remains to be established.1709,1733 Variable results have been reported for the benefit versus toxicity of combination regimens with interferon alfa and conventional antineoplastic agents compared with interferon alfa monotherapy.1700,1730,1731,1732,1733 Response rates in patients with advanced renal cell carcinoma are similar1700,1732,1733 or increased1731 when vinblastine is added to interferon alfa therapy, but no difference in survival has been observed;1731,1732,1733 in some studies, increased toxicity has been reported with the addition of vinblastine.1700,1732 No differences in overall response rates, progression-free survival, or overall survival were observed in a large randomized trial of interferon alfa-2a (no longer commercially available in the US) and 13-cis-retinoic acid (isotretinoin) versus interferon alfa-2a alone.1730
Interferon alfa also has been used in combination with aldesleukin and fluorouracil for the treatment of metastatic renal cell carcinoma. 1714,1729,1734,1735,1736,1737,1738 Although early reports from small uncontrolled studies suggested that interferon alfa used in combination with aldesleukin and fluorouracil produced favorable response rates,1714,1734,1735 longer follow-up and subsequent phase II studies did not confirm higher response rates or comparable durability of responses, and some variations of the 3-drug regimen showed substantial toxicity.1729,1736,1737,1738 Results from one randomized trial indicate that the addition of fluorouracil does not improve response rate in patients receiving a regimen of subcutaneous interferon alfa and subcutaneous aldesleukin.1739 In another randomized trial, patients receiving combination therapy with subcutaneous interferon alfa-2a (no longer commercially available in the US), subcutaneous aldesleukin, and IV fluorouracil had higher response rates and prolonged overall and progression-free survival compared with those receiving oral tamoxifen alone.1749 Further study is required to establish the comparative efficacy and toxicity of combination therapy with interferon alfa, aldesleukin, and fluorouracil.1696,1737,1752 In small, uncontrolled studies, the addition of fluorouracil did not appear to improve response rates compared with interferon alfa alone but added toxicities associated with fluorouracil.1740,1741,1742
Evidence from a randomized trial indicates that the addition of coumarin and cimetidine, potential immunomodulating agents, did not improve response rates or survival duration in patients receiving interferon alfa for metastatic renal cell carcinoma.1744 The addition of aspirin did not enhance or interfere with the efficacy of interferon alfa therapy for metastatic renal cell carcinoma, nor did it lessen overall treatment-associated toxicity. Concomitant treatment with prednisone (10-20 mg daily) reportedly may improve the subjective tolerability of therapy by reducing flu-like symptoms without reducing response rates in patients with renal cell carcinoma receiving interferon alfa at dosages of 18 million units or more 3 times weekly; however, prednisone had little effect on the hepatic toxicity associated with high-dose interferon alfa therapy.1100
Other Considerations
The optimum dosage and duration of interferon alfa therapy for patients with metastatic renal cell carcinoma have not been established,225,299,331,333,334,336,935,1094,1462,1542 but limited data suggest that response to the drug may be dose dependent;259,302,331,333 dosages of interferon alfa ranging from 5-20 million units daily or 3 times weekly225,331,332,333,334,335,1094,1099,1694,1696,1698,1707,1752 appear to be required to achieve optimum response with manageable toxicity.225,299,331,333,334,336,1094,1099,1694,1752 The period from initiation of treatment to occurrence of an objective response averages 3-4 months, and responses to interferon alfa rarely last longer than 2 years.1694
Although median duration of survival generally appears to be greater in patients with renal cell carcinoma who respond to interferon alfa than in those who do not,302,332,333,1094 it is unclear whether therapy with the drug actually results in a prolonged survival or merely selects out patients with a better initial prognosis.261,302,332,333,1094,1549,1700,1745 Factors associated with higher rates of response to interferon alfa therapy include a low tumor burden with lung-predominant metastases (including mediastinum, pleural, and mediastinal node metastases), good performance status, prior nephrectomy, prolonged disease-free interval between nephrectomy and disease recurrence, relatively low nadir granulocyte counts, and perhaps in vitro sensitivity of the tumor to interferon alfa, as determined by clonogenic assay.183,225,259,260,261,299,300,302,331,332,333,334,335,1094,1097,1098,1099,1101,1462,1694,1700,1731,1732 Although reliable criteria for selecting patients most likely to benefit from cytokine therapy have not been established, prognostic factors have been identified that are associated with poor outcome despite treatment with interferon alfa and/or aldesleukin (e.g., multiple sites of metastasis, metastasis to the liver, metastasis within 1 year following diagnosis of primary tumor.1698
Except in rare cases,225,1095 interferon alfa has not exhibited antitumor activity against unresected renal cell carcinoma or retroperitoneal, brain, or hepatic metastases.333,335,1097,1098 Patient selection appears to have considerable influence on outcome of therapy,225,332,333,1094,1099,1462 and no single prognostic factor appears to correlate strongly with therapeutic response.332 Many patients with renal cell carcinoma who respond to interferon alfa therapy develop anti-interferon antibodies which, in some299,331,333,343 but not all298,299,331,342 studies, appear to have been associated with loss of response to therapy.299,331,333,343 However, many factors influence the frequency, magnitude, and importance of this antibody response, and further studies are needed to determine whether such antibody development affects outcome of therapy with interferon alfa in patients with renal cell carcinoma.299,331,333 (See Dermatologic, Local, Sensitivity, and Immunologic Reactions: Antibody Formation, in Cautions.)
Bladder Cancer
Intravesical therapy† with interferon alfa has been used in the prophylaxis351 or treatment356,448,1552 of superficial bladder cancer†. Although intravesicular BCG generally is preferred for superficial bladder cancer,351,448,1625 responses to intravesical interferon alfa have been noted in patients with disease that failed to respond to or is refractory to other intravesical agents (e.g., BCG).351,448,1552
Interferon alfa administered intravesically has been used alone or in combination therapy as adjuvant or prophylactic therapy to prevent the recurrence of superficial bladder cancer following transurethral resection (TUR).351 Interferon alfa used alone as an intravesical agent generally appears to be less effective but less toxic than intravesical therapy with BCG or chemotherapeutic agents for the prophylaxis of superficial bladder cancer.351,352,353,354,1664 At a mean follow-up of 43 months, relapse rates were similar in patients with stage T1, grade 2 or 3 or relapsed grade 1, bladder cancer receiving TUR with or without adjuvant intravesical therapy with interferon alfa-2b 60 million units once weekly for 12 weeks and then once monthly for up to 1 year of treatment.353 In a comparative study, intravesical interferon alfa-2b was inferior to intravesical mitomycin for preventing tumor recurrence in patients with papillary bladder tumors.1664 In a small randomized trial, interferon alfa-2a (no longer commercially available in the US) was inferior to BCG as intravesical therapy for recurrent stage T1, grade 1 to 3, superficial bladder cancer.354 In a large randomized trial using a single intravesical instillation immediately following TUR, interferon alfa-2b was inferior to epirubicin for preventing recurrence of stage Ta or T1 superficial bladder cancer.352
Interferon alfa also has been used in combination therapy for the prophylaxis of superficial bladder cancer.351 In a few randomized studies with small numbers of patients, combination therapy with interferon alfa and epirubicin administered intravesically did not appear to be more effective than either agent alone in preventing or delaying the recurrence of superficial bladder cancer at low risk of recurrence.355,1130 Further study is needed to evaluate the additive or synergistic effects of interferon alfa used in combination therapy with other intravesical agents (e.g., BCG) for the prophylaxis of superficial bladder cancer.351,1134
Limited evidence suggests that interferon alfa administered intravesically is an active agent in the treatment of superficial bladder cancer, both as primary therapy and as secondary therapy after intravesical administration of other agents has failed.356,448,1552 The drug has produced objective response rates ranging from 30-60% when administered intravesically for the treatment of superficial cancer of the bladder.351,356,1552 Complete responses to intravesical interferon alfa have been observed in some patients with noninvasive papillary tumors and/or carcinoma in situ, including patients with recurrent disease or disease refractory to intravesical therapy with BCG live or cytotoxic agents.356,1552,1663 Limited data suggest that high intravesical doses (e.g., 100 million units) of interferon alfa may be more effective, with minimal toxicity, than lower doses (e.g., 10 million units) in achieving complete responses in patients with carcinoma in situ .1552
Responses have been reported in small numbers of patients receiving intralesional administration (into the base of the tumor or surrounding tissue) of interferon alfa for papillary tumors of the bladder.1129,1132 In limited numbers of patients, little or no efficacy has been demonstrated for the use of interferon alfa administered IM for the prophylaxis1550 or treatment1131 of superficial bladder cancer. Continuous intra-arterial administration† of interferon alfa showed no efficacy and considerable toxicity in 5 patients with advanced bladder cancer.1560
Intravesical administration of interferon has been associated with minimal toxicity;356,1552,1663,1665 local symptoms rarely have been observed,356 and the most commonly observed systemic toxicity has consisted of mild to moderate flu-like symptoms.356,1552,1663 Comparative studies in larger numbers of patients are needed to determine the role of interferon alfa therapy in the prophylaxis and treatment of superficial bladder cancer.351,356,1663,1664,1665,1666,1667,1668,1669
Ovarian Cancer
Agents other than interferon alfa are preferred for the treatment of ovarian cancer.449,1625 Interferon alfa has been administered intraperitoneally† for the treatment of minimal residual epithelial ovarian cancer† in a limited number of patients.358,359,360 Interferon alfa appears to be an active agent in ovarian cancer when administered intraperitoneally, particularly in patients with small-volume, platinum-sensitive disease.357,358,359 Further studies are needed to establish the role of interferon alfa administered intraperitoneally as a single agent or in combination with conventional antineoplastic agents to patients with minimal or no evidence of residual ovarian carcinoma. 357,359,360
Objective responses (mostly partial responses) have been reported in less than 20% of a small number of patients with advanced ovarian cancer receiving IV or IM administration of interferon alfa.987,1135,1136,1137
Multiple Myeloma
Interferon alfa has been used for the palliative treatment of multiple myeloma† in patients whose disease has relapsed or become refractory to conventional antineoplastic therapy (e.g., melphalan plus prednisone);19,299,300,313,314,315,316,317,318,319,320,321,325,327,328,329,330,528,1017,1020,1046,1047 the drug also has been used as induction therapy in a limited number of patients with the disease.299,313,317,318,1044 Although therapy with interferon alfa alone appears to produce objective responses in only 10-30% of patients with relapsed or refractory disease,19,299,300,313,314,315,316,317,318,319,320,321,325,327,328,330,528,1017,1020,1046,1047 limited data suggest that some of these patients may respond to reinstitution of antineoplastic therapy following treatment with interferon alfa.316,317,326,328,1052 Responses to interferon alfa therapy may be more common in patients who have relapsed from previous therapy than in individuals with initially refractory disease.300,316,319,328 Limited data indicate that interferon alfa may prolong duration of response and survival when given as maintenance therapy to patients following successful induction therapy with antineoplastic agents.299,316,317,1016,1042,1043 In one study in patients who achieved an objective response following multiple courses of induction chemotherapy (a regimen of melphalan and prednisone or a regimen of vincristine, melphalan, cyclophosphamide, and prednisone [VMCP] alternating with vincristine, carmustine, doxorubicin, and prednisone [VBAP]), the median duration of response for those who subsequently received interferon alfa maintenance therapy (3 million units/m2 subcutaneously 3 times weekly) compared with those who did not was 26 versus 14 months and the median duration of survival was 52 versus 39 months; differences in survival between interferon alfa maintenance and no maintenance were particularly evident in the subset of patients who had achieved a substantial objective response to induction chemotherapy;1043 Previously untreated patients receiving interferon alfa in a combined regimen with conventional antineoplastic therapy (i.e., melphalan and prednisone) may have at best a marginally improved response rate compared with those receiving antineoplastic therapy alone, although no substantial difference in overall survival was observed.298,299,316,1048,1472,1562,1563
When used for induction of remission in a limited number of previously untreated patients with multiple myeloma, therapy with interferon alfa has been associated with response rates of up to 50-75%.299,313,317,318,1044 Evidence suggests that patients most likely to benefit from interferon therapy are those who have received limited or no prior treatment, those with early-stage disease, and those who have a small tumor burden.317,319,320,1022,1355,1549 Patients responding to interferon alfa therapy may have subjective improvement in bone pain,316,319,321,330,1017 recalcification of osteolytic lesions,317,319,321,330,1044 decreases in bone marrow plasma cells,316,318,319,321,330,1044 decreased concentrations of monoclonal (M-component) immunoglobulins (e.g., myeloma or Bence-Jones proteins) in serum and/or urine,316,317,318,319,326,327,330 and an increase in performance status.319,327,328 IgM synthesis and decreased serum concentrations of IgG, IgA, and IgM reportedly normalize in patients who respond to interferon,313,317,318,320 which suggests that interferon alfa stimulates the recovery of normal immune function in these individuals;313 this restoration to normal of immunoglobulin concentrations is uncommon in patients who respond to therapy with antineoplastic agents alone.318,320,1021 Preliminary results of studies in which multiple-drug regimens of antineoplastic agents (e.g., vincristine, carmustine, melphalan, cyclophosphamide, and prednisone) have been alternated with courses of interferon alfa suggest that such alternating therapy may increase the rate of response and duration of survival in patients with multiple myeloma, although combined therapy also may increase toxicity (e.g., neutropenia).1018,1019,1049,1050 Further long-term follow-up, and randomized studies comparing such alternating regimens with antineoplastic therapy alone, are needed to confirm these results.1018,1049,1050
Other Uses
Interferon alfa has been used for the management of various angiomatous (angiogenic) disorders† in a limited number of patients.1334,1335,1336,1337,1338,1597 Although experience to date is limited, interferon alfa has been used with encouraging results in some such conditions that previously were fatal in most cases (e.g, pulmonary hemangiomatosis†).1334,1335,1336,1337,1597 Initiation of interferon alfa therapy in a 12-year-old boy with pulmonary hemangiomatosis resulted in substantial improvement in pulmonary function, pulmonary angiograms, exercise tolerance, and other manifestations (e.g., digital clubbing) of this disorder;1334,1336 the condition has remained in remission for at least 30 months with long-term interferon alfa maintenance therapy.1336 Encouraging results also have been observed following initiation of interferon alfa therapy in several other patients with pulmonary hemangiomatosis or other angiomatous disorders,1336,1597 and in at least 2 infants with progressive hemangioendotheliomas†.1338 It has been suggested that interferons may inhibit angiogenesis in part by inhibiting proliferation of endothelial cells, smooth muscle cells, and fibroblasts1334,1335,1336,1597 that have been stimulated by fibroblast growth factor (FGF);1335 decreasing collagen production;1334,1336,1597 and increasing endothelial prostacyclin production.1334,1336 Other mechanisms also may be involved.1336,1567,1597 Additional study and experience are needed to establish the role of interferon alfa in the management of these disorders and to determine the optimum dosage and duration of therapy.1334,1335,1336,1337,1338,1597 Some clinicians recommend that, pending further accumulation of data, interferon alfa therapy be reserved for consistently life-threatening or fatal angiomatous conditions for which effective alternative treatment is not available (e.g., pulmonary hemangiomatosis), patients with life-threatening complications of angiomatous disease that fail to respond adequately to conventional therapy or in whom such therapy is not tolerated (e.g., those developing excessive corticosteroid toxicity during the management of Kasabach-Merritt [ hemangioma-thrombocytopenia] syndrome†), conditions that seriously compromise vital organs or structures, and conditions that result in disfigurement, disability, or potential amputation.1336,1597
Interferon alfa also has been used in the treatment of metastatic small intestinal carcinoid tumors†.86,1287,1625 The drug has reduced the frequency and/or severity of symptoms associated with the carcinoid syndrome and has produced substantial reductions in urinary 5-hydroxyindoleacetic acid concentrations, serum human chorionic gonadotropin concentrations, and serum pancreatic peptide tumor markers.86,1287
Dosage and Administration ⬆ ⬇
Reconstitution and Administration
Interferon alfa-2b is administered by IM, subcutaneous, or intralesional injection or by IV infusion.2
Interferon alfa-2b may be self-administered if the clinician determines that the patient and/or their caregiver are competent to reconstitute and safely administered the drug after appropriate training and with medical follow-up as necessary.2 Patients and/or their caregivers who administer interferon alfa in a home setting should be cautioned against reuse of syringes and needles, supplied with a puncture-resistant container for the safe disposal of such equipment after use, and instructed on the proper disposal of full disposal containers.2
Interferon alfa-2b is available in various strengths in single-dose vials containing a powder for injection that requires reconstitution prior to injection and in multiple-dose vials containing solution for injection.2 Not all dosage forms and strengths are appropriate for all indications.2
Interferon alfa solutions should be inspected visually for discoloration and particulate matter prior to administration whenever solution and container permit.2
Patients should be well hydrated during interferon alfa therapy, especially during initial stages of treatment.2
Some adverse effects associated with interferon alfa therapy (e.g., flu-like syndrome) may be prevented or ameliorated by administering the drug in the evening or at bedtime.2 In addition, the incidence of adverse effects may be reduced by administration of acetaminophen or other nonopiate analgesic at the time the interferon alfa dose is given.2
IV Administration
Melanoma
For use as an adjunct to surgery in the treatment of malignant melanoma, interferon alfa-2b is given initially by IV infusion (induction therapy) and then by subcutaneous injection (maintenance therapy).2 (See Melanoma under Reconstitution and Administration: Subcutaneous Injection, in Dosage and Administration.)
IV solutions should be prepared using single-dose vials of interferon alfa-2b powder for injection containing 10, 18, or 50 million units of the drug.2 Solutions of the drug commercially available in multiple-dose vials should not be used for IV administration.2
Single-dose vials of interferon alfa-2b containing 10, 18, or 50 million units of the drug should be reconstituted by adding 1 mL of the sterile water for injection diluent provided by the manufacturer and gently swirling the vial;2 the resultant solution contains 10, 18, or 50 million units/mL, respectively.2
The appropriate dose of reconstituted solution should be withdrawn from the vial and added to 100 mL of 0.9% sodium chloride injection.2 The final concentration of the IV solution should not be less than 10 million units/100 mL (100,000 units/mL).2
IV solutions of interferon alfa-2b should be given by IV infusion over 20 minutes.2
IM Injection
IM injections of interferon alfa-2b should be made into the anterolateral thigh, upper arm, or outer area of the buttocks.2
Hairy Cell Leukemia
For IM injection for the treatment of hairy cell leukemia, single-dose vials of interferon alfa-2b powder for injection containing 10 million units of the drug should be reconstituted with 1 mL of the sterile water for injection diluent provided by the manufacturer and the vial gently swirled;2 the resultant solution contains 10 million units/mL.2 The appropriate dose of reconstituted solution should be administered IM undiluted.2
Alternatively, the appropriate dose of interferon alfa-2b solution for injection from a multiple-dose vial containing 6 or 10 million units/mL can be administered IM undiluted.2
Interferon alfa-2b should not be administered IM in patients with hairy cell leukemia and platelet counts less than 50,000/mm3.2
AIDS-related Kaposi's Sarcoma
For IM injection for the treatment of AIDS-related Kaposi's sarcoma, single-dose vials of interferon alfa-2b powder for injection containing 50 million units should be reconstituted with 1 mL of the sterile water for injection diluent provided by the manufacturer and the vial gently swirled;2 the resultant solution contains 50 million units/mL.2 The appropriate dose of reconstituted solution should be administered IM undiluted.2
Multiple-dose vials containing interferon alfa-2b solution for injection should not be used for treatment of AIDS-related Kaposi's sarcoma.2
Subcutaneous Injection
Subcutaneous injections of interferon alfa-2b should be made into the anterolateral thigh, upper arm, or abdomen (avoiding the navel).115 Subcutaneous injections should not be made into an area where the skin is irritated, red, bruised, infected, or has scars, stretch marks, or lumps.115
Hairy Cell Leukemia
For subcutaneous injection for the treatment of hairy cell leukemia, single-dose vials of interferon alfa-2b powder for injection containing 10 million units of the drug should be reconstituted with 1 mL of the sterile water for injection provided by the manufacturer and the vial gently swirled;2 the resultant solution contains 10 million units/mL.2 The appropriate dose of reconstituted solution should be administered subcutaneously undiluted.2
Alternatively, the appropriate dose of interferon alfa-2b solution for injection from a multiple-dose vial containing 6 or 10 million units/mL can be administered subcutaneously undiluted.2
AIDS-related Kaposi's Sarcoma
For subcutaneous injection for the treatment of AIDS-related Kaposi's sarcoma, single-dose vials of interferon alfa-2b powder for injection containing 50 million units should be reconstituted with 1 mL of the sterile water for injection diluent provided by the manufacturer and the vial gently swirled; the resultant solution contains 50 million units/mL.2 The appropriate dose of reconstituted solution should be administered subcutaneously undiluted.2
Multiple-dose vials containing interferon alfa-2b solution for injection should not be used for treatment of AIDS-related Kaposi's sarcoma.2
Follicular non-Hodgkin's Lymphoma
For subcutaneous injection for the treatment of follicular non-Hodgkin's lymphoma, single-dose vials of interferon alfa-2b powder for injection containing 10 million units should be reconstituted with 1 mL of the sterile water for injection diluent provided by the manufacturer and the vial gently swirled;2 the resultant solution contains 10 million units/mL.2 The appropriate dose of reconstituted solution should be administered subcutaneously undiluted.2
Alternatively, the appropriate dose of interferon alfa-2b solution for injection from a multiple-dose vial containing 6 or 10 million units/mL can be administered subcutaneously undiluted.2
Melanoma
For use as an adjunct to surgery in the treatment of malignant melanoma, interferon alfa-2b is given initially by IV infusion (induction therapy) and then by subcutaneous injection (maintenance therapy).2 (See Melanoma under Reconstitution and Administration: IV Administration, in Dosage and Administration.)
For subcutaneous injection for maintenance therapy, single-dose vials of interferon alfa-2b powder for injection containing 10 or 18 million units of the drug should be reconstituted with 1 mL of the sterile water for injection diluent provided by the manufacturer and the vial gently swirled;2 the resultant solution contains 10 or 18 million units/mL, respectively.2 The appropriate dose of reconstituted solution should be administered subcutaneously undiluted.2
Alternatively, the appropriate dose of interferon alfa-2b solution for injection from a multiple-dose vial containing 6 or 10 million units/mL can be administered subcutaneously undiluted.2
Dosage
Hairy Cell Leukemia
The usual adult dosage of interferon alfa-2b for induction of remission in hairy cell leukemia is 2 million units/m2 given by IM or subcutaneous injection 3 times weekly.2,124,126,129,131,132,135,141,172,179,186,193,220,252,278,1152,1153 The drug should be administered subcutaneously (not IM) in patients with platelet counts less than 50,000/mm3.2
Improvement in one or more hematologic variables generally occurs within 2 months after initiation of interferon alfa therapy in patients with hairy cell leukemia;2 however, improvement in granulocyte and platelet counts may require up to 6 months or longer of interferon alfa therapy.2,122,134,135,136,137,141,246,250 The manufacturer states that interferon alfa-2b therapy should be continued for up to 6 months;2 patients who are responding may benefit from continued treatment, but the drug should be discontinued if disease progresses or fails to respond after 6 months of treatment.2 Some clinicians suggest that therapy with interferon alfa be continued for at least 12 months before discontinuance for nonresponse is considered, unless there is evidence of disease progression.124,141,220,243,250,1549 The minimum effective dosage and optimum duration of therapy with interferon alfa for hairy cell leukemia have not been clearly established.141,191,202,219,220,1549
If severe adverse effects occur during interferon alfa-2b therapy, dosage should be decreased by 50% or the drug should be temporarily discontinued.2 If adverse effects abate, interferon alfa-2b therapy may be resumed using reduced dosage (1 million units/m2 3 times weekly).2 The drug should be permanently discontinued if severe adverse effects persist or if they recur when reduced dosage is used.2
AIDS-Related Kaposi's Sarcoma
For the treatment of AIDS-related Kaposi's sarcoma, the manufacturer recommends that adults receive interferon alfa-2b in a dosage of 30 million units/m2 3 times weekly given by IM or subcutaneous injection.2 The manufacturer states that interferon alfa-2b should be continued until disease progression or maximal response has been achieved after 16 weeks of treatment.2 Response to interferon alfa is slow, and the maximum effect occurs after 6 or more months of treatment.440
If severe adverse effects occur during interferon alfa-2b therapy, dosage should be decreased by 50% or the drug should be temporarily discontinued.2 If adverse effects abate, interferon alfa-2b therapy may be resumed using reduced dosage.2 The drug should be permanently discontinued if severe adverse effects persist or if they recur when reduced dosage is used.2
Follicular non-Hodgkin's Lymphoma
If interferon alfa-2b is used in conjunction with anthracycline-containing chemotherapy for the treatment of follicular lymphoma, the manufacturer recommends that adults receive interferon alfa-2b in a dosage of 5 million units given by subcutaneous injection 3 times weekly for up to 18 months.2
When interferon alfa-2b is added to the chemotherapy regimen, myelosuppressive drug dosage has been reduced by 25% from full dose and the cycle length increased by 33% (e.g., from 21 to 28 days).2 The chemotherapy cycle should be delayed if neutrophil counts are less than 1500/mm3 or platelet counts are less than 75,000/mm3.2
Interferon alfa-2b therapy should be withheld if neutrophil counts are less than 1000/mm3 or platelet counts are less than 50,000/mm3.2 Dosage of interferon alfa-2b should be decreased by 50% (2.5 million units 3 times weekly) if neutrophil counts are greater than 1000/mm3 but less than 1500/mm3.2 If hematologic toxicity resolves (absolute neutrophil count greater than 1500/mm3), interferon alfa-2b dosage may be reescalated to the initial starting dosage (5 million units 3 times weekly).2 Interferon alfa-2b therapy should be permanently discontinued if serum AST concentrations exceed 5 times the upper limit of normal or if serum creatinine concentrations exceed 2 mg/dL.2
Melanoma
For use as an adjunct to surgery in the treatment malignant melanoma, interferon alfa-2b is given in 2 phases (induction therapy and maintenance therapy).2
For induction therapy, the recommended adult dosage of interferon alfa-2b is 20 million units/m2 daily given by IV infusion 5 consecutive days per week for 4 weeks.2 For maintenance therapy, the recommended adult dosage of interferon alfa-2b is 10 million units/m2 given by subcutaneous injection 3 times weekly for 48 weeks.2
If severe adverse effects occur during interferon alfa-2b therapy (e.g., granulocyte counts greater than 250/mm3 but less than 500/mm3, serum ALT and/or AST concentrations greater than 5-10 times the upper limit of normal), the drug should be withheld until adverse effects abate.2 Interferon alfa-2b therapy may then be resumed at 50% of the previous dosage.2 If toxicity does not abate when the drug is withheld, serious adverse effects recur with reduced dosage, or granulocyte counts decrease to less than 250/mm3 or serum ALT and/or AST concentrations increase to more than 10 times the upper limit of normal, interferon alfa-2b therapy should be permanently discontinued.2
Cautions ⬆ ⬇
Almost all patients experience adverse effects at some time during the course of interferon alfa therapy.2,260,1533 However, evaluation of some adverse effects and establishment of a causal relationship to interferon alfa have been difficult since the drug has been used principally in patients with serious underlying diseases, such as acquired immunodeficiency syndrome (AIDS),2,145,149,154,381,383,385 various cancers,2,135,153,219,254,255,257,259,260,261,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,317,318 and/or viral hepatitis.267,268,269,270,271,272,273,274,275,276,279,280,294
The incidence and severity of many adverse effects associated with interferon alfa therapy may be related to the underlying disease,2,431 type and dosage (including duration of therapy) of interferon alfa administered,2,209,260,376,431,461,467,960 route of administration (e.g., systemic versus local injection),2,43,260,376 and age and/or performance status of the patient.260,376,408 Patients receiving relatively low dosages and local administration of interferon alfa (e.g., in the management of exophytic genital warts) generally appear to have a lower incidence of adverse effects compared with patients receiving relatively high systemic dosages (e.g., in the management of AIDS-related Kaposi's sarcoma),2,209,260,376,431,461,467,490,1533 although most types of adverse effects reported with systemic administration of the drug2 also have been reported with local administration.88,431,1466,1467,1468,1469,1549 When administered 2-3 times weekly, interferon alfa doses of 1-9 million units generally are well tolerated while doses of 18 million units or more usually produce moderate to severe adverse effects and those of 36 million units or more usually produce severe adverse effects.376,1533 Intermittent doses of 50 million units or more rarely are tolerated for periods exceeding 8 weeks,11,376,419 and intermittent or daily doses of 100 million units or more rarely are tolerated for periods exceeding 4-8 or 1-2 weeks, respectively.376
The most common adverse effect associated with interferon alfa therapy is a flu-like syndrome, which generally occurs within the first several hours to days and has been reported in up to 98% of patients receiving the drug.2,146,148,161,166,204,209,223,228,230,240,241,260,376,431,453,459,464,494,1533,1549
Most of the adverse effects associated with interferon alfa therapy are mild to moderate in degree of severity2,148,156,206,234,1533 and diminish in intensity and frequency with continued therapy.2,145,1533 However, adverse effects may be severe enough to require discontinuance of the drug in about 3-11% of patients;2,245,156,207,231,241,260,500 the likelihood that intolerance will require dosage reduction and/or discontinuance increases with increasing doses.260,1549 Noncompliance secondary to adverse effects also may increase with increasing doses.1549 Some interferon alfa-induced adverse effects may be alleviated by dosage reduction2,161,206,209,386,461,467,468,500 or may subside despite continued therapy at the same dosage.376
For information on adverse effects, cautions, and precautions related to use of interferon alfa for the treatment of viral infections, see Cautions in Interferon Alfa 8:18.20.
Flu-like Syndrome
A flu-like syndrome develops to some degree in almost all patients receiving 1 million units or more of interferon alfa but its severity appears to be dose related.2,88,145,156,161,166,167,197,204,206,208,209,211,223,228,229,231,241,260,374,376,467,494,1533,1549 The syndrome is characterized by the development of fever (in about 40-98% of patients),2,146,148,156,161,166,167,206,208,209,211,223,228,229,230,231,240,245,260,374,376,386,451,455,461,467,492,493,494,526,1338,1533 fatigue/malaise (in about 50-95% of patients),2,145,146,148,151,155,161,166,167,204,206,208,211,223,228,230,238,376,386,431,1533 myalgia (in about 30-75% of patients),2,148,161,167,206,208,228,229,230,231,376,431,451,1533 chills (in about 40-65% of patients),2,148,156,161,166,167,206,208,223,228,230,231,245,374,376,431,1533 headache (in about 20-70% of patients),2,146,148,161,166,167,208,211,223,228,229,230,231,376,431,451 arthralgia (in about 5-24% of patients),2,161,208,228,374,376,431,468 rigors,2,260,431 tachycardia,376 anorexia,2,408,431,494,1533 dry mouth,2,431 dysgeusia,2 back pain,2 sweating,2 and dizziness.2 Abdominal cramps and diarrhea also may be associated with the syndrome.1533
Fever frequently reaches 38-40°C within 6 hours of administration of interferon alfa,368,376,1533 generally persists for 2-12 hours if untreated,148,223,228,231,240,376,1533 and usually is preceded by chills,467,468,1533 which can be severe.492 Pretreatment with a nonsteroidal anti-inflammatory agent (NSAIA) or acetaminophen may minimize the risk of developing fever and/or its severity.2,166,197,204,211,244,260,376,453,455,464,493,1533 Such pretreatment also may attenuate some other effects (e.g., myalgia) associated with interferon alfa-induced flu-like syndrome.453,455,1533 However, fever usually becomes self-limiting after the first several weeks of therapy, manifesting as a low-grade fever that does not require specific treatment.376,1549 Therefore, subsequent development of high fever during prolonged interferon alfa therapy should prompt consideration of other possible causes (e.g., infection).376 The pyrogenic response to interferon alfa therapy may be mediated by a drug-induced increase of hypothalamic prostaglandin (PGE2) production and/or release rather than by an increase in interleukin-1.2,166,197,204,211,244,260,376,453,455,493,1090 This response does not appear to be secondary to an exogenous pyrogenic contaminant in interferon alfa preparations.376,461 Patients receiving high doses of interferon alfa (e.g., 50-120 million units) may experience a sharp febrile response accompanied by severe rigors260,376,461,490 and occasionally may develop peripheral cyanosis, vasoconstriction, nausea, vomiting, severe myalgias, intense headaches, and exhaustion.376 Transient hypotension and syncope also may occur in these patients, especially when the drug is administered IV.376
There is considerable interindividual variation in the development of tolerance to interferon alfa-induced flu-like effects;376 however, tolerance of such effects appears to be optimized by employing relatively low (e.g., 10 million units or less 3-7 times weekly) dosages of interferon alfa, and such dosages usually permit continuous treatment for prolonged periods.137,166,206,248,376,1533 In patients receiving daily interferon alfa therapy, fever and other flu-like symptoms usually diminish within a few days to weeks;166,167,228,260,376,1533 malaise often recurs with each dose for the first few weeks of therapy.1533 In patients receiving less frequent, intermittent therapy with the drug, flu-like symptoms may recur with each dose,376,1533,1549 particularly when the interval between doses exceeds 3 days or therapy is temporarily withheld and subsequently reinstituted.1533,1549
A persistent and pervasive fatigue, which usually is preceded by fever and is characterized by weakness or tiredness, also can occur as a component of an interferon alfa-induced chronic flu-like syndrome;376,461,494,1418,1549 such patients frequently report a feeling of lassitude and/or lack of motivation to participate in normal activities (e.g., job absenteeism, social withdrawal), thus exhibiting decreased performance status.376,451,494,1418,1549 Fatigue/malaise may be the most prominent adverse effect associated with continued interferon alfa therapy and may include an increased need for sleep, anorexia and weight loss, myalgias, backache, headache, difficulty concentrating, chilliness, and low-grade fever.1533 Although manifestations of this fatigue usually are intermittent, they can be severe enough to substantially impair physical activity and require interruption of therapy.376,451,1418,1533 Fatigue may be an important dose-limiting effect of interferon alfa therapy in patients receiving high dosages of the drug;145,146,155,204,206,208,376,386,451,461,467,468,1533 dosage reduction or interruption of therapy with the drug usually is required in such patients but may only ameliorate rather than eliminate such symptoms.145,146,155,156,204,206,376,386,460,461,467,468 Tolerance to fatigue may be enhanced with intermittent dosing schedules,145,376 and some patients may better tolerate the drug when it is administered in the evening rather than in the morning.204,211,376,451,452 However, persistent and pervasive fatigue also has been reported in patients receiving relatively low dosages (e.g., 2-10 million units/m2 three times weekly) of the drug.1418
It has been postulated that interferon alfa-induced fatigue may result from a neurotoxic effect of the drug preferentially manifesting as a frontal lobe482 or more generalized1418 encephalopathy. Therefore, some clinicians have suggested that a distinct (from the flu-like syndrome), reversible neurasthenia syndrome may exist.482,1418 However, the possibility that such manifestations may be secondary to the patient's underlying condition cannot be excluded, and additional study is necessary.482 This neurasthenia syndrome has been described as a constant, pervasive, nonspecific symptom complex, manifested characteristically as a psychomotor retardation (i.e., sudden adynamic state with loss of cognitive, verbal, and motor spontaneity, incentive, and interest).482,494,1418 While intellectual activity may be disturbed, formal intellect appears to be preserved (i.e., drive rather than ability is impaired).482 For additional information on these and other adverse nervous system effects, see Cautions: Nervous System Effects.
Musculoskeletal Effects
Myalgia and arthralgia, often associated with a flu-like syndrome, are the most frequent adverse musculoskeletal effects of interferon alfa, occurring in up to 70 and 24% of patients, respectively.2,148,160,161,166,167,168,206,229,230,231,240,376,431,1362,1533 These effects generally are transient, mild, and self-limiting.148,160,161,166,167,168,206,229,230,231,240,376 More severe myalgias, generally involving the lower extremities and associated with limitation of movement, have been observed in patients with chronic myelogenous leukemia receiving the drug.376 Such myalgias frequently require 1-2 weeks of bed rest and corticosteroid and/or analgesic (e.g., opiate) therapy for relief.376 These severe myalgias generally were not associated with an increase in serum muscle enzymes, and electromyograms have failed to reveal evidence of myositis.376 Skeletal pain, which frequently is one of the first adverse effects associated with interferon alfa therapy, has been reported in some patients with multiple myeloma who were receiving the drug; however, arthralgias were not observed in patients with metastatic osseous lesions associated with renal cell carcinoma or other malignancies.376
Muscle (e.g., leg cramps)2,431,1418 and bone disorders2 have been reported in less than 5% of patients receiving interferon alfa. Back pain,2,431,1533 muscle pain,431 and stiffness of the shoulders431 have been reported in 1-4% of patients. Muscle weakness,2 arthrosis,2 polyarticular arthropathies,1362 and arthritis2,1362 have been reported in less than 1% of patients receiving the drug. Interferon alfa-associated arthropathies may be autoimmune in nature in some patients.1362
GI Effects
Anorexia has been reported in about 19-65% of patients with hairy cell leukemia or AIDS-related Kaposi's sarcoma receiving interferon alfa.2,376,408,431,463,467,468,493,494,500,1533 Anorexia and associated weight loss also are common in other patients during continued therapy with the drug.1533 Anorexia, which usually occurs after continued dosing of the drug,408,1533 also may be accompanied by flu-like symptoms2,376,408,431,494,1533 and may require dosage reduction.26,468,493,500,1533 Occasionally, associated weight loss may be striking and dose limiting, especially in patients who were underweight prior to initiating therapy with the drug.1533
Nausea,2,166,167,211,230,231,260,376,431,500 vomiting,2,260,376,500 diarrhea,2,156,260,376,463,1338 dysgeusia (metallic or salty taste),2,376,467,1418 and abdominal pain2,260,463 have been reported in about 17-50, 6-50, 20-45, 13-25, and 5-20% of patients, respectively, receiving interferon alfa therapy. Dysgeusia may be particularly likely during initiation of therapy and, at high dosages, may be accompanied by saburral (foulness resulting from accumulation of epithelial matter and debris) tongue and/or halitosis.376,467 Hypogeusia (especially for meat) also has been reported,1418 and alterations in taste may be accompanied by alterations in smell.1418 Diarrhea, which can be severe at high doses, generally is watery376,463 and usually is not accompanied by abdominal cramps or blood, mucus, or fat in the stools.376 Nausea rarely may require antiemetic therapy.376
Dry mouth or gingivitis has been reported in up to 28 or 14% of patients, respectively, receiving interferon alfa.2,431 Stomatitis2,431 and eructation2 has been reported in up to 6% of patients.2,431 Dyspepsia,2,431 hypersalivation,2,431 thirst,2,431 GI hemorrhage2 melena,2 esophagitis,2 hyperesthesia of the tongue,431 discoloration of the GI mucosa,2 gastric ulcer,2 oral pain,431 bleeding gums,2 and hyperplasia of the gums2 have been reported rarely.
Nervous System Effects
Although interferon alfa distributes poorly into the CNS,5,8,21,23,30,42,494,1598 adverse nervous system effects have been reported in patients receiving the drug and have ranged from mild mental disturbances (e.g., anxiety, irritability), fatigue, and headache to more severe delirium and global dysfunction with mental obtundation and stupor.2,408,431,480,482,492,494,1418,1533,1598 In some cases, the patient's underlying condition may have contributed to or caused the observed effect.376,381,408,480,482,485,1533 Patients, especially geriatric patients, receiving relatively high systemic dosages of the drug2,376,408,467,468,492,493,494 and those with underlying CNS impairment376,408,480 appear to be particularly likely to develop adverse nervous system effects. However, nervous system effects also have been reported in patients receiving relatively low dosages (e.g., 2-10 million units/m2 three times weekly) of the drug.1418,1598 Most adverse nervous system effects are mild and rapidly (e.g., within a few days) reversible following dosage reduction or interruption of interferon alfa therapy, although several (e.g., 2-4) weeks may be required for resolution, especially in severe cases.2,260,376,483,484,492,493,1533
Depression, suicidal behavior (e.g., suicidal ideation, suicide attempts), and suicides have been reported in association with the use of interferon alfa.2 If severe depression occurs, discontinuance of interferon alfa therapy generally is required.2
The most common adverse nervous system effects associated with interferon alfa therapy are fatigue (usually as a component of a flu-like or neurasthenia syndrome) (see Cautions: Flu-like Syndrome),2,145,146,148,151,155,161,166,167,204,206,208,211,223,228,230,238,376,386,431,492,494,1418,1533 headache,2,146,148,161,167,208,211,223,228,229,230,231,376,431,451,1533 malaise,2,431,494,1533 and dizziness,2,204,431 which have been reported in up to 95, 10-50, 20-70, and 9-40% of patients, respectively. Headache also may be a component of a flu-like syndrome2,431 and, in some cases, was described as migraine.2 Depression2,155,376,431 (including exacerbation of underlying depression, which can be debilitating),1533,1549 circumoral and/or peripheral paresthesias (e.g., tingling of the extremities),2,208,218,376,419,431,461,467,487,492,493,568 unspecified pain,2,1537 altered mental status,2,376,480,492,493,494,1533 amnesia,2 and confusion2,260,376,461,480,484,493,494 have been reported in up to 28, up to 21, up to 17, up to 17,2 up to 14, and up to 12% of patients, respectively, receiving interferon alfa therapy.2 In some patients, especially geriatric patients, with malignancy receiving relatively high systemic dosages of the drug, alterations in mental status have been severe, manifesting as substantial mental obtundation and coma.2,376,408 In addition, paresthesia may be severe in some patients468,487 and may be more likely in patients previously exposed to vinca alkaloid therapy.376,487 (See Antineoplastic Agents: Vinca Alkaloids, in Drug Interactions.)
Somnolence,2,376,431,480,492,493,494 sleep disturbances (e.g., hypersomnia,145,482,484 insomnia),2 anxiety,2 hypoesthesia,2 nervousness,2,431 emotional lability,2,479 and vertigo2,1418 have been reported in 5% or less of patients receiving interferon alfa. Lethargy,376,484,492,493,494 tremor,2 hallucinations,376,480,494 abnormal thinking,2 psychomotor retardation,482,1418 stupor,2 coma,2 stroke,2 and transient ischemic attacks2 have been reported in less than 1% of patients receiving interferon alfa. Impaired coordination,2 extrapyramidal reactions,2,306,1533 paralysis,2,1102 bradykinesia,482,1418 hypertonia,2 dysphasia,2,376,493,494 and aphasia2 also have been reported in less than 1% of patients receiving the drug.2,431
Patients receiving interferon alfa also have developed decreased tendon reflexes,492 hyporeflexia,1418 mild to marked motor loss,492 and slowing of motor and sensory conduction velocities.376,487,492 Such changes were suggestive of a mild sensory motor neuropathy;376,487,492 in some patients with preexisting neurologic dysfunction and/or receiving high dosages of the drug, severe neurotoxicity (e.g., polyradiculopathy) and neurogenic muscle atrophy (e.g., neuralgic amyotrophy) were reported.376,485,486,493 Exacerbation of neurologic manifestations also has been reported in some patients with multiple sclerosis following initiation of interferon alfa therapy.488,489,490,491 (See Cautions: Precautions and Contraindications.)
Reversible EEG abnormalities,376,480,482,484,492,493,494,1418 which may be severe,461,494 have been reported in patients receiving interferon alfa and were characterized by progressive slowing of background activity, with a dominant slowing of alpha rhythm376,461,492,493,494,1418 and appearance of diffuse slow waves (e.g., theta and delta),376,484,494,1418 and mainly involved the frontal and temporal lobes.376,482,492,493,494,1418 Other EEG abnormalities (e.g., paroxysmal bursts of moderate- to high-voltage frontal rhythmic delta waves) also have been reported.484 Seizures have been reported occasionally in patients receiving the drug.376,408,431,1598 The risk of EEG abnormalities does not appear to correlate with serum interferon alfa concentrations,494 and the drug generally was undetectable in the CSF of these patients.376,492,494 However, the risk of such abnormalities may be increased with increasing dosages,482,483,484,493,494 and some patients may tolerate reduced interferon alfa dosages.484
EEG abnormalities reported in patients receiving interferon alfa often have been associated with profound but selective CNS dysfunction (e.g., psychomotor retardation, marked somnolence, fatigue, confusion, disorientation, social withdrawal, general mental slowing, expressive dysphagia) that was characteristic of a frontal lobe neurasthenia syndrome.376,480,482,492,493,494 However, other clinicians have described the syndrome as a more complex and generalized encephalopathy.1418 The syndrome also may mimic viral encephalitis.480 Patients with manifestations of this syndrome most notably exhibit a sudden adynamic state (psychomotor retardation) that includes loss of higher mental function such as cognitive, verbal, and motor spontaneity, incentive, expressions, gestures, and interest;482,492,494,1418 such patients may exhibit moderate to severe behavioral changes.482,494,1418 Loss of libido also may occur.1418 The mechanism(s) for this possible neurotoxic reaction has not been elucidated,482,494,1418,1533 although alterations in central neurotransmitters may contribute, at least in part, since metoclopramide or methylphenidate occasionally have reversed neuropsychiatric effects associated with interferon alfa therapy.482,1533
Other neuropsychiatric effects associated with interferon alfa therapy have included phobias,480 obsessional thoughts and rituals,480 tearfulness,479,482,1533 delirium (which may include clouding of consciousness, agitation, paranoia, and suicidal ideation),479,1533,1549 disruption of interpersonal relationships,479,482,1533 irritability,479,1533 and psychosis.408 In some cases, the patient's underlying condition may have contributed to the observed effects.376,408 Difficulty in concentration,145,482,1533 mental clouding,1433 disorientation to time and space,294,494 visuospatial disorientation,482 numbness,376 and speech disorders492,494,1418 also have been reported. Delirium appears to be the most severe adverse neuropsychiatric effect associated with interferon alfa therapy and appears to be a continuum of such effects since patients developing delirium usually are irritable, depressed, withdrawn, and agitated and occasionally suicidal, paranoid, and anxious.479,1533 In patients receiving relatively low doses of the drug, delirium appears to occur only rarely and probably only in patients with underlying CNS dysfunction (e.g., those with a history of CNS insult or injury).1533 Tearfulness that develops in some patients receiving interferon alfa usually is labile, often unpredictable and uncontrollable (e.g., characterized by excessive sentimentality), and out of proportion to the precipitating situation (e.g., gestures of kindness, viewing television news).479,482,1533
Patients with a history of brain injury, severe substance abuse, or brain dysfunction such as mild organic brain syndrome associated with early hepatic failure may be at increased risk of developing delirium.479,1533 In addition, the risk of adverse neuropsychiatric effects appears to be increased with increasing dosages.1533 However, even during long-term interferon alfa therapy at relatively low dosages, neuropsychiatric effects reportedly occur in up to 20% of patients, and they are some of the most frequent reasons for dosage reduction or discontinuance of the drug during prolonged therapy.479,1533 Patients with a history of alcohol or substance abuse may be vulnerable to interferon alfa-induced neuropsychiatric effects during prolonged therapy, developing craving, fear of recidivism to abuse, or actual relapse; therefore, such patients should be advised of the possibility of this effect and offered counseling if necessary.1533
Because the goal of interferon alfa therapy generally is to continue therapy if possible until the optimum benefit is achieved, efforts aimed at detecting and managing adverse psychiatric effects often become important during prolonged therapy.482,1533 It is important that patients and their partners and family members be apprised of the potential for such effects and encouraged to aid clinicians in early detection.479,482,1533 They should be advised that the onset of these effects often is insidious, and they initially may manifest as irritability and resultant problems at work or with interpersonal relationships.479,1533 Tolerance of interferon alfa-induced adverse neuropsychiatric effects can be increased by providing encouragement, counseling, and reassurance that the effects are drug related and generally resolve once therapy is complete; dosage adjustment and symptomatic management may be required.479,482,1533 Simple reassurance that irritability and associated effects are caused by interferon alfa and will decrease with dosage adjustment often is sufficient to relieve anxiety and make the effects tolerable.482,1533 When irritability and associated symptoms are severe, reassurance may be insufficient to enable the patient to function socially or control their mood and behavior; dosage reduction (e.g., by one half) in such cases may improve neuropsychiatric manifestations within a few days.479,1533 There is limited evidence that methylphenidate or metoclopramide may provide relief in some patients,482,1533 but controlled studies are needed to confirm this finding.1533 Rarely, discontinuance of interferon alfa therapy may be necessary.479,1533 If delirium or severe depression occurs, dosage reduction or interruption of interferon alfa therapy generally is required.2,1533 Limited data suggest that fluoxetine may be useful in treating depression associated with interferon alfa therapy.1631 Because of the potential severity of delirium, discontinuance of interferon alfa and close observation (e.g., in a hospital setting) has been recommended for patients who develop this effect.479,1533
Hematologic Effects
Adverse hematologic effects occur frequently in patients receiving interferon alfa2,145,146,148,151,155,156,161,167,204,208,209,222,223,230,231,244,260,376,460,461,468,515,517,518,521,524,528 but, unlike the marked myelosuppression that frequently occurs with conventional antineoplastic (cytotoxic) agents, interferon alfa generally is mildly myelosuppressive and produces hematologic toxicity that generally is well tolerated and transient.376,461,467,468,524,1533 Hematologic toxicity occasionally may be apparent within a few hours of interferon alfa administration376 and may not be cumulative.260 The incidence of adverse hematologic effects appears to be decreased in patients with exophytic genital warts receiving local, low-dose therapy compared with patients with AIDS-related Kaposi's sarcoma or other malignancies.2,431
The predominant manifestations of interferon alfa-induced hematologic toxicity include leukopenia2,148,155,156,208,223,260,431,461,468,515,1533 (mainly neutropenia),2,524,1533 anemia,2,260,431,461 and thrombocytopenia,2,209,223,260,376,431,461,468,500,515,519,520,521 which occur in about 3-69, 5-69, and 3-42% of patients, respectively.2,260,376,431 Thrombocytopenia and anemia generally are well tolerated,461,521 although thrombocytopenia occasionally may be severe enough to require discontinuance of interferon alfa.500,521 Marked decreases in erythrocytes can occur in patients with preexisting anemia.1533 Leukopenia (e.g., granulocytopenia) also occasionally may be severe enough to require discontinuance of the drug.155,156,208,210,461 Reductions in interferon alfa dosage can ameliorate decreased blood cell counts.1533 Following discontinuance of interferon alfa therapy, recovery from leukopenia260,524 and/or thrombocytopenia260 generally are rapid (e.g., within a few days),260,376,468,1549 while recovery from anemia generally is slow (e.g., within weeks to a few months).260 Despite these adverse hematologic effects associated with interferon alfa therapy, patients generally do not experience abnormal blood loss,223 evidence of hemolysis,223 or bleeding diathesis.209,223 However, transient myelosuppression occasionally may be severe enough to require red blood cell and/or platelet transfusions.250,252
Leukopenia, which may occur within a few hours of administration of interferon alfa,146,148,156,166,167,208,222,230,231,240,376 usually is asymptomatic26 and dose-related,260 may be dose-limiting,524,1533 and may result both from granulocytopenia208,209,223,376,461 and lymphocytopenia.160,161,166,208,222,223,376,461 Leukopenia may improve following conversion to intermittent (e.g., every 3 or more days) administration or interruption of interferon alfa therapy.376,1533 Interferon alfa-induced leukopenia appears to result from reversibly impaired bone marrow release of mature cells and/or from depletion or sequestration of circulating leukocytes rather than from direct myelotoxicity (e.g., maturation arrest).260,376,461,524 However, there is in vitro evidence that interferons may inhibit myeloid524,529 and erythroid531 progenitor cells. In patients with normal pretreatment blood cell counts, the risk of infection may not be increased substantially by interferon alfa-induced leukopenia since the leukocytic response to infection does not appear to be impaired by the drug in such patients.260,376,461 However, leukopenia may be more frequent and severe in patients with multiple myeloma376,528 or lymphoma,376 and these and other patients with preexisting leukopenia may be at increased risk of infection during interferon therapy.376,528
Decreased hemoglobin concentration have occurred in patients, receiving chronic interferon alfa therapy.2,209,223 Prolonged administration of the drug occasionally may result in a normochromic, normocytic anemia;376,461 recovery from anemia generally requires weeks to months following discontinuance of interferon alfa, suggesting that some interference with erythropoiesis may be involved.376,1010 Positive direct antiglobulin (Coombs') test results occasionally have been observed in patients receiving interferon alfa.376,517,518 Rarely, immunologically mediated hemolytic anemia has occurred, which generally improved following discontinuance of the drug and administration of corticosteroids;376,517,518 anemia recurred in several patients who were rechallenged with the drug.376,518
Interferon alfa-induced thrombocytopenia usually is mild and asymptomatic and generally develops slowly over several weeks, and its incidence appears to be related to the patient's underlying condition.26,376 Patients with chronic lymphocytic leukemia or multiple myeloma appear to be at increased risk of developing thrombocytopenia during therapy with drug compared with patients with solid tumors.10,321,376,528 Platelet counts usually reach a nadir within 2-4 weeks.519 In some patients (e.g., those with malignant erythrocytosis or thrombocytosis associated with renal cell carcinoma or chronic myelocytic leukemia), the anemic and thrombocytopenic effects of interferon alfa may be therapeutically beneficial.376,1023,1101 Immunologically mediated thrombocytopenia (e.g., as reflected by platelet-associated immunoglobulin) has been reported rarely and disappeared following discontinuance of the drug and administration of corticosteroids.376,519,520 In several patients, thrombocytopenia has recurred following rechallenge with interferon alfa,519,520 and in at least one such patient, the drug subsequently was tolerated following splenectomy.519 Occasionally, immunologically mediated thrombocytopenia may be severe and result in bleeding complications.519,520 In a patient with preexisting thrombocytopenic purpura, rapid deterioration of the purpura, which became unresponsive to corticosteroid and IV immune globulin therapy, occurred following initiation of interferon alfa therapy; the patient died several weeks later from intracerebral hemorrhage.525 Purpura and cyanosis have been reported in less than 1% of patients receiving interferon alfa therapy.2,525 Petechiae have been reported rarely, but a causal relationship to interferon alfa has not been established.520 In some patients with leukemia who were receiving interferon alfa therapy, prolongation of prothrombin and partial thromboplastin times occurred.346,376,465,466
Hepatic Effects
Increased serum concentrations of AST (SGOT)155,260,376,431,434 and ALT (SGPT)2,155,260,376,494 have been reported in about 10-50% of patients receiving interferon alfa therapy, although such increases appear to be dose-related and have been reported in up to 80% of patients receiving relatively high dosages of the drug.376 In addition, increases in these enzymes generally are more marked in patients with preexisting elevations.376 Increased serum concentrations of LDH,209,260,376 alkaline phosphatase,2,148,209,260,376,431,434,457,461,494 and bilirubin260,431 also have been reported frequently in patients receiving the drug, although less commonly than increased aminotransferase (transaminase) concentrations.376 Changes in LDH and alkaline phosphatase concentrations occur principally in patients with preexisting abnormalities and do not necessarily correlate with aminotransferase changes.376 Increases in hepatic enzymes generally are mild to moderate145,148,208,468,494 and transient.2 (See Cautions: Precautions and Contraindications.) However, substantial increases occasionally may occur in patients receiving relatively high dosages of interferon alfa; such increases generally are reversible following dosage reduction or discontinuance of the drug.2,146,148,155,260,460,465 Elevations of serum aminotransferase concentrations generally return to normal within several days to a week following discontinuance of interferon alfa.260
Respiratory Effects
Dyspnea, cough (which may be nonproductive), pharyngitis, sinusitis, and drying of the oropharynx have been reported in up to 34% of patients receiving interferon alfa and may be severe.2,431 Nasal congestion,2,376 rhinitis,2 and rhinorrhea2 have been reported in up to 2-10% of patients. Antihistamines reportedly may alleviate some of these symptoms.88,376,1549 Pulmonary infiltrates, pneumonitis, and pneumonia have been reported rarely in patients treated with interferon alfa; fatalities reportedly have occurred.2,1610 Such effects have been reported most frequently in patients with chronic hepatitis C virus (HCV) infection receiving interferon alfa, but they also have occurred in patients receiving the drug for oncologic diseases.2,1610 The etiology of these adverse effects has not been established.2 Epistaxis,2 drainage of sinus secretions,431 throat tightness,431 wheezing,2 and bronchospasm2 have been reported less frequently. Pneumonia or respiratory disorder was reported in at least one patient receiving the drug.2 While a causal relationship has not been established, some clinicians suggest that immunomodulating effects of interferons could predispose to the development of pulmonary sarcoidosis during prolonged therapy.516,1362
Dermatologic, Sensitivity, and Immunologic Reactions
Dermatologic Reactions
The most common adverse dermatologic effects of interferon alfa are rash2,9,206,260,360,376,468,1452 and transient alopecia or thinning of the hair,2,204,206,228,260,376,461,467,1533,1548 which occur in about 25% or less of patients.
Interferon alfa-induced rash, which may be maculopapular,376 papular,431 macular,468 or urticarial,2,376,461 generally is intermittent or transient,260,376 does not require dosage reduction, and does not progress to more serious manifestations.260 Rash occurs most frequently on the extremities376 and trunk376 and, occasionally, on the neck431 and may be accompanied by pruritus2,206,260,431 and erythema.2,376,438,464,1452 In several patients with rash, skin testing failed to show evidence of a true hypersensitivity reaction,260 and limited evidence suggests that some local erythematous reactions may result in part from a direct interferon alfa-induced vasodilation.1452 In at least one patient with repeated flare-ups of rash, skin biopsy revealed evidence of mild vasculitis.376,461 While it previously was believed that many adverse dermatologic effects associated with interferon alfa therapy resulted from impurities in early preparations of the drug rather than from the drug itself,461,1452 experience with currently available purified preparations suggests otherwise.2,88,260,376,461,464,1549
Interferon alfa-induced alopecia usually has been associated with prolonged (e.g., 3 months or longer) therapy376,1533 and is manifested as thinning and slight to mild hair loss,376 which occasionally becomes more marked when therapy with the drug is interrupted.376 Hair loss generally is reversible but often persists for 1-3 months after discontinuance of interferon alfa;2,1533 occasionally, an irreversible androgenetic (male-pattern) alopecia has developed in patients receiving prolonged therapy.1533 It has been suggested that alopecia and hair thinning may result from the cytotoxic activity of interferon alfa.461 In addition, hair loss in some patients may be a manifestation of hypothyroidism associated with interferon alfa therapy.508,510 (See Cautions: Endocrine Effects.) Excessive growth of eyelashes also has been reported,376,454 and abnormal hair texture has been reported rarely.2
Dry skin260 and dermatitis2,260,360 have been reported in approximately 8-13% of patients receiving interferon alfa. Excessive sweating or night sweats have been reported in 2-8% of patients.2,431 Acne,2 nail disorder,2 epidermal necrolysis,2 photosensitivity,2,431 skin discoloration,2 and exfoliative dermatitis260 have been reported less frequently.2
In some patients with psoriasis, interferon alfa exacerbated the disease within 2-4 weeks of initiation of therapy with the drug for other conditions.2,376,501 Endogenous interferons (e.g., gamma and possibly alfa) have been detected in psoriatic blister fluid from patients with the disease, suggesting that local production of interferons may contribute in part to the pathogenesis of this skin condition.376,501,502
Cutaneous vascular lesions with punctate telangiectasis have developed in patients with malignant melanoma who were receiving interferon alfa.503 The lesions developed principally on the trunk and extremities, but not at the sites of injection, after 4-8 months of therapy and showed histologic evidence of increased production of epidermis and proliferation of mature dermal blood vessels; it was suggested that these effects may have resulted indirectly secondary to interferon alfa-induced effects on interleukin-1 and/or epidermal thymocyte activating factor.503
Sensitivity Reactions and Autoimmune Disorders
Severe, acute hypersensitivity reactions, characterized by urticaria, angioedema, bronchoconstriction, or anaphylaxis, have been reported rarely with interferon alfa.2 If a severe hypersensitivity reaction occurs during interferon alfa therapy, the drug should be discontinued and the patient given appropriate therapy.2 Sensitivity to allergens, which may be severe, has been reported occasionally in patients receiving interferon alfa,431 and anaphylactic reactions have been reported rarely.228 Autoimmune diseases, which rarely were fatal, including thrombocytopenia, vasculitis, Raynaud's phenomenon, rheumatoid arthritis, lupus erythematosus, and rhabdomyolysis, have occurred in patients receiving interferon alfa.2,519 The mechanism(s) of these effects has not been determined, and a direct causal relationship to interferon alfa has not been established.2 Patients who develop an autoimmune disease while receiving interferon alfa therapy should be monitored closely and the drug discontinued if necessary.2 In addition, a systemic lupus erythematous (SLE)-like syndrome, manifested as myalgia, low-grade arthritis, leukopenia, and a high titer of antinuclear (ANA) and anti-double-stranded DNA antibodies, was observed in at least one patient receiving interferon alfa and resolved following administration of a corticosteroid and discontinuance of the drug; the syndrome recurred following interferon alfa rechallenge.499 Antinuclear antibodies also have been reported in other patients receiving the drug, some of whom had positive titers prior to therapy.86,1362,1374 There is some evidence to suggest that interferons (particularly alfa) may be involved, at least in part, in the pathogenesis of SLE.499,1356,1357,1358,1359,1360 Parotitis and epididymitis, which were described as allergic or autoimmune reactions and subsequently progressed to unilateral scrotal and bilateral facial parotid swelling, also have been reported in at least one patient receiving the drug;498,518 resolution occurred 1 week after discontinuance of interferon alfa therapy but manifestations returned following rechallenge.498 Other possibly autoimmune sequelae of interferon alfa therapy have included hemolytic anemia,517,518 thyroid abnormalities,507,508,509,1361,1362,1565 and hepatitis.512
Antibody Formation
Numerous studies have confirmed that interferon neutralizing antibodies, probably of the IgG class,80,83,95,98,218,260,1364 develop occasionally in patients receiving natural, partially purified interferons as well as in those receiving highly purified recombinant interferons,11,53,80,81,82,83,84,85,86,87,89,95,98,141,169,216,217,218,224,225,235,260,376,1364,1365,1366,1367,1368,1533 but their clinical importance has not been fully established.2,80,169,218,225,376,1366,1367,1374 Such antibodies also can be present in patients with no history of exposure to exogenous interferon preparations.98,235,376,1547 The prevalence of interferon neutralizing antibodies has not been clearly elucidated, in part because of differences in detection methods, sampling times, and interest in monitoring.86,87,95,141,218,376,1366,1368,1372 In studies in which antibodies were monitored, the reported prevalence of their development showed considerable variability, ranging from 0-30% in patients receiving interferon alfa--2b.2,80,86,141,260,971,1364,1365,1367,1368,1370 There is some evidence to suggest that patients with renal cell carcinoma95,376 or Kaposi's sarcoma95 may be at increased risk of developing neutralizing antibodies to interferon alfa. The reason for the increased risk of developing antibodies in these patients is not known,376 but it has been suggested that exogenously administered interferon alfa may induce phenotypic changes in these tumor cells and that newly exposed antigens may cross react with the interferon alfa molecule.376 Some,95,1366 but not all,80 evidence suggests that the risk of developing neutralizing antibodies increases with increasing duration of interferon alfa therapy.95 In addition, other factors such as type of interferon preparation, dose, dosing regimen, and route of administration have been suggested to affect the risk of antibody development,80,95,218,1366 but carefully designed, comparative studies using standardized assay techniques are needed to more fully elucidate the relative risk associated with various interferon preparations and regimens.218,1366
The presence of interferon alfa neutralizing antibodies does not appear to alter the spectrum, incidence, or severity of interferon alfa-associated adverse effects, and dosage adjustment or interruption of therapy usually is not necessary;2,11,53,80,87,95,218,225,235,1374,1533 however, some evidence suggests that certain adverse effects occasionally may abate once such antibodies develop.82,235,376 Patients with detectable levels of interferon alfa neutralizing antibodies do not appear to be at increased risk of developing adverse effects that might be attributable to immune complex formation (e.g., renal, lung, or articular disorders or collagen vascular disease),80,82 and no correlation appears to exist between the development of interferon alfa neutralizing antibodies and the development of interferon alfa-associated autoimmune factors (e.g., antinuclear or antithyroid antibodies, rheumatoid factor) or disorders.86,1374
While many patients who develop interferon neutralizing antibodies continue to respond to interferon alfa therapy,11,53,82,83,87,89,95,216,217,218,225,376,1366,1373 other patients, some of whom had previously responded to therapy with the drug, exhibit evidence of disease progression and decreased serum interferon concentrations as neutralizing antibodies develop.11,53,80,82,84,85,86,87,216,224,225,376,419,1366,1370,1371 In patients who continue to respond to interferon alfa therapy despite the development of antibodies, data are conflicting regarding the effect of such antibodies on the duration of response; some evidence suggests that the duration of response may be adversely affected (i.e., shortened),225 while other evidence suggests that the time to onset and the duration of response, including survival rates, are not affected.89,95,216,217
Anti-interferon antibodies elicited by recombinant DNA-derived preparations usually do not neutralize the natural, partially purified, multispecies human interferon alfa obtained from leukocytes83,235,1364 but instead neutralize a restricted range of recombinant DNA-derived interferon alfa species.235 Preliminary evidence suggests that patients who develop anti-interferon antibodies and show evidence of disease progression while receiving recombinant interferon alfa therapy may respond to treatment with a preparation of natural interferon alfa (e.g., a purified preparation of natural leukocyte interferon).53,84,85,86,87 There also is evidence that antibodies to recombinant interferon alfa-2a (no longer commercially available in the US) or interferon alfa-2b can cross-react with some naturally occurring interferon alfa subtypes.69,83,1364,1368 In addition, limited evidence suggests that some neutralizing antibodies to interferon alfa-2a also can neutralize interferon alfa-2b.87 Therefore, substituting one recombinant interferon alfa preparation for another may not provide effective second-line therapy in patients who develop anti-interferon antibodies to a given interferon preparation and show evidence of disease progression.87,88,1549
Renal, Electrolyte, Fluid, and Genitourinary Effects
Proteinuria is the most common adverse renal effect associated with interferon alfa therapy and occurs in about 15-20% of patients.376,419,462,463,465,467,515,528,803 Proteinuria generally is mild, rarely exceeds 1 g daily, is not associated with a decrease in serum protein, and has not been clearly related to prior renal impairment or to dose of interferon alfa.376,419,528,803 Urinary excretion of leukocytes and erythrocytes have been reported in about 5-14% of patients.2 Increased BUN and serum creatinine concentrations have been reported in up to 10% of patients.2,494 The possibility that the patient's underlying condition (e.g., multiple myeloma) may have contributed to the development of renal dysfunction should be considered.260,462 However, in some patients with multiple myeloma and preexisting light-chain proteinuria, interferon alfa was well tolerated and did not produce worsening of renal function.376,528
Acute renal failure and nephrotic syndrome accompanied by interstitial nephritis and minimal change nephropathy have been reported rarely in patients receiving interferon alfa;260,376,462,463,515 manifestations in such patients have included peripheral edema, marked nonselective proteinuria, and decreased creatinine clearance.463 Renal function improved following discontinuance of interferon alfa, but adverse renal effects recurred upon rechallenge with the drug.462,463 Nephrotic syndrome, secondary to membranoproliferative glomerulonephritis and associated with hypertension and proteinuria, has been reported in at least one patient receiving long-term interferon alfa therapy.506 Although measurements of urinary albumin and β2-microglobulin in a limited number of patients receiving short-term (up to 28 days) interferon alfa therapy did not reveal glomerular or tubular lesions,43 glomerulonephritis has been reported in animals receiving high doses of the drug,1103 and the drug has produced nephrotoxic effects at the proximal renal tubule cell membrane (e.g., inhibition of glucose and alanine uptake) in animals similar to those produced by other low-molecular-weight proteins.1551
Dehydration has been reported in less than 1% of patients receiving interferon alfa,2 and may be secondary to fever, loss of appetite, and/or other factors.88,1549 Some patients receiving high dosages of the drug have developed hyperkalemia and hypercalcemia.376,461 Hyponatremia, probably secondary to a syndrome of inappropriate secretion of antidiuretic hormone (SIADH),376 and hypocalcemia494 also have been reported in some patients receiving high dosages.
Transient impotence has been reported in up to 6% of patients receiving interferon alfa.2 Micturition disorders,2 nocturia,2 dysuria,431 and polyuria2 occurred in 1% or less of patients receiving the drug. Menstrual irregularities also have been reported.228,431
Ocular and Otic Effects
Visual disturbances have been reported in up to 7% of patients receiving interferon alfa.2 Ocular pain,2,431,1559 including that associated with ocular rotation,431 blurred vision,431 and stye (hordeolum) formation2 have been reported in 1-6% of patients receiving the drug. Conjunctivitis,2 lacrimal gland disorder,2 photophobia,2 and abnormal vision2 have been reported in less than 1% of patients, and periorbital edema has been reported in at least one patient.2 Retinal hemorrhages, cotton-wool spots, and retinal artery or vein obstruction have been observed rarely in patients receiving interferon alfa, but the mechanism of these adverse effects has not been determined.2 Although most cases of interferon alfa-associated visual loss have been mild and nonprogressive, at least one patient receiving interferon alfa-2b as adjuvant therapy (following surgical resection of melanoma at high risk of recurrence) experienced permanent and irreversible loss of visual function.1556 Adverse retinal effects develop most commonly after several months of therapy with the drug; however, such effects occasionally have developed in patients receiving interferon alfa for shorter periods.2 Therefore, patients who experience ocular disturbances or changes in visual acuity or in visual fields during interferon alfa therapy should have an ophthalmologic examination.2 Baseline ophthalmologic examinations are recommended prior to initiation of interferon alfa therapy.2 (See Cautions: Precautions and Contraindications.)
Hearing disorders have been reported in less than 5% of patients2 and earache2 and tinnitus2,431 in less than 1% of patients receiving interferon alfa therapy.
Endocrine and Metabolic Effects
Thyroid dysfunction (hypothyroidism2,376,507,508,510,1361,1533,1565 or hyperthyroidism)2,376,507,509,510,1361,1362,1533,1565 has been reported occasionally in patients receiving interferon alfa and, in some patients, may not resolve spontaneously following discontinuance of the drug.2,1565 Most such cases reported to date were in patients receiving the drug for the treatment of breast cancer,376,508,509,510 carcinoid tumors,507,509 or chronic HCV infection.2,509,1565 However, the possibility that any patient receiving interferon alfa could develop thyroid abnormalities should be considered.2,507,508,509,510,1361,1362,1533,1565 In some patients, clinical manifestations as well as laboratory evidence of thyroid dysfunction were observed, and thyroidal therapy (thyroid replacement for hyperthyroidism, antithyroid agents for hyperthyroidism) was required.2,507,508,509,510,1361,1362,1565 Although the mechanism by which interferon alfa may alter thyroid function has not been established,2 antibodies to thyroid microsomal antigen, thyroid receptors, and thyroglobulin have been observed in interferon-treated patients with thyroid dysfunction, suggesting an autoimmune mechanism (e.g., Graves' disease, thyroiditis).507,508,509,1361,1362,1565 While a causal relationship to interferon alfa has not been clearly established, and some evidence suggests that interferon gamma present as a contaminant in interferon alfa preparations may in part be responsible,376,507,509 thyroid dysfunction has been reported in patients receiving highly purified interferon alfa preparations and a temporal relationship has been observed.2,509,1362,1565 If manifestations of possible thyroid dysfunction develop in a patient receiving interferon alfa, the patient's thyroid function should be evaluated and appropriate therapy instituted if needed.2 Interferon alfa therapy should be discontinued in patients whose serum thyrotropin concentrations cannot be maintained in the normal range with antithyroid therapy or hormone replacement therapy, depending on the thyroid dysfunction.2 However, thyroid dysfunction is not always reversible by discontinuance of the drug.2
Increased concentrations of follicle-stimulating hormone (FSH, follitropin)495 and low concentrations of testosterone have been reported occasionally in patients receiving interferon alfa.495 Serum estradiol and progesterone concentrations were decreased in certain women and in at least one man receiving the drug.2,376,457,461,1013 Inconsistent fluctuations of prolactin, somatotropin (growth hormone), thyrotropin (TSH), and insulin also were observed in some of these women.457,461 Gynecomastia and loss of libido have been reported in less than 5%2 and virilization in less than 1% of patients receiving interferon alfa.2 Increased serum concentrations of 11-hydroxycorticosteroids also have been reported.376,461,1012
Weight loss, which often is associated with anorexia (see Cautions: GI Effects) and may be severe,467,468,1533 has been reported in up to 25% of patients receiving interferon alfa therapy.2,206,209,228,461,467,468,1533 Cachexia has been reported in less than 1% of patients receiving interferon alfa.2 Interferon alfa has produced glycosuria in healthy adults.376,461,464,1012
Hypertriglyceridemia,147,1633,1634 which has been severe (e.g., serum triglyceride concentration exceeding 1000 mg/dL) in some cases but reversible upon drug discontinuance,1633,1634 has been reported in patients receiving interferon alfa. (See Cautions: Precautions and Contraindications.) Serum total and/or HDL-cholesterol concentrations have decreased376,1013,1014 or increased1633 in patients and healthy individuals receiving the drug.
Cardiovascular Effects
The most common adverse cardiovascular effects of interferon alfa therapy include edema (e.g., facial, peripheral)2,149 and hypotension,2,148,206,208,257,260,261,376,431,470 which occur in up to 9% of patients. Certain adverse cardiovascular effects (e.g., tachycardia, vasoconstriction, distal cyanosis, hypotension) may be related to the febrile reaction that occurs frequently during initial therapy with interferon alfa,2,11,211,300,374,376,461,465,1363 and substantial hemodynamic changes may occur in some patients.2,148,155,204,206,208,257,469,470,1362,1366 Hypotension may occur during administration of interferon alfa or up to 2 days after therapy and may be severe, requiring dosage reduction and/or supportive therapy such as fluid replacement to maintain intravascular volume;2,148,206,208,257,1366 however, hypotension that develops gradually during interferon alfa therapy may not respond to volume repletion.473 The risk of hypotension appears to increase with age260,374,470,475 and increasing dosages.257,260,376,470,475 Chest pain,2,472,475 which may be severe,2 and vasodilation2 have been reported in less than 5% of patients receiving interferon alfa. Flushing also has been reported in less than 5% of patients receiving the drug,2,376 and vasovagal reactions,431 heat intolerance,431 and hot sensation at the bottom of the foot431 have been reported in 2% or less of patients.
Cardiac arrhythmias,2,260,300,374,376,461,465,469,470,475 which were mainly supraventricular (e.g., paroxysmal atrial tachycardia, sinus tachycardia, atrial fibrillation),2,374,465,469,475 have been reported in less than 3% of patients receiving interferon alfa therapy, although ventricular arrhythmias (e.g., ventricular premature complexes)461,465,473,475 also have been reported.461,465,473,475 Most individuals in whom cardiac arrhythmias occurred were geriatric patients2,300,374,461,465,470,475 and some had preexisting heart disease,2 a history of arrhythmias,2,374,461,465,470,471,475 or received a potentially cardiotoxic drug (e.g., doxorubicin).2,374,461,465,470,475 Rarely, arrhythmias associated with interferon alfa therapy may be life-threatening.235,469,472 Hypertension2,469 and palpitations2 have been reported in less than 3% of patients receiving interferon alfa.2
Cardiomyopathy, which generally is reversible, has been reported in up to 2% of patients receiving interferon alfa.2,155,204,469,470,1340,1362 Cardiomyopathy has been reported in some patients without a history of heart disease.2 Frank manifestations of congestive heart failure (e.g., cardiomegaly, pulmonary congestion, pleural effusions, T-wave flattening, fluid retention, shortness of breath, dyspnea) can occur in these patients,155,204,469,470,1362 and it has been suggested that patients with limited cardiac reserve may be at risk of developing congestive heart failure secondary to acute cardiovascular changes associated with severe febrile reactions induced by interferon alfa.2,11,211,300,376,963 A causal relationship to the drug has not been established,2 but a temporal relationship was observed in several case reports.469,1340,1362 In several patients with AIDS-related Kaposi's sarcoma who developed cardiomyopathy during prolonged, high-dose therapy with the drug,155,204,469 it was suggested that a synergistic interaction between the HIV infection and interferon alfa may have been responsible in part for the observed myocardial depression.469,1340 However, other mechanisms (e.g., interferon alfa-induced impairment of myocyte metabolic processes) also appear to be involved.1363 The incidence of hypotension, arrhythmias, and cardiomyopathy in patients with preexisting heart disease is not known.2 These adverse cardiovascular effects may require dosage reduction, discontinuance of interferon alfa, or supportive therapy.2,1362 In patients without preexisting cardiac dysfunction, return to normal function can occur following discontinuance of the drug.1363
Raynaud's phenomenon,2 bradycardia,2 cardiac failure,2 peripheral ischemia,2 and syncope2 have been reported in less than 1% of patients receiving interferon alfa therapy. Sudden death259,261,376,471,472,474,963 and/or myocardial infarction2,11,235,259,261,341,376,461,465,470,471,473,474,490,963 also have been reported rarely (in less than 1% of patients); these adverse effects usually occurred in individuals with a prior history of heart disease,11,235,341,376,461,465,470,471,473,474 including previous myocardial infarction465,470 and ischemic heart disease (e.g., angina),465,470,473 and a causal relationship to interferon alfa has not been established.376,469,471,474 However, myocardial infarction also has been reported in some patients without a history of heart disease.2 Nonmalignant pericardial effusion has been reported in at least one patient with renal cell carcinoma who received interferon alfa, suggesting the possibility of an interferon-induced perimyocarditis.376
Local Reactions
Adverse local effects associated with parenteral administration of interferon alfa generally have been mild to moderate163,213,226,240 and were reported in up to 12-20% of patients.2,431 Burning,2 pruritus,2,260,431 pain,2,163,168,204,213,226,229,231,240,241,431 edema,260 erythema,260,464,1452 rash,260 and vesiculation260 may occur at the injection site. Aseptic skin necrosis was reported in a few patients after inadvertent intra-arterial injection of interferon alfa.505
Infectious Complications
Infectious complications have been reported in patients receiving interferon alfa, possibly secondary in part to neutropenia induced by the drug.2,431,467,1533,1564 Patients with preexisting cirrhosis (hepatic decompensation)1533,1564 and those with multiple myeloma,376,528 lymphoma,376 or other preexisting leukopenia376,528 may be at increased risk of developing such complications during therapy with the drug. Serious bacterial infections (e.g., cellulitis, septicemia, peritonitis, pneumonia, lung abscess, brain abscess) appear to be particularly likely during interferon alfa therapy for viral hepatitis in patients with cirrhosis,1533,1564 being reported in 5 of 7 such patients in one study.1533 Candidiasis (moniliasis) has been reported in up to 18% of patients with AIDS-related Kaposi's sarcoma receiving relatively high doses of the drug; the infection has been reported less frequently in other patients receiving lower dosages.2 Exacerbation or reactivation of herpes simplex (e.g., herpes labialis) has been reported in 1-8% of patients receiving the drug.2,431,467 Abscess formation,2 furunculosis,2 viral or fungal infections,2 nonherpetic cold sores,2 and sepsis2 occurred in less than 1% of patients receiving the drug. Swollen lymph nodes431 and lymphadenopathy2 have been reported in 1% of patients, and mucositis has been reported in at least one patient.431
Precautions and Contraindications
Interferon alfa-2b is contraindicated in patients with known hypersensitivity to interferon alfa or any ingredient in the preparation.2 If a severe hypersensitivity reaction occurs during interferon alfa therapy, the drug should be discontinued and the patient given appropriate therapy.2
Interferon alfa-2b is contraindicated in patients with autoimmune hepatitis or decompensated liver disease.2
Interferon alfa may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.2 Patients should be closely monitored with periodic clinical and laboratory evaluations and the drug discontinued in those with persistently severe or worsening signs or symptoms of these disorders.2 In many, but not all cases, these disorders resolve after interferon alfa is discontinued.2
The potential benefit to the patient must be carefully weighed against the possible risks involved, and the patient should be apprised of these risks.2 Patients should be instructed about the proper use of interferon alfa2 and should read the patient information and medication guide provided by the manufacturer.2,112
Interferon alfa should be used with caution in patients with a history of preexisting psychiatric disorders, especially those with a history of depression.2 All patients receiving interferon alfa should be informed that depression and suicidal ideation may be adverse effects of treatment and should be advised to immediately report these effects to a clinician if they occur.2 All patients should be closely monitored for evidence of depression and other psychiatric symptoms.2 Patients who develop such symptoms should be carefully monitored during therapy and for 6 months after discontinuing therapy.2 If symptoms persist or worsen, or suicidal ideation or aggressive behavior toward others is identified, interferon alfa should be discontinued and the patient followed with appropriate psychiatric intervention.2 If severe depression and/or other psychiatric condition develops, interferon alfa therapy should be discontinued immediately and appropriate psychiatric intervention provided.2
Use of interferons may be associated with exacerbation of psychiatric symptoms in patients with concomitant psychiatric and substance use disorders.2 When initiating treatment in patients with a history of psychiatric conditions or substance use disorders, clinicians should consider the need for drug screening and periodic clinical evaluation, including psychiatric symptom monitoring.2 Re-emergence or development of neuropsychiatric symptoms or substance use should prompt early intervention.2
Because interferon therapy has been associated with fever and flu-like symptoms (see Cautions: Flu-like Syndrome), the drug should be used with caution in patients with debilitating diseases such as cardiac disease (e.g., unstable angina, uncontrolled congestive heart failure), pulmonary disease (chronic obstructive pulmonary disease), or diabetes mellitus (who may be prone to ketoacidosis).2,211,254,431,461,465 The acute and generally self-limiting manifestations associated with the flu-like syndrome may exacerbate these preexisting conditions.2,465 In addition, the drug also should be used with caution in patients with cardiac disease or a history of any cardiac condition since hypotension,2,148,206,208,257,260,261,376,431,470 arrhythmias,2,260,300,374,376,461,465,469,470,475 myocardial infarction,2,11,235,259,261,341,376,461,465,470,471,473,474,490,963 sudden death,259,261,376,471,472,474,963 and cardiomyopathy2,155,204,469,470,1340,1363 have been reported occasionally in patients receiving the drug. (See Cautions: Cardiovascular Effects.) Patients with a history of cardiac disease must be monitored carefully when receiving interferon alfa therapy.2,254,461,465,475 Electrocardiographic monitoring should be performed prior to initiating and periodically during interferon alfa therapy in patients with preexisting cardiac disease and/or advanced stages of cancer.2 Certain adverse cardiovascular effects, (e.g., tachycardia, vasoconstriction, distal cyanosis, hypotension) may be related to the febrile reaction that occurs frequently during initial therapy with interferon alfa,2,11,211,300,374,376,461,465,1363 and the drug should be used with caution in individuals with limited cardiac reserve.2,211,235,254,300,376,461,465,475 Because patients with underlying massive hemangiomas also may be at increased risk of developing substantial hemodynamic changes during initiation of interferon alfa therapy, the hemodynamic status of such patients should be monitored closely when therapy with the drug is started and for several days thereafter; if such changes occur, dosage should be reduced or the drug discontinued, and supportive and symptomatic care should be initiated as necessary.1366
Pulmonary infiltrates, pneumonitis, and pneumonia have been reported rarely in patients treated with interferon alfa; fatalities have occurred.2,1610 Baseline chest radiographs are suggested before interferon alfa therapy is initiated, and should be performed when clinically indicated in patients who develop fever, cough, dyspnea, or other respiratory symptoms.2 If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored and, if appropriate, interferon alfa should be discontinued.2 Recurrence of respiratory failure has occurred with interferon rechallenge.2
Although fever frequently occurs during initiation of interferon alfa therapy,2,146,148,156,161,166,167,206,208,209,211,223,228,229,230,231,240,245,260,374,376,386,451,455,461,467,492,493,526 any change in pattern of fever should be regarded as a possible sign of some underlying condition (e.g., infection) rather than assumed to be induced by the drug.376,1533,1564 In addition, the subsequent development of high fever during prolonged interferon alfa therapy should prompt consideration of such other possible causes.376,1533,1564 The possibility that patients with viral hepatitis and cirrhosis1533,1564 and those with multiple myeloma,376,328 lymphoma,376 or other preexisting leukopenia may be at increased risk of infection during interferon alfa therapy should be considered. (See Cautions: Hematologic Effects and Cautions: Infectious Complications.)
Increased serum concentrations of AST260,376,431 and/or ALT2,260,376,512,1595,1616 have been reported in patients receiving interferon alfa. (See Cautions: Hepatic Effects.) Therefore, the drug should be used with caution in patients with hepatic disease,2,465 and liver function tests should be performed prior to initiating interferon alfa therapy and periodically thereafter.2,1549 In patients with melanoma, liver function tests should be monitored weekly during the induction phase and monthly during the maintenance phase of interferon alfa therapy.2
Adverse renal effects and fluid and electrolyte abnormalities (e.g., dehydration) have been reported occasionally in patients receiving interferon alfa.2,376,419,461,462,463,465,467,515 (See Cautions: Renal, Electrolyte, Fluid, and Genitourinary Effects.) In addition, all patients should be well hydrated during interferon alfa therapy, especially during initial stages of therapy.2,211,492 Electrolytes should be evaluated prior to initiation of therapy with the drug and monitored periodically thereafter.2 Because of the risk of acute rejection episodes, interferon alfa should be used with caution in renal transplant recipients, particularly when relatively high doses are considered.515 (See Cautions: Renal, Electrolyte, Fluid, and Genitourinary Effects.)
Because of the risk of potential adverse nervous system effects associated with interferon alfa therapy2,204,376,431,480,492,493,494,1418 (see Cautions: Nervous System Effects), the drug should be used with caution in patients with seizure disorders,254 brain metastases,254,376,408 and/or compromised CNS;254,408,485,486 the drug should only be used in these patients if the possible benefits of therapy outweigh the potential risks.254 Because of the risk for adverse CNS effects and possible symptomatic exacerbation of previously asymptomatic brain lesions, some clinicians state that consideration should be given to performing computerized tomography scans prior to initiation of interferon alfa therapy in patients with malignancies that have a high incidence of brain metastasis;376 if brain metastases are detected, the drug should be used with caution and high doses probably should be avoided.376 In addition, all patients receiving interferon alfa should be monitored periodically for the possible development of drug-related neuropsychiatric effects;480,1533 efforts at early detection and intervention are important, since a possible association to interferon alfa therapy may be overlooked by the patient until their life has been severely affected.479,482,1533 (See Cautions: Nervous System Effects.) Because partners or family members may be the first to observe such changes, they should be advised that the drug can induce changes in mood and personality that potentially can affect interpersonal relationships.479,482,1533 Patients should be warned that interferon alfa may impair their ability to perform hazardous activities requiring mental alertness (e.g., operating machinery, driving a motor vehicle), especially at high doses,2,1533 and that CNS depressants (e.g., opiates, sedatives) should be used concomitantly with caution.2 In addition, because the drug can cause mental clouding and impair concentration ability, especially at high doses, patients whose job or life-style requires unimpaired intellectual function should be advised that their mental abilities may be impaired during interferon alfa therapy.1533
Baseline ophthalmologic examinations should be performed in all patients prior to initiation of interferon alfa therapy.2 Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive ophthalmologic examinations periodically during therapy.2 A prompt and complete ophthalmologic examination should be performed in any patient who develops ocular symptoms;2 the drug should be discontinued in patients who develop new or worsening ophthalmologic disorders .2
Serum TSH concentrations should be determined prior to initiation of interferon alfa therapy since thyroid dysfunction (hypothyroidism2,376,507,508,510,1361,1533,1565 or hyperthyroidism)2,376,507,509,510,1361,1362,1533,1565 has been reported occasionally in patients receiving interferon alfa. Patients with preexisting thyroid dysfunction whose serum thyrotropin concentrations cannot be maintained in the normal range with antithyroid therapy or hormone replacement therapy should not receive interferon alfa therapy.2 In addition, if manifestations of possible thyroid dysfunction develop in a patient receiving interferon alfa, the patient's thyroid function should be evaluated and appropriate therapy instituted if needed.2 (See Cautions: Endocrine and Metabolic Effects.)
Patients with preexisting diabetes mellitus and those who develop diabetes mellitus during interferon alfa therapy may continue to receive interferon alfa as long as their diabetes can be controlled with drug therapy.2 Patients with diabetes that cannot be controlled with drug therapy should discontinue interferon alfa therapy.2
The possibility that interferon alfa may precipitate or exacerbate manifestations of autoimmune disorders (e.g., arthropathies, systemic lupus erythematosus, psoriasis, hemolytic anemia, thrombocytopenia, hepatitis, sarcoidosis) should be considered in patients receiving the drug.376,498,499,501,512,516,517,518,519,520,1360,1361,1362,1565 (See Cautions: Hepatic Effects.) In addition, since potentially fatal autoimmune diseases have occurred in patients receiving interferon alfa (see Cautions: Sensitivity Reactions and Autoimmune Disorders), patients who develop an autoimmune disease while receiving interferon alfa therapy should be monitored closely and the drug discontinued if necessary.2
Interferon alfa should be used with caution in patients with myelosuppression and in those receiving drugs that may be myelosuppressive.2,211,431 Complete blood cell counts, platelet counts, and appropriate blood chemistry tests should be performed before initiating interferon alfa therapy and periodically thereafter.2 In patients with melanoma, differential leukocyte counts should be monitored weekly during the induction phase and monthly during the maintenance phase of interferon alfa therapy.2 Interferon alfa should be used with caution in patients with coagulation disorders2,211,431 (e.g., thrombophlebitis,2,431 pulmonary embolism,2,431 hemophilia),431 preexisting leukopenia,376 or increased risk of infection.376
Because substantial increases in serum triglyceride concentrations have been reported with interferon alfa therapy,1633,1634 some clinicians suggest that serum triglyceride concentrations be monitored during interferon alfa therapy.1633,1634 (See Cautions: Endocrine and Metabolic Effects.) Since hypertriglyceridemia may result in pancreatitis, discontinuance of interferon alfa therapy should be considered in patients with persistently elevated triglycerides (e.g., serum triglyceride concentration exceeding 1000 mg/dL) associated with symptoms of potential pancreatitis (e.g., abdominal pain, nausea, vomiting).2
Pancreatitis, sometimes fatal, has occurred in patients receiving interferon.2 Interferon alfa should be suspended in patients with signs and symptoms of pancreatitis (e.g., abdominal pain, nausea, vomiting); the drug should be discontinued if a diagnosis of pancreatitis is established.2
Pediatric Precautions
Safety and efficacy of interferon alfa-2b have not been established in pediatric patients for any indications other than treatment of chronic hepatitis B virus (HBV) and chronic HCV infection.2 (See Interferon Alfa 8:18.20.)
In general, adverse effects (e.g., fever, chills, GI effects, nervous system effects, hematologic effects, hepatic effects, local effects at the injection site) observed in adolescents and younger children appear to be dose related, generally reversible, and similar to those observed in adults,162,366,369,372,484,894,924,1069,1139,1140 although children may be more likely than adults to develop alopecia or thinning of the hair during prolonged therapy.1533 In addition, delay in weight and height increases compared with baseline have been reported in pediatric patients receiving interferon alfa for the treatment of chronic HBV or HCV infection.2,12,52
Geriatric Precautions
Clinical studies of interferon alfa have not included sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.2 In studies evaluating use of interferon alfa in conjunction with oral ribavirin, geriatric patients had a higher frequency of anemia (67%) than younger patients (28%).2 There also is some evidence that adverse cardiovascular effects and confusion are reported more frequently in geriatric patients than in younger adults.2,260,300,374,461,465,470,475 Alterations in mental status associated with interferon alfa therapy can be severe in geriatric patients;376,408 mental obtundation and coma have been reported.2,376,408 (See Cautions: Cardiovascular Effects and Cautions: Nervous System Effects.)
Interferon alfa should be used with caution in geriatric patients because of age-related decreases in hepatic, renal, bone marrow, and/or cardiac function and concomitant disease and drug therapy.2 Dosage reduction or interruption of interferon alfa therapy and/or initiation of appropriate supportive measures may be necessary.2,260,300,376
Mutagenicity and Carcinogenicity
Studies using interferon alfa-2b (Intron® A) have not shown evidence of mutagenicity.2 Studies to determine the carcinogenic potential of interferon alfa-2b have not been performed to date.2
Pregnancy, Fertility, and Lactation
Pregnancy
Interferon alfa should be used during pregnancy only when potential benefits justify possible risks to the fetus.2 Women of childbearing potential should use an effective method of contraception during therapy with the drug.2
Although there are no adequate and controlled studies to date in humans, interferon alfa-2b has exhibited abortifacient activity in rhesus monkeys when given in dosages of 15 and 30 million units/kg daily (estimated human equivalent of 5 and 10 million units/kg, respectively, based on body surface area adjusted for a 60-kg adult).2
Fertility
Interferon alfa may impair fertility.2 Menstrual cycle abnormalities have been observed in nonhuman primates2 and menstrual cycle irregularities and decreased serum estrogen and progesterone concentrations have been reported in humans receiving interferon alfa.2,431,457 Impaired spermatogenesis495 and transient impotence2 have been reported occasionally. Interferon alfa-2b should be used with caution in fertile males.2
Lactation
It is not known whether interferon alfa is distributed into milk,2 but murine interferons distribute into milk in mice.2,431,975 Because of the potential for serious adverse effects to interferon alfa in nursing infants if the drug were distributed into milk, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.2
Drug Interactions ⬆ ⬇
Antineoplastic Agents
Interferon alfa should be used with caution in patients receiving drugs that are potentially myelosuppressive.2,149,211,265,398,431
The antineoplastic activity of interferon alfa and certain cytotoxic agents (e.g., cisplatin, cyclophosphamide, doxorubicin, eflornithine [difluoromethylornithine, DFMO], fluorouracil, mechlorethamine, melphalan, methotrexate, mitomycin, nitrosoureas, vinblastine, vincristine) may be additive or synergistic in vitro and in vivo against some tumors.339,996,1042,1143,1159,1434,1435,1436,1437,1438,1439,1440 However, animal and in vitro studies may not accurately predict human response, and results of preliminary clinical studies using various combinations of interferon alfa and conventional antineoplastic agents generally have been disappointing.1042 The mechanism(s) of potential synergistic activity has not been fully elucidated,1042,1159 but it appears to be complex.1042 In addition, the resultant activity appears to depend not only on the specific cytotoxic drug that is combined with interferon alfa, but also on the concentrations, relative amounts, and duration and sequence of exposure of the drugs.1042 Further studies are needed to determine the potential interactions between interferon alfa and antineoplastic agents, and to establish the optimum regimens, including dosages and sequencing.235,1042,1104,1126,1159,1174,1176,1420,1423,1441,1442,1448,1449,1450
There is some evidence to suggest that combined therapy with interferon alfa and vinblastine156,207,385,386,394 or etoposide156,197,385,386,392 may produce greater systemic toxicity without enhanced therapeutic benefits in patients with AIDS-related Kaposi's sarcoma.156,207,385,386,392,394,395 (See the discussions on Vinca Alkaloids and on Etoposide that follow.)
Interferon alfa combined with carmustine1042,1434,1435 or eflornithine339,996,1042,1436,1437,1438,1439,1440 has produced additive or synergistic antineoplastic activity in vitro and in animal models. While the clinical importance of these experimental data remains to be determined, limited evidence from clinical trials suggests that combined therapy with interferon alfa and carmustine,1440,1450 dacarbazine,338,1346,1347 or eflornithine235,1441,1442,1448 does not appear to produce unacceptable toxicity but may be beneficial in some advanced cancers. Further long-term, controlled studies are needed to establish the potential therapeutic benefits of these combinations.1347,1441,1442,1448,1449,1450
Vinca Alkaloids
Limited data indicate that the antineoplastic activity of interferon alfa and vinblastine does not appear to be additive against renal cell carcinoma†932,1700,1732,1733 or AIDS-related Kaposi's sarcoma.385 However, vinblastine may potentiate the toxicity of interferon alfa when these drugs are used concomitantly.156,207,227,260,299,331,332,333,336,376,385,386,394,459,931,932,1700,1732 In patients with metastatic renal cell carcinoma, increased incidence and/or severity of hepatic toxicity1700 and hematologic toxicity932,1732 were reported with the addition of vinblastine to interferon alfa. In a limited number of patients with AIDS-related Kaposi's sarcoma,227,931 the incidence of nausea,227,931 vomiting,227,931 thrombocytopenia,227,931 hepatic dysfunction,227,931 and fever227,931 usually was comparable to that observed with interferon alfa alone, but granulocytopenia,227 neurotoxicity,227,931 and malaise227 occurred at a higher incidence and with a greater degree of severity in patients receiving vinblastine concomitantly with interferon alfa; 70% of the patients with AIDS-related Kaposi's sarcoma experienced severe fatigue, chills, and asthenia.227,931
Neurotoxicity (e.g., paresthesia, peripheral neuropathy) in patients receiving interferon alfa usually occurs more frequently in those who have previously received or are concomitantly receiving vinca alkaloids (e.g., vinblastine, vincristine).376,487 The mechanism of this additive neurotoxic effect is not known; however, mild sensorimotor neuropathy was observed in patients who underwent neurologic evaluation.376 Some clinicians suggest that high doses of interferon alfa may produce severe neuronal lesions and neurogenic muscle atrophy.376,485,486,493
Etoposide
Response rates in patients with AIDS-related Kaposi's sarcoma receiving combination chemotherapy with interferon alfa and etoposide suggest that the combination has no synergistic antineoplastic activity against this malignancy, and the incidence of toxicity (e.g., hematologic effects) is higher with the combination than with either drug alone.156,197,385,386,392
Antiviral Agents
Antiretroviral Agents
Concomitant use of interferon alfa and zidovudine can increase the risk of hematologic (e.g., neutropenia,2,149,1051 thrombocytopenia)149 and hepatic toxicity.149 The increased risk of such toxicity may be synergistic,2,149,153,398,1051 although the mechanism of such potential synergy is not known.149,1051 In a study in patients with AIDS-related Kaposi's sarcoma in which tolerance to varying subcutaneous interferon alfa dosages of 5-35 million units daily and oral zidovudine dosages of 50-250 mg every 4 hours daily were evaluated, the incidence of neutropenia, thrombocytopenia, and hepatic toxicity was higher than expected (based on experience with either drug alone)145,148,149,208,957,958,959 in patients receiving a 100- or 250-mg regimen of zidovudine combined with interferon alfa.149 In addition, interferon alfa dosages of 15 units or more daily were not tolerated in any patient receiving the 100- or 250-mg zidovudine regimen.149 Life-threatening toxicity, consisting of acute respiratory decompensation that possibly was caused by intrapulmonary hemorrhage associated with severe thrombocytopenia, developed 5 days after initiation of interferon therapy and resolved in at least one patient within a week after discontinuance of therapy.149,1549
Potentially fatal hepatic decompensation has been reported in HIV-infected patients coinfected with hepatitis C virus (HCV) who received antiretroviral therapy concomitantly with interferon alfa with or without ribavirin.423 Patients receiving zidovudine with interferon alfa with or without ribavirin should be closely monitored for toxicities (e.g., hepatic decompensation, neutropenia, anemia).423 Discontinuance of zidovudine should be considered as medically appropriate.423 Dosage reduction or discontinuance of interferon alfa and/or ribavirin also should be considered if worsening clinical toxicities, including hepatic decompensation (e.g., Child-Pugh score exceeding 6), occur.423
Although no major alterations in the pharmacokinetics of zidovudine or interferon alfa were apparent in HIV-infected patients with Kaposi's sarcoma receiving both drugs,149 a trend for increased area under the plasma concentration-time curve (AUC) and decreased clearance of zidovudine after 3 weeks of administration of interferon alfa was observed in some other patients.398
HCV Antivirals
In vitro, interferon alfa-2b and boceprevir have had additive effects against HCV without evidence of antagonism.185
In vitro, interferon alfa and simeprevir have had synergistic effects against HCV;120 there is no in vitro evidence of antagonism.120,187
There is no in vitro evidence of antagonistic anti-HCV effects between interferon alfa and sofosbuvir or telaprevir.184,188
Telbivudine
Peripheral neuropathy has been reported when alfa interferons were used concomitantly with telbivudine.2 In one study, increased risk and severity of peripheral neuropathy were observed in patients receiving conjugated interferon alfa (peginterferon alfa-2a) concomitantly with telbivudine compared with those receiving telbivudine alone.2 The safety and efficacy of concomitant use of telbivudine with any interferon for treatment of chronic hepatitis B virus (HBV) infection have not been established.2
Biologic Response Modifiers
Aldesleukin
Hypersensitivity reactions, consisting of erythema, pruritus, and hypotension, have been reported in patients receiving combination regimens that included sequential administration of high-dose aldesleukin and antineoplastic agents, specifically, interferon alfa, dacarbazine, cisplatin, and tamoxifen.1747 These hypersensitivity reactions occurred within hours of administration of chemotherapy, and medical intervention was required in some patients.1747
Interferon alfa used in combination with aldesleukin has been associated with the development or exacerbation of autoimmune disease and inflammatory disorders.1747 Exacerbation or presentation of thyroiditis,1747 inflammatory arthritis,1747 oculo-bulbar myasthenia gravis,1747 crescentic IgA glomerulonephritis,1747,1748 Stevens-Johnson syndrome,1747 or bullous pemphigoid1747 has been reported following concurrent use of interferon alfa and aldesleukin. In one patient who developed rapidly progressive renal failure following combination therapy with interferon alfa and aldesleukin for metastatic renal cell carcinoma, renal biopsy revealed crescentic glomerulonephritis.1748
The incidence of myocardial injury, including myocardial infarction,1747 myocarditis,1747 ventricular hypokinesia,1747 and severe rhabdomyolysis,1747 appears to be increased in patients receiving concurrent interferon alfa and aldesleukin.1747
Effects on Hepatic Clearance of Drugs
Interferon alfa has been shown to inhibit the metabolism of theophylline,106,107,108,950 possibly via the hepatic cytochrome P-450 (microsomal) enzyme system.41,104,105,106,164,950,951,952,953,954 (See Pharmacology: Effects on Cytochrome P-450 System.) It is not known whether interferon alfa itself interacts with the cytochrome P-450 enzyme system or the drug exerts this effect through an interaction with the immune system.41,104,164,951 Concomitant use of interferon alfa with theophylline in healthy adults106,107 or in patients with chronic active hepatitis B107,108 has prolonged the terminal elimination half-life and increased areas under the plasma concentration-time curves (AUCs) of theophylline by reducing hepatic clearance of the drug.106,107,108 Concomitant use of interferon alfa and theophylline has resulted in a 100% increase in serum theophylline concentrations.2 It appears that the reduction of hepatic clearance of theophylline was greatest in individuals who were the fast metabolizer phenotype.107
Interferon alfa also may inhibit metabolism of barbiturates.863 Initiation of interferon alfa in a patient stabilized on phenobarbital resulted in increased serum phenobarbital concentrations and manifestations of toxicity (e.g., lethargy, fatigue).863 Although these adverse effects can be induced by interferon alone, associated serum phenobarbital concentrations of 54 mcg/mL suggested that they were manifestations of barbiturate toxicity.863 While the mechanism of this potential interaction was not determined, it was suggested that inhibition of barbiturate metabolism may have resulted from inhibition of the hepatic cytochrome P-450 enzyme system.863
Further studies and experience are needed to establish the clinical importance of this potential drug interaction41,106,164,950,951 and to determine whether interferon alfa interacts with other drugs that are metabolized by the hepatic cytochrome P-450 (microsomal) enzyme system.41,106,107,164,950,951 It has been reported that interferon alfa also inhibits the metabolism of antipyrine.107,108,109
Radiation Therapy
Interferon has been used as an adjunct to radiation therapy in patients with various neoplasms; however, severe toxicity has been reported in some patients receiving such combined therapy.235,522,523,936,937,938,939 Severe oral mucositis, manifested by ulceration, bleeding, soreness, or edema of the lips, tongue, oral mucosa, oropharynx, or esophagus, has been reported in a limited number of patients with AIDS-related Kaposi's sarcoma receiving concomitant administration of interferon alfa and radiation therapy.235,523 Severe mucositis, accompanied by airway obstruction, respiratory distress, life-threatening hemorrhage, or oropharyngeal edema, also has been reported in some patients with chronic myelogenous leukemia receiving interferon alfa and total body irradiation prior to bone marrow transplantation.522 In some patients with small cell lung cancer, interferon alfa appeared to potentiate the effects of radiation therapy; an increased incidence of severe radiation pneumonitis and esophagitis has been observed in these patients.235,939 Interferons may have either radioprotective235,936,940,943,946 or radiosensitizing235,936,941,944,946 properties, depending on the tumor cell type and/or type of interferon;941,944,945 however, some other evidence suggests that the drugs may not affect cellular sensitivity to radiation.942
Patients receiving interferon alfa with radiation therapy should be closely monitored.523 Further studies are needed to evaluate the exact nature of interaction between radiation and interferon alfa therapy and to determine the safety and efficacy of the concomitant administration of these therapies.235,946
Other Information ⬆ ⬇
Acute Toxicity
Studies in mice, rats, and cynomolgus monkeys receiving parenteral recombinant interferon alfa-2b 0.1 or 1 million units daily; 4, 20, or 100 million units/kg daily; and 1.1 million units/kg daily or 0.25, 0.75, or 2.5 million units/kg daily, respectively, for up to 9 days, 3 months, and 1 month, respectively, have revealed no evidence of toxicity.2 However, in cynomolgus monkeys receiving parenteral recombinant interferon alfa-2b 4, 20, or 100 million units/kg daily for 3 months, toxicity was observed at the mid- and high doses and mortality was observed at the high dose.2 Because interferon alfa-induced effects generally are species specific, animal toxicity studies may not be predictive of human response.2
Resistance
Cells that are sensitive to the antiviral and antiproliferative effects of interferon alfa possess specific high-affinity saturable interferon receptor sites on their cell surface;73,78,103,114,118 however, the presence of such receptors is not necessarily a sufficient criterion for ensuring cellular sensitivity to the drug.73,78,87,103,114,116,118,232 Tumor cells may be resistant to the antiproliferative effects of interferon alfa despite the presence of functional, specific high-affinity interferon receptors on their cell surface.73,78,103,114,116,117,118,232 Resistance to the antiproliferative effects of interferon alfa usually occurs at the cellular level;73,116 however, the precise mechanism responsible for resistance to the drugs may differ among cell populations.78,103,117,232
An association has been observed between the presence of neutralizing anti-interferon antibody and clinical resistance to interferon alfa in some patients with hairy cell leukemia, suggesting that resistance to the drug may not always arise at the intracellular level.87 However, a causal relationship between the presence of antibodies and disease progression and/or resistance to interferon alfa therapy was not established,87 and some patients who developed neutralizing antibodies to interferon continued to respond to the drug.87 Therefore, the development of antibodies should not necessarily be interpreted as indicating resistance to the drug.87 For a more complete discussion of anti- interferon antibodies, see Dermatologic, Local, Sensitivity, and Immunologic Reactions: Antibody Formation, in Cautions.
Pharmacology
Mechanism of Action
Interferon alfa exists as at least 23 proteins and, occasionally, glycoproteins that possess complex antiviral, antineoplastic, and immunomodulating activities.8,47,70,255,259,261,456,648,714,717,719,740,906,1211,1240,1241,1426 Interferons, including interferon alfa, are biologic response modifiers.254,255,256,257,258,259,260,261,262,263,1174,1175 Endogenous interferon alpha is produced and secreted in response principally to viral (especially double-stranded RNA viruses) infection mainly by peripheral blood leukocytes (e.g., monocytes; macrophages; non-B, non-T lymphocytes, natural killer [NK] cells) and interferon beta by fibroblasts and epithelial cells,8,73,216,256,262,306,374,1549 although certain other synthetic and biologic substances (e.g., certain bacteria and other microorganisms capable of intracellular growth, endotoxins, surface glycoproteins, lipopolysaccharides, polynucleotides) also can induce their production.5,7,8,9,26,51,71,73,998,1001,1002,1461 In addition, other cells may produce and secrete these interferons.51,53,1461 Interferons are produced endogenously according to information encoded by species of interferon genes, and exert virus-nonspecific antiviral activity, at least in homologous cells, through cellular metabolic processes involving synthesis of RNA and proteins.8,424,425,426,428,429,526,1453,1461
The precise mechanisms of action of interferons have not been fully elucidated but appear to be complex, and the resultant activities appear to be substantially interrelated.256,259,261,262,1174,1175,1176,1461 Unlike classic antiviral and cytotoxic agents,255,259,262,1175 the antiviral and antineoplastic properties of interferons appear to result from a complex cascade of biologic modulation and pharmacologic effects rather than from direct virucidal or cytocidal effects.254,255,256,257,259,260,261,262,263 The drugs affect many cell functions producing restoration, augmentation, and/or modulation of the host's immune system;254,255,256,259,260,261,262,263,1544 direct antiproliferative and antineoplastic activities;254,255,256,259,260,261,262,263 modulation of cell differentiation;254,255,259,260,261,263 and modulation of cellular transcription and translation, 254,255,256,259,261,263 including a reduction in oncogene expression.259,261,263 Some or all of these effects may be interrelated and ultimately responsible for the antiviral and antineoplastic activity of interferons.254,255,256,257,259,260,261,262,263,1174,1175,1176
Interferons must bind to specific cell surface receptors in order to exert biologic and pharmacologic effects (e.g., antiviral activity);2,78,113,114,177,215,236,282,989,1190,1197,1426,1463,1464 such binding appears to involve high-affinity sites.78,282,113,114,236,989,1190,1197,1463,1464 In addition, some evidence suggests that the principal effects of interferons result not from direct intracellular actions but rather from ligand-receptor complexes at the cell surface that can mediate and induce intracellular events.2,55,63,71,78,177,214,533,534,1177 The biologic and pharmacologic effects of interferons are relatively species specific,8,47,73,456,933,949,999,1000,1175,1192,1544 and such specificity may reside at the receptor level.78,215,236,550,551,552,1463 In addition, there is some evidence that while interferon alfa and interferon beta bind to and compete for the same receptors,5,7,51,78,214,257,1189,1198,1464 interferon gamma appears to bind to other receptors5,51,78,214,215,1190,1196,1197,1198,1464 and therefore potentially acts via different cellular pathways;5,47,51,671,1200,1201,1202,1203,1206,1207,1208 synergistic antiviral and antineoplastic activities may result from combined use of interferon gamma with interferon alfa or beta.5,743,1199,1200,1201,1202,1203,1204,1205
The mechanism(s) by which interferons ultimately elicit various intracellular effects has not been fully elucidated,5,63,214,256,259,261,262,1174,1175,1176 but binding at the cell surface appears to induce differential gene transcription and translation of cellular mRNA;5,63,177,214,254,255,256,259,261,263,535,536,537,538,539,541,542,543,544,545,546,553,555,565,569,1464 this selective increase in gene expression results in modulation of RNA and protein synthesis.63 Interferons can either enhance or suppress transcription and translation, with resultant alteration in the synthesis of numerous cellular proteins.63 However, it is not clear whether intact interferon, interferon degradation products, interferon receptors, or receptor-ligand complexes must be incorporated within the cell to elicit cellular responses, or whether interferon-receptor complexes at the cell surface are capable of generating intracellular signals that mediate interferon modulation of gene expression.55,78,177,1177,1178,1179,1180,1185,1193 Likewise, the importance of a second messenger177 or other mediators (e.g., cyclic adenosine monophosphate [cAMP], cyclic guanosine monophosphate [cGMP],78,177,595,597,1182,1183,1184,1194,1242 diacylglycerol,177,1186,1221 prostaglandins)177,594,595,596,1182,1183,1184,1194 in eliciting intracellular effects of interferons has not been determined. While changes in intracellular concentrations of cAMP and cGMP occur soon after interferons bind to cell surface receptors,78,177,595,597,598,1182,1183,1184 the biologic and pharmacologic importance of these changes is uncertain78,597 since the antiviral and antineoplastic effects of interferons do not appear to depend on changes in intracellular concentrations of cyclic nucleotides.177,597 Receptor binding of interferons does not activate a protein kinase with tyrosine phosphorylating activity nor does interferon binding inhibit the epidermal growth factor (EGF)-induced increase in protein kinase activity.78 Inhibition of viral replication is merely one of the multiple biologic effects mediated by interferons that involve selective gene activation and the synthesis of newly induced mRNAs and proteins.70,214 The antiviral and antiproliferative effects of interferons depend both on de novo RNA and protein synthesis;8,177,564,580,581,582 however, there is no convincing evidence to suggest that the clinical antineoplastic effects of interferon are linked to the antiviral properties of the drug in humans.5,70,604,605,1222 The antiviral activity of interferon alfa generally is evident at lower doses than are the antiproliferative effects of the drug.75,604
Antiviral Effects
The antiviral effects of interferons are complex.8,539,586,587,848,849,850,851,852,853,854,906,1461,1463 In addition, the potential therapeutic effect of interferons against viral infections also is complex and appears to depend on the immunomodulating as well as antiviral effects of the drug.5,13,410,862,1403,1461 Interferons generally can prevent but not cure certain viral infections,5,903,919,920,921,1461 although progression of the infection may occur in some cases secondary to adverse immunologic effects of the drugs.269,284,1054,1461 Administration of interferons does not directly improve signs and symptoms of viral infections;13 in fact, endogenous interferons have been implicated as mediating some of the manifestations (e.g., fever, malaise, myalgia) associated with such infections.2,53,254,306,374,376,1461
Interferon alfa exhibits a broad spectrum of antiviral activity against numerous viruses including human immunodeficiency virus (HIV),149,411,821,845,877,891,896,897,898,960,961,962,1051 human papillomaviruses (HPV),13,81,160,161,163,167,168,231,244,245,259,366,367,368,372,922,923,1400 hepatitis B virus (HBV),267,268,269,270,271,272,273,274,275,281,284,285,289,295,296,297,1054,1087,1400 hepatitis C virus (HCV),272,273,276,277,293,294,1081,1082 hepatitis D virus (HDV),272,915,916,1054,1085,1089 herpes simplex virus (HSV) types 1 and 2,743,1397,1398,1399,1400,1401,1426,1427,1428,1429 cytomegalovirus (CMV),410,1400,1403,1405 varicella-zoster virus (VZV),5,13,256,892,893,894,895,1400 poliovirus,899,903,904 vaccinia virus,177,906,908,909,910,911 rhinoviruses,912,914,1400,1406,1407,1408,1410,1414 coronaviruses,695,1412,1414 adenoviruses,1400 encephalomyocarditis virus (a cardiovirus),899,900,901,902 and vesicular stomatitis virus (a vesiculovirus).177,899,905,906,907,911 The antiviral activity of interferons against a given virus appears to depend in part on the host cell and the ability of the interferon to induce an antiviral mechanism within that cell,177,850,906,911,927,928,929,1473 the inoculum size,926 and the interferon type and subtype employed.177,552,861,925,1424
Interferons exhibit virus-nonspecific antiviral activity through cellular metabolic processes involving synthesis of RNA and proteins.8,424,425,426,429,564,1426 Interferon-induced inhibition of viral replication appears to involve several mechanisms,8,177,584,585,587,1426,1482 and different mechanisms may apply to various types of viruses.8,177,539,586,587,848,849,850,851,852,853,854,855,856,960,961,962,1051,1426,1482 The degree of viral inhibition may be determined in part by the replicative characteristics of the virus as well as the dose of interferon.177 Inhibition of viral replication involves several processes, and the replicative properties of the individual virus and the host cell-virus interaction may determine which steps of viral proliferation are affected by interferons.177,539,564,587,848,849,850,906,1426 For most viruses, however, inhibition of viral protein synthesis appears to be the principal process involved.564,906,1426,1464
The antiviral properties of interferons generally are only evident when cells are exposed to the drugs before viral exposure.5,903,919,920,921 Although interferons may inhibit viral penetration,906,1426,1480 the drugs generally do not prevent the virion or viral nucleic acid from entering the cell5,564,599,600 and do not directly produce cellular resistance to viral infection,5,8,599,600,1482,1483 but rather mediate transcription of mRNA with resultant formation of potent antiviral proteins;8,177,215,564,580,581,582,1426,1463 such changes in gene expression occur rapidly (e.g., within several hours) after exposure to the drugs.177,286,1187,1188,1191,1482 These proteins can inhibit viral replication by inhibiting viral protein synthesis or enhancing the degradation of viral nucleic acid.13,215,1426,1463,1482 Interferon-mediated inhibition of mRNA methylation852,853,854,855,906,1426 and the drug's effects on viral uncoating,906,1426,1471 assembly, and release906,960,961,962,1051,1481 also may contribute to the antiviral activity.
The antiviral activity of interferons appears to depend in part on two enzymes, a 2'-5'-oligoadenylate synthetase (polymerase) and a protein kinase; synthesis of these enzymes is induced when cells are exposed to the drugs.76,541,553,599,1266 The activity of these enzyme systems depends on the presence of double-stranded RNA (dsRNA) formed during viral replication,7,177,537,542,546,553,558,564 and it has been suggested that interferons may have an effect on dsRNA that contributes to their antiviral activity.177 Interferon-induced degradation of mRNA and resultant inhibition of protein synthesis, inactivation of transfer RNA (tRNA), and inhibition of post-transcriptional modifications of mRNA are mediated principally by the actions of 2'-5'-oligoadenylate synthetase, protein kinase, and a 2'-phosphodiesterase.8,536,583,1426,1463
Interferons induce an endonuclease system that can cleave single-stranded RNA regions of the RNA-replicative intermediate of RNA viruses5,7,177,214,553,554,555,568,569,570 and host-cell single-stranded RNA.5,7,177,214,553,554,555,568,569,570 Induction of 2'-5'-oligoadenylate synthetase, a nucleotide polymerase and the first enzyme in this system, by interferons converts ATP to several 2'-5'-linked oligonucleotides (polyadenylic acids).5,7,8,53,177,553,568 In the presence of dsRNA, certain 2'-5'-linked oligonucleotides can activate a latent ribonuclease (endoribonuclease RNase L, RNase F)5,7,8,214,553,554,555,556,557,559,561,565,566,569,570 that cleaves the replicative intermediate of RNA viruses5,177,214,553,554,555,568,569,570 and host single-stranded RNA.214,553,177,554,555,568,569,570 The oligonucleotides (polyadenylic acids) also are potent inhibitors of mRNA-dependent protein synthesis and can enhance the degradation of mRNA.8,553,556,557,561,565,566 Activation of the ribonuclease by the oligonucleotides is reversible.7,177,561,564 While these effects appear to be involved in the antiviral activity of interferons against RNA viruses,177 it remains to be elucidated whether the action of interferons on these enzymes also is involved in antiviral activity against DNA viruses.5
The presence of the 2'-5'-phosphodiester linkage in these oligoadenylates makes them resistant to most cellular nucleases;177 however, a 2'-5'-phosphodiesterase that can degrade the oligonucleotides has been detected in murine177,565,571 and human cells.177,572 This enzyme, which has greater affinity for 2'-5'- phosphodiester bonds than for 3'-5' bonds present in DNA and RNA, can rapidly hydrolyze the oligoadenylates to ATP and AMP,8,177,554,1264 can reportedly cleave the cytosine-cytosine-adenine (CCA) terminus from tRNA,8,571,1264 and may be responsible for the reversible tRNA inhibition of translation in interferon-treated cells.8,177,555,571,1264
In addition to effects of the drugs on gene transcription, interferons reportedly decrease the extent of methylation of cap structures on mRNA transcripts.177,1426 5'-Terminal cap structures are present on most eukaryotic cellular and viral mRNA,177 and the extent of methylation on the cap may influence its stability and the efficacy of translation of proteins, including viral proteins.177,575,1484
Interferons also induce the synthesis of a protein kinase,5,7,8,51,55,177,255,261,374,535,536,537,538,539,542,543,544,545,546 which, when activated by dsRNA in the presence of ATP,537,542,543,544,545,546 phosphorylates and inactivates one of the proteins (eIF-2) necessary for initiation of elongation (protein synthesis),5,7,8,53,177,535,539,540,541,546 a ribosome-associated protein P-1,53,76,177,541,1426 and possibly the enzyme itself.8,542 The inactive eIF-2 cannot participate in the initial stage of protein synthesis.53,547,1195 The resultant inhibition of protein synthesis can prevent the formation of the viral coat protein and thereby inhibit the formation of viral progeny.5,564 While the protein kinase also is capable of phosphorylating other substrates, such as histones, in interferon-treated cells,177,537 it is not known whether such substrates are physiologic substrates for the enzyme.177 The action of the protein kinase can be antagonized by the presence of a phosphoprotein phosphatase that dephosphorylates the phosphorylated P-1 and the eIF-2.177,1464
Although the precise role of protein kinase in the antiviral activity of interferons remains to be more fully elucidated,1464 the increase in protein kinase activity induced by interferons correlates well with the establishment of antiviral activity, at least in some virus cell systems, and is a function of the duration of drug exposure and the concentration of interferon.8,76,547,548,549,1464 In murine cells, for example, the rate and extent of antiviral activity induced by the drugs have been shown to be correlated with their ability to induce the P-1/eIF-2 protein kinase,76,549,1464 suggesting that induction of the enzyme and phosphorylation of eIF-2 may contribute substantially to the antiviral effects of interferons, at least in this cell line.76 Likewise, declines in antiviral and protein kinase activities have been shown to be correlated, and such activities can be reinduced with subsequent reexposure to interferons.76 Continuous exposure to interferons prevents the decline in protein kinase activity and prolongs the antiviral activity induced by the drugs.76 In other virus-cell systems, however, other mechanisms may be principally responsible for the antiviral activity of interferons.8,177,584,585,586,587,848,849,850,851,852,853,854,1464
The extent to which the oligoadenylate synthetase and protein kinase systems contribute to the antiviral activity of interferons remains to be more fully elucidated, but other mechanisms also appear to be involved.8,177,584,585,587,1464 Viral replication probably can be inhibited at more than one stage of the viral replicative cycle presumably secondary to different mediators of interferon actions, and not all pathways may be functioning in a given interferon-exposed cell.177,539,850,855,856,960,961,962,1051,1464,1481 Thus, even within the same cell line, interferons may inhibit the replication of certain viruses but not others.8,177,539,586,587,848,849,850,851,852,853,854,855,856,1424
The biochemical basis for the selectivity of interferons against virus-infected rather than uninfected host cells has not been established.177,214,536,539,543,564,570,573,574,579,603 The oligoadenylate synthetase system cannot adequately explain the selectivity of the drugs for viral replication since endoribonuclease RNase L cleaves viral and host mRNA nonselectively in vitro;8,536,588 in some in vivo systems, however, viral protein synthesis is inhibited preferentially with respect to host protein synthesis.177,539,564,573,603 It has been suggested that the dsRNA-induced RNase system works at a subcellular level,177 and that the close proximity of ribosomes, ribosomal RNA, ds-RNA, 2'-5'-oligonucleotide synthetase, polyadenylate, and 2'-phosphodiesterase to each other may contribute to interferon selectivity for virally infected cells.5,177,214,536,543,570,579 The protein kinase-mediated inhibition of protein synthesis that inhibits binding of tRNA to the ribosome may discriminate between cellular and viral RNA, and may exhibit some selectivity for viral nucleic acid.53,177,576
Interferons also may inhibit viral replication by augmenting the response of immune effector cells involved in the recognition and killing of virally infected cells.5,13,862,1482 However, interferon-induced inhibition of viral replication does not eliminate the infection; instead, the antiviral effect of the drugs minimizes the viral burden to the host's immune system.13,630,1482,1483 Thus, the antiviral efficacy of interferons depends on the host's immunologic status.410,1403
For information on antiviral uses of interferon alfa, see Interferon Alfa 8:18.20.
Antiproliferative Effects
Interferons exhibit antiproliferative (growth inhibitory) activity against normal and malignant cells with resultant antineoplastic effects in vitro and in vivo,54,70,71,215,216,255,605,606,611,620,621,629,633,845,875,944,996,1243 and can alter both the structure8,70,610,747,774,1214,1216,1217 and behavior62,70,198,216,264,615,1218,1219,1220 of these cells. In addition, the drugs can inhibit the growth of primary tumors as well as metastatic foci.70,872,873,1211,1241 The mechanism(s) of this antiproliferative activity has not been fully elucidated but appears to be complex.51,62,63,65,75,198,254,255,256,260,261,262,263,286,615,617,647,648,649,650,651,857,1219,1220,1241,1243 The ability of interferons to inhibit or enhance the synthesis of specific proteins, to modify expression of cell surface antigens, and/or to induce modulation of the immune system may be involved.70,606 Although some evidence suggests that the antiviral and antiproliferative activities of interferons may share some common biochemical and physiologic pathways,51,214,539,566,587,589,831,832,833,834,835,836,837,838,839,841 the possible roles of the 2'-5'-oligoadenylate synthetase51,53,255,374,537,538,545,546,547,825,826,841,865 and protein kinase587,840,842 systems (see Mechanism of Action: Antiviral Effects, in Pharmacology) in mediating the antiproliferative effects of interferons have not been clearly established. It has been suggested that the oligoadenylate synthetase system may be involved in the regulation of cellular proliferation214,630,1336,1469 and may contribute to the antiproliferative effects of interferons, since levels of this enzyme decrease substantially in rapidly proliferating cells51,214,841,825 and increase when cell growth is inhibited.832,836,837,838 Other evidence also indicates that the oligoadenylate synthetase system may contribute to the antiproliferative effects of interferon.539,566,587,589,831,833,834,835,839,841 However, there also is evidence to suggest that no correlation exists between the antiproliferative activity of interferons and induction of these enzyme systems by the drugs,587,829,830,842,844,845,846,865,1209,1243 and, in some studies, the relative antiproliferative activity of various interferons actually was the reverse of the relative antiviral activity.633,1122
The antineoplastic activity of interferons may result from a direct antiproliferative effect on the tumor cell and/or the ability of the drugs to induce a host response to the tumor.70,606,616,618,619,693,1241,1243 However, the drugs generally do not appear to be directly cytocidal to tumor cells;70,259,261,612,613,614,630,1224 instead, the cytostatic effects of interferons may decrease the rate of cell proliferation to a level incompatible with cell survival.70,261,611,612,613,630 Interferons also may alter the host-tumor relationship by affecting host humoral factors (e.g., growth factors)51,263,286,1241,1243,1244 or by modulating the response of immune effector cells (e.g., natural killer [NK] cells, T and B cells).8,66,70,261,637,701,732,736,750,768,778,779,799,800 However, evidence from studies in immunocompromised mice suggests that inhibition of tumor growth by interferons can occur independently of certain cellular immunologic mechanisms of the host.255,622,704,705 The ability of the drugs to modify cell surface morphology and function may result in altered transport of substances necessary for cell survival and thus contribute to their antiproliferative activity.8,70,612,614,1171,1172,1173 The biologic effects of interferons on the host also may contribute to their antineoplastic properties70,606,616,618,619,640 since interferon-induced inhibition of tumor growth has been observed with some malignant cell lines despite resistance of the cells to the antiproliferative properties of the drugs.70,606,616,618,619,640 In addition, interferons have exhibited antineoplastic activity against tumors that lacked receptors for the drug, suggesting that an indirect effect may have been responsible for the observed activity against some cells.216,627
Inhibition of Cell Division
Interferon-induced prolongation of the cell cycle appears to be principally responsible for the antiproliferative effects of the drugs.51,53,70,71,215,216,255,261,621,579,583,237,605,606,625,626,627,628,629,631,632,633,634 Interferons inhibit or reduce the synthesis of RNA and protein during the G1 (first “gap,” post-mitotic, or presynthesis) phase of the cell cycle that is required for cells to enter the S (DNA synthetic) phase of the cell cycle.53,261,579,631 Interferons also inhibit ornithine decarboxylase, the rate-limiting enzyme in the synthesis of polyamines, which are necessary for the assembly of DNA.631,1234 Interferons prolong all phases of the cell cycle,51,53,54,70,255,261,583,627,628,629,632,633,634,1162 induce cells to enter the nonproliferative G0 (resting) phase,53,216,261,483,579 and delay cells at the G0/G1 border from entering the cell cycle;51,54,237,255,261,605,623,624,625,626,633,635,636,1160,1163,1164 the antiproliferative effects of the drugs may be more pronounced in this latter subpopulation of cells.51,255,623,624,1161,1163 These antiproliferative effects are dose dependent215,255 and reversible,215,216,237,255,606 with normal growth rate being restored within 24-72 hours after removal from exposure to the drug.215,255,606,643 Continued treatment with interferons in vitro and in vivo results in a more prolonged inhibition of cell proliferation.255,622,643 The antiproliferative effects of interferons on normal hematopoietic stem and progenitor cells may be responsible for the reversible myelosuppression that may occur secondary to therapy with the drugs.255,620
The cytostatic property of interferons is not differentially selective for transformed or malignant cell populations, and thus can affect normal cells.54,61,70,71,215,216,255,606,611,620,621,633,635,636,637,638,640,641,642,643,644,1160,1161,1162 Optimum antiproliferative activity generally is attained when interferons are administered repeatedly and are in direct contact with the cells or tumor.70,255,622,1211 Human cell lines reported to be sensitive to the drugs include a lymphoblastoid cell line,61,606,633,638,1222 osteosarcoma,61,638,639,1088,1465 myeloid leukemia,1222 colon carcinoma,1224 , hepatoma,1222 neuroblastoma,1222 and normal, hyperplastic, and malignant breast tissue.1162 Interferon alfa also inhibits colony formation of transplantable murine tumors640,642 and fresh biopsies of human tumors61,644 including melanoma, lung cancer, myeloma, ovarian carcinoma,61,644 sarcoma, adenocarcinoma of unknown primary origin, acute leukemia, and renal cell carcinoma.61
Effect on Cell Phenotype and Oncogene Expression
Interferons can decrease the transcription and expression of several oncogenes (e.g., c- myc , c- mos, c- abl, c-Ha- ras, c- sis, c- src )51,62,65,75,198,214,216,237,239,264,523,655,1218 and in growth factor receptors,51,286 and can inhibit the expression of a protein induced by platelet-derived growth factor (the formation of this factor depends on the c- sis oncogene).656,657,1237 In some transformed cell lines, this decrease in transcription and expression of the oncogene product has been correlated with inhibition of tumor cell proliferation.62,65,75,198,216,237,626 Long-term exposure of some transformed cell lines to interferons can lead to a reversion of the cells to a more normal phenotype, characterized by more normal growth characteristics and cellular morphology.62,198,216,255,261,264,615,1218,1219,1220 This phenotypic reversion has been associated with a specific decrease in oncogene expression51,75,237,239,523,655,1219 and loss of tumorigenicity and oncogenic potential of the cells.62,70,237,264,615,658,1220 The interferon-induced reduction in c-Ha- ras and c- myc RNA appears to be selective for the oncogene transcripts;62,65 however, despite this selective decrease in the levels of the oncogene mRNA and the expression of their gene products, interferons do not alter the quantity or distribution of the transfected DNA present in the cell.62,198,1219 Interferons principally may act at the level of gene transcription and subsequent mRNA translation;62,198,1218,1219 however, some evidence suggests that this effect on oncogene expression may be mediated in part by interferon-induced decreases in the number of copies of viral genome.422
It has been suggested that expression of the c- myc gene plays a major role in the malignant transformation of some cells.65 Therefore, although a causal relationship between modulation of oncogene expression by interferons and growth inhibition has not been established, it has been proposed that the decrease in expression of this and other oncogenes by the drugs may contribute to their antiproliferative activity.65 Interferon-mediated decreases in the expression of c- myc gene in a Burkitt's lymphoma cell line has been proposed as a model for interferon-induced cellular differentiation.53,198 Decreased c- myc oncogene expression occurs relatively early during interferon exposure and does not appear to be mediated by the accumulation of cells at the0/G1 border of the cell cycle.198,829,1268 Interferons disrupt DNA replication in these cells in several ways, including inhibiting the synthesis of Okazaki fragments (short segments of base pairs that are formed and subsequently joined during DNA replication) and decreasing the stability of these newly synthesized replicons.198,1267 A cell line resistant to the antiproliferative effects of an interferon does not exhibit this drug-induced decrease in oncogene expression.214,655 Similar observations regarding changes in the expression of c- myc , c- mos , and c- ras genes generally have been noted in patients with hairy cell leukemia who have received interferon alfa therapy,239 and the gradual reduction in the percentage of cells in bone marrow expressing the Philadelphia chromosome associated with interferon alfa therapy in patients with chronic myelogenous leukemia also may reflect the tendency of the leukemic cells to progress from a malignant phenotype and genotype toward a more normal nonmalignant state.301,307,309,312,1225,1549
Limited evidence suggests that oncogenes present in transformed cell lines may modulate cellular sensitivity to different types of interferons,212 resulting in some cell types that are resistant to the effects of one interferon type (e.g., gamma) while sensitive to another interferon type (e.g., alfa).212 Interferons can inhibit the growth of numerous cell lines, without altering the level of the c- myc mRNA transcript or distribution of cells in the cell cycle,198 and can block the platelet-derived growth factor (PGDF)-induced stimulation of cell proliferation without affecting the increased expression of c- myc that precedes this stimulation.198,1238 However, other evidence indicates that the importance of modulation of oncogene expression and alterations in phenotypic expression and differentiation of malignant cells in the antineoplastic activity of interferons remains to be established.198,261,655,1237,1238,1239
Effect on Cell Differentiation
Interferons generally enhance cellular differentiation,8,51,53,69,198,215,237,255,286,647,648,649,650,651,652,653,654 but can inhibit the functional and morphologic differentiation of some cells (e.g., fibroblasts).652,653 Interferons can alter the phenotypic expression of pre-natural killer (NK) cells8,1166 and lymphocytes (e.g., T cells)8,1165,1226 and can augment the expression of Fc receptors on the cell surface of immune effector cells that require these receptors for immunologic reactivity.8,774,775 These changes in phenotypic expression, interferon-mediated increases in phagocytosis by macrophages8,760,1227 or monocytes,8,720 augmentation of antibody-dependent cell-mediated cytotoxicity by killer (K) cells,8,716 and enhancement of histamine release by basophils8,738 presumably are related to the ability of interferons to modulate cellular differentiation.8,51,53,69,198,215,237,255,286,647,648,649,650,651,652,653,654 Interferons also can enhance69 or inhibit256,259,1269 the maturation of normal monocyte and macrophage precursors, activate monocytes and macrophages,69,645,646 and enhance the differentiation of a human leukemic cell line to macrophages69 and/or granulocytes.69,237 Evidence from studies in which interferons stimulated their own immunologic neutralization by augmenting the expression of certain cell surface antigens also indicates that the drugs enhance cell differentiation.8,51,215,237,647,648,649,650,651,747,748,749
Other Antiproliferative Mechanisms
There is limited evidence that some of the biologic and pharmacologic effects, including antiproliferative effects, of interferons may be mediated in part by prostaglandins.8,70,659,660,691,692 Prostaglandins can modulate cell proliferation and function as immunomodulators,8,691,692 and interferons have been shown to stimulate prostaglandin biosynthesis.8,70,659,660 In addition, the absence of cyclooxygenase in some cells may explain the resistance of these cells to the antiviral and antiproliferative effects of interferons.689 However, prostaglandins also produce effects on the immune system that can oppose those induced by interferons.8,662,663,689,691,692 In addition, cyclooxygenase inhibitors and exogenous prostaglandins have complex effects on the biologic activity of interferons,681,683,684,686,689,1194,1236 and interferons do not appear to affect phospholipase or cyclooxygenase activities.661,683,684,686,689 Further study is needed to establish the role, if any, of the cyclooxygenase system and prostaglandins in the biologic effects mediated by interferons.8,70,659,660,661,662,663,683,684,686,687,688,689
It also has been suggested that the biologic and pharmacologic effects of interferons may be related partly to their ability to alter intracellular concentrations of cyclic nucleotides (e.g., cAMP, cGMP).8,612,665,667,674,676 Cells exposed to cyclic nucleotide derivatives or agents that increase the intracellular concentration of cyclic nucleotides exhibit increased sensitivity to the antiviral and antiproliferative properties of interferons.8,664,665 Interferon-induced elevations in the concentration of cAMP and cGMP occur prior to or concomitantly with the development of the antiproliferative and antiviral effects of the drugs8,665,666,667,668 and do not occur in cells resistant to the effects of interferons.8,666,667 However, such increases in cAMP and cGMP apparently are not essential to the antiviral and antiproliferative actions of interferons,70,612,666,674,677 since blocking these increases does not reduce the activity of the drugs.674,677 In addition, because of the complex role of cyclic nucleotides in the regulation of cell proliferation,674,675,678,679,680,681,682,1242 it remains to be determined whether these second messengers have an established role in mediating these effects of interferons.8,70,612,664,665,666,667,668,674,677
Effects on Cell Plasma Membrane
Agents (e.g., amphotericin B, colchicine, vinblastine) that alter plasma membrane and cytoskeletal components can inhibit the antiviral effects of interferons,8,669,670,671 whereas agents (e.g., sodium butyrate) that increase synthesis of microfilaments and the number of cellular desmosomes may enhance the action of interferons.8,1228,1229 Interferons can alter the cell surface expression of gangliosides and other membrane components8,1217 and can decrease the unsaturated fatty acid content of major phospholipids,8,1216,1236 which may lead to a more rigid lipid bilayer in the plasma membrane8,1232,1233 and a decrease in cell motility.8,1210,1231 The overall cellular net charge becomes more negative,630,1230 as does the intramembranous charge.8,1217
Interferons can alter the ion flux across plasma membranes8,630,1217 and can increase neuronal excitability,8,1235 decrease the release of plasminogen activator from the plasma membrane,8,1234 increase the size and number of actin filaments,8 alter the cell surface distribution of fibronectin, and increase cell volume and surface area.8,1231 These changes in cell size and degree of arrangement, polymerization, and amount of actin generally correlate with a decrease in the rate of cell proliferation.8
Interferons also can alter nucleoside transport8,614,1171,1172,1173 and cell surface antigen and immunoglobulin expression and can produce a relative increase in histocompatibility antigens on lymphocytes.8,610,747,748,749 Expression of membrane receptors for Fc fragments of IgG and IgM can be increased and decreased, respectively, by interferons alfa or beta.8,256,630,774,1214,1240
Immune System Effects
Interferons are cytokines that exhibit complex and variable immunologic activity,693 including both immunomodulating and immunosuppressive effects.693 The immunomodulating activity of interferons may have important effects on the immunologic relationship between tumors and the host.8,64,70,237,255,286,697,698 However, despite the wide range of regulatory actions of interferons on the immune system51,63,64,66,237,255,693,694,698 and the possibility that these actions may contribute at least in part to the antineoplastic activity of the drugs,63,261,286,618,619,627,640,702 there currently is little direct evidence to support the theory that the antineoplastic activity of interferons depends on their effects on the immune system.63,255,703,704,705 While interferons generally exhibit similar pharmacologic actions, including many actions involving the immune system, differences between interferon types appear to be greatest for immunologic effects, with interferon gamma appearing to be the most distinct, particularly in its macrophage (phagocyte)-activating properties.694,1544
Interferons can influence the proliferation of immune effector cells, such as those that are cytotoxic to tumor cells,8,255,261,714,717,779 and can also modulate antibody production and the release of other lymphokines (e.g., interleukin-2 [IL-2], MIF, LIF), which may be important in the host's immune response to tumors.8,237,255,693,694,698,699,700,701,789,1244 Interferons also may alter host response to tumors and other cells by modulating the expression of cell surface antigens, including major histocompatibility antigens (e.g., interferon alfa increases class I histocompatibility molecules on lymphocytes and interferon gamma increases both class I and II molecules) and tumor-associated antigens, which may alter the immunogenicity of tumor and other cells.8,51,70,237,286,648,693,697,740,750,751,752,754,842,1207 Interferons also can enhance natural killer (NK) cell activity and macrophage activity,8,51,64,66,237,255,286,693,701 although there currently is no direct evidence that such enhancement of the cytotoxicity of immune effector cells is responsible for the therapeutic effects of interferons.63,286,1245,1246,1247 While some evidence also suggests that the effect of interferons on the host immune system may be an important determinant of the antiproliferative activity of the drugs63,216,286,618,619,627,640 and that the antineoplastic activity of interferons may be mediated in part by their effects on the host's immune system,63,261,286,618,619,627,640,702 other evidence suggests that the effects of the drugs on host response may be mediated by nonimmune mechanisms,63,255,622,703,704,705 such as depletion of growth factors286,1241 and inhibition of angiogenesis51,857 and stroma development.63
Interferons, principally interferon gamma but also interferon alfa, can modulate cellular and humoral immune responses51,70,255,261,693,694,698 and can enhance the cytotoxicity of immune effector cells64,66,70,237,255,261,693,698,758,768,778,779,780 and the phagocytic activity of macrophages.70,237,255,261,606,694,757,758 In addition, the secretion of interferons alfa and beta is increased in activated macrophages,694 and mature B cells express receptors for interferons that probably contribute as governing signals to the complex immune responses of these cells.696 Interferon gamma appears to be a particularly important macrophage-activating cytokine (lymphokine);694,1544 this interferon type, but not alfa or beta, exhibits clinically important effects on the production of intracellular, superoxide radicals that are capable of mediating killing activity against certain microorganisms.1544 There also is limited evidence that interferons can stimulate lymphocytic infiltration.70 Although interferons can enhance antibody production, the effect of the drugs on the production of antibody to tumor-associated antigens has not been clearly established.5,8,70,215,606,694,729,731
Interferons also may augment cytotoxicity of cytotoxic T cells (CTL, killer T cells) and lymphokine-activated killer (LAK) cells by potentiating interleukin-2 (IL-2) release.237,255,698,699 While it has been suggested that interferon-mediated stimulation of LAK production may increase the host's response against tumor cells,700,701,1244 some in vitro evidence indicates that interferons can inhibit the proliferation of interleukin-2-stimulated lymphocytes and can inhibit the induction of LAK activity.1252
Effects on Natural Killer Cell and Killer Cell Activity
Interferons, including interferon alfa, augment natural killer (NK) cell activity,693,872,1488 but there reportedly is substantial variation in the ability of the numerous subtypes of interferon alfa to enhance NK-cell activity.64,67,633,824,876 NK cells possess some surface characteristics of both the myeloid and lymphoid lineage,8,1249,1250,1251 and are defined in part by their ability to lyse certain types of tumor cells and normal targets.67 In animal models, NK cells can inhibit the formation of metastatic foci in the host,867,868,869,870,871 and interferons reportedly can augment this antimetastatic effect of these immune effector cells.872 Interferons augment NK-cell cytotoxicity directly and do not require the presence of an accessory cell population.64 In vitro, human NK-cell activity may increase 16-fold in the presence of interferon alfa, although substantial individual variation exists in response to interferon enhancement of NK-cell activity.66,261,701,750,792,796,805,809,810,811,812,813
Interferons enhance NK-cell activity by increasing the proportion of NK cells that become cytotoxic5,799,800 and by decreasing both their cell cycle time and the time required for the cells to lyse their targets.5,799,800 An acceleration in lytic kinetics results,8,67,799,801 and the increased recyclability of NK cells allows the same effector cell to lyse more than one target.5,8,67,799,800 Interferons also can recruit cytotoxic cells from a non-cytotoxic pre-NK cell population5,8,67,261,630,799,801,815,1258 that is capable of binding but not lysing target cells8,67,799,801 and can enhance NK-cell binding to less sensitive targets.67,879 Limited data suggest that the recruitment of pre-NK cells may be the principal mechanism by which interferons enhance NK-cell activity.630,799 Interferons are only capable of activating pre-NK cells and NK cells when present before these effector cells bind their target cells,5,8,799 and NK cells are activated only while in the presence of interferon.5,799 The drugs can enhance NK-cell activity against fresh or freshly frozen tumor cells of diverse origin;8,781,874,875 however, they consistently have failed to enhance the activity of the same effector cells against autologous tumor cells.8,630,781
Interferons also may have effects on NK-cell activity that could negatively affect host responses.8,67,215,772,817,818,819 For example, interferons are capable of protecting malignant cells from NK cell-mediated lysis.67,722,1253 Interferons also can inhibit the host's immune response by decreasing NK-cell activity67,215,254,259,261,805,810,811,812,813,1254 and by inducing increased resistance to NK cell-mediated lysis.8,67,772,817,818,819 This inhibition of NK cell activity may serve to protect from NK cell-mediated lysis any target cell population that expresses interferon receptors.8,67,818 Some evidence suggests that this protection of target cells from NK cell-mediated lysis may provide a mechanism whereby interferons could activate NK cells to lyse tumor cells preferentially while ensuring that normal cells were protected;8,630,798,817,822 however, other evidence indicates that certain malignant cells that possess interferon receptors also can be protected from NK cell-mediated cytotoxicity by preexposure to an interferon.67,630,818,819,1253 This interferon-induced target cell protection from NK-cell lysis requires de novo RNA and protein synthesis,67,722,818,1253 is specific for NK cell-mediated lysis,67 and is not accompanied by a decrease in antibody-dependent cellular cytotoxicity.67,722,820 It has been suggested that interferon-induced protection from NK cell-mediated cytolysis actually may result in a slight enhancement of immune-mediated target-cell killing secondary to increased expression of histocompatibility antigens67,610,728,822,1253 and a stimulation of the alloimmune response from cytotoxic T cells (CTL, killer T cells).67,818,1253
The dose, schedule, and route of interferon administration can have profound effects on NK-cell activity.53,255,261,794,802,803,804,808 The optimum dose of interferons required for immune stimulation has not been established, but for interferon alfa, some evidence suggests that lower doses achieve higher NK-cell activity when the drug is administered for sustained periods53,794,802,803,804,808 and that NK-cell activity actually is depressed with continued administration of the drug.255,805 Other studies, however, have shown either consistent increases261,792,750,809 or decreases261,805,810,811,812,813 in NK-cell activity, or have shown individual variation and no consistent changes in such activity.261,701,1247 Therefore, it has been suggested that a threshold dose of interferon exists, above which there is a negative influence on NK cells.261 The long-term effects of interferon alfa on NK-cell activity also have varied, with reports of increases261,802,814 or decreases261,810,811 in such activity. In one study, low-dose interferon alfa produced an increase in NK-cell activity within 48 hours, but this increase was not sustained despite repeated administration of the drug.261,814 High-dose interferon alfa gave a more sustained increase of NK-cell activity but did not produce the same initial increase observed with the low dose.261,814 In a study in which interferon alfa was administered on an intermittent schedule, the drug produced a dose-related decrease in NK-cell activity over a 6-week period, following an initial stimulatory effect.261,802 In addition, the route and schedule of administration appear to influence the effect of interferons on NK-cell activity.261,802,814 In general, no clearly defined relationship exists between stimulation of NK-cell activity by interferons and the clinical antineoplastic activity of these drugs.63,1245,1246,1247
Interferons generally enhance antibody-dependent cell-mediated cytotoxicity (ADCC) against a variety of antibody-coated target cells.8,714,715,716,717,718 While the mechanism of this enhancement in ADCC is not known, killer (K) cells, the subpopulation of lymphocytes that mediates ADCC, may be involved8,708,709,710,711,712,713 since these cells have Fc receptors to IgG,709,713,1549 and interferons are known to enhance expression of these receptors.8,630,756,774,1214,1240,1549
Effects on Macrophage and Monocyte Activity
Interferon-induced activation of macrophages and monocytes results in morphologic changes in these cells,8,79,630,756 increased phagocytic activity,8,79,215,606,630,757,758,1259 and nonspecific cytotoxicity against tumor cells and other target cells.64,1255,1256,1257,1258 Interferons enhance the number of phagocytic cells and the degree of phagocytosis of individual cells.79,758 Interferons also enhance Fc receptor-mediated phagocytosis.8,630,759,760 Activated macrophages can recognize cell-surface properties characteristic of transformed cells and can selectively destroy these malignant cells.79,761,762,763,764,765
Interferon-mediated enhancement in macrophage phagocytosis can be neutralized by anti-interferon globulin.79 In addition, such enhancement of macrophage killing of leukemic cells can be suppressed when these effector cells are incubated with PGE1, PGE2, or hydrocortisone after interferon treatment,8,1260,1261,1262,1263 although the prostaglandins have no effect on unstimulated macrophages.8 This effect of prostaglandins may be mediated by increased intracellular concentrations of cAMP.8,1261,1263 (See Other Antiproliferative Mechanisms, under Mechanism of Action: Antiproliferative Effects, in Pharmacology.)
Effects on T Cells
Interferons have varied effects on T cells, a cell population that may influence tumor growth in several ways.8,215,776,778,779,780,1478 T cells may interact directly with tumor cells or indirectly through regulatory influences on other immune effector cell types.8,1478 The effects of the drugs on T cells most likely reflect the diverse functional activities of various T-cell subsets.8 While there is some in vitro and in vivo evidence that the drug either has no effect on or actually decreases (secondary to the drug's antiproliferative activity) CTL-mediated killing,775,776,777,781 other evidence indicates that interferon alfa can enhance killing by CTL cells despite decreases in T-Cell proliferation.630,1489,1490 Therefore, interferon alfa may produce a selective increase in a specific population of cytotoxic T cells.8,768
Interferon alfa also can affect delayed-type hypersensitivity responses, but the nature of the drug's effect depends on the timing of interferon administration.8,215,782,783,784,785,786 Interferon alfa inhibits delayed hypersensitivity reactions when the drug is administered prior to sensitization or secondary challenge with antigen8,782,783,784 but enhances the response when it is administered a few hours after sensitization.8,785,786 Antigen-specific leukocyte-induced inhibition of granulocyte migration and leukocyte migration inhibition reactions resulting from exposure of lymphocytes to phytohemagglutin can be partially or totally suppressed by interferon alfa.8,787,788 Interferons also can modulate lymphokine release from mitogen-stimulated lymphocytes.8,788,789 Relatively low concentrations of interferon alfa reportedly can decrease8,788 or increase8,789 production by mitogen (concanavalin A)-stimulated lymphocytes of the lymphokines—leukocyte inhibitory factor (LIF) and macrophage inhibitory factor (MIF, migration inhibiting factor), while higher concentrations of the drug reportedly inhibit production of these migration inhibitory factors.8,789
Limited data suggest that interferons may augment suppressor T-cell activity.8,768,769,770,771,814 Antigen-specific suppressor T cells may play a particularly crucial role in suppressing the host's immune response to tumors; however, it has not been established how interferons may affect this subset of suppressor T cells.8
Interferon alfa can modulate the expression of cell surface receptors on T cells8,773,774,775 (see Pharmacology: Effect on Cell Surface Antigens) and can increase the expression of IgG Fc receptors.8,774,775 Interferon alfa's effect on CTL-cell activity in mixed lymphocyte culture (MLC) appears to depend on the duration of exposure of the lymphocytes to interferon.8,768,772
Effects on B Cells
Interferons can either enhance or suppress B-cell responses depending on dose and sequence of administration relative to antigenic stimulation.5,8,215,606,630,724,725,726,729,731,858 Low or high doses of interferon alfa followed by antigen stimulation can increase or decrease antibody production, respectively.5,606,729,858 Interferons enhance the B-cell responses when added during late stages (48-72 hours after antigen) of the response,8,630,637,724,727,730 presumably secondary to a modulatory effect on T cells.8,724,730 Exposure to interferon prior to or immediately after exposure to antigen generally suppresses antibody response.18,256,630,637,724,725,726 In animal studies, B-cell antibody production and the proper functioning of memory cells generally was inhibited by interferons when the drugs were given prior to antigen exposure.5,8,732,733,734,735 More generally, in vivo administration of interferons 48-72 hours after antigen results in a twofold to sixfold enhancement of the antibody response.8,732,736
Interferon-induced suppression of antibody responses affects both IgM and IgG antibodies.8,733 Interferon alfa also can modulate IgE production and action,8,737,738,739,1235 and the drug has depressed the ability of spleen cells to elicit an anaphylactic response, probably by inhibiting IgE synthesis or release.8,737 However, exogenous addition of antibody enhances interferon alfa-mediated histamine release from human basophils in vitro8,738 via a mechanism that requires de novo RNA synthesis.8,739
Effect on Cell Surface Antigens
Interferons also may affect immune responses by modulating cell surface antigen expression7,8,215,648,740,741,742,744,745,746,754 and by enhancing expression of transplantation antigens and alloantigens.8,648,740,747,748,749,750,751,752,754 In addition, interferon alfa has enhanced the expression of a major histocompatibility complex (MHC) class I antigen on hepatocytes infected with hepatitis B virus,647 thereby resulting in a more efficient induction of cytotoxic T-cell (CTL, killer T-cell) activity against viral antigens, and elimination of the infected cells from the liver.647 A similar immune-mediated mechanism has been suggested for tumor cells, since interferons are known to increase the expression of MHC antigens and tumor associated antigens on melanoma648,649 and other tumor cells.650
Effect on Hepatic Cytochrome P-450 System
Interferons, including interferon alfa, and various agents that induce their production and/or secretion (e.g., viruses, quinacrine, tilorone, polyribonucleotides, endotoxin) have been shown to depress to varying degrees the hepatic cytochrome P-450 (microsomal) enzyme system,8,31,41,44,104,105,106,107,108,109,164,950,951,952,953,954,1544 and the ability of interferon-inducing agents to depress this oxidative (monooxygenase) enzyme system may be mediated by interferons rather than by a direct effect of the agents.41,164,951 Depression of the cytochrome P-450 system has been manifested as reductions in the amount of hepatic microsomal protein, including the cytochrome P-450 and b 5 hemoproteins, and in the activities of several cytochrome P-450-dependent enzymes.8,31,104,105,107,164,950,952,953,954
It remains to be established whether interferon-induced depression of the cytochrome P-450 enzyme system results from increased degradation, suppressed synthesis, or inhibition of cytochrome P-450.31,41,104,105,108,952 Evidence mainly from studies with interferon inducers suggests that increased degradation of hepatic hemoproteins rather than suppressed synthesis may be principally involved;41,952 however, other evidence from such studies suggests that decreased synthesis of the apoprotein of cytochrome P-450, probably secondary to disturbances in heme turnover, is an important mechanism.31,104,105 A second mediator (e.g., interleukin-1), in addition to interferons, also has been suggested.108 The importance of the effects of interferons on the cytochrome P-450 enzyme system remains to be established, but interferon alfa can inhibit the metabolism of certain drugs (e.g., theophylline) (see Drug Interactions: Effects on Hepatic Clearance of Drugs), possibly secondary to depression of this enzyme system.44,106,107,108,950 In addition, the extent of effect on the cytochrome P-450 system depends in part on the type953 and subtype of interferon employed.104,109,953
Other Effects
Interferons appear to be intrinsically pyrogenic.2,166,197,204,211,215,244,260,376,453,455,493,1090 The pyrogenic response associated with administration of interferon alfa may be mediated by a drug-induced increase in the production and/or release of prostaglandin (PGE2) in the hypothalamus rather than by an increase in interleukin-1.2,166,197,204,211,215,244,260,376,453,455,493,1090 The response does not appear to be secondary to an exogenous pyrogenic contaminant in interferon alfa preparations.376,461
Pharmacokinetics
Few, if any, studies in humans are available that directly compare the pharmacokinetics of recombinant DNA-derived (e.g., interferon alfa-2a [no longer commercially available in the US], interferon alfa-2b) and mixtures of naturally occurring human interferons.88,1549 Some data suggest that the overall disposition of these preparations is similar29,30,32,45,218,401,407,413,418,434,445,447 and that these interferons produce comparable serum concentration-time profiles in humans and several species of animals following IM administration.19,88,150,218,401,407,412,416,436,974,1549 Although substantial interindividual variability in serum interferon concentrations has been observed after administration of recombinant interferon alfa-2a in healthy individuals and patients with disseminated cancer,420 the overall disposition of the drug was similar following IM or IV dosing in these individuals and in patients with amyotrophic lateral sclerosis (ALS),29,30,409 except for the possibility of a higher clearance in patients with ALS.9,30 Observed differences in interferon pharmacokinetics among patient populations may be related to differences in disease states, dosing schedules, or inherent interindividual variability.19,417,420,434,971
In most studies of the pharmacokinetics of recombinant and mixtures of naturally occurring human interferons, interferon concentration or activity in serum, urine, or CSF was determined using hemadsorption inhibition tests with 51Cr-labeled erythrocytes,22 bioassays,23,24 radioimmunoassays,2 or enzyme-linked immunosorbent assays (ELISA).28,29,30,31 In patients with normal renal function, both ELISA and a bioassay based on inhibition of viral cytopathic effect give comparable results for serum concentrations of interferon alfa-2a;150,973 bioassay results with interferon alfa-2b reportedly also correlate well with those of radioimmunoassay.408
Absorption
For systemic effects, interferon alfa is administered parenterally because the drug is susceptible to degradation by proteolytic enzymes in the GI tract.5,9,13,401,1461 Interferon alfa is well absorbed following IM or subcutaneous injection;9,21,29,409 the apparent fraction of the dose absorbed after IM or subcutaneous injection exceeds 80%.9,29,436 Peak serum interferon alfa concentrations following IV administration of the drug generally occur within 15-60 minutes13,15,29,254 and are substantially greater than those attained after IM or subcutaneous administration.8,9,13,29,144,165,409,421 However, serum interferon alfa concentrations following IM or subcutaneous administration generally are maintained for longer periods of time than those produced by rapid IV injection or rapid (e.g., 40 minutes or less) IV infusion.2,5,13,21,29,144,254,409,421 Following a 36 million-unit dose of interferon alfa administered by IV infusion or by IM or subcutaneous injection, peak serum interferon alfa concentrations averaged approximately 2320, 340, or 290 units/mL, respectively;9,29 24 hours after administration, concentrations of interferon alfa administered by all of these routes were less than 17 units/mL.29 Depending on the administered dose, serum interferon concentrations generally are detectable for approximately 4-8 hours after rapid IV injection or infusion or for approximately 16-30 hours after IM or subcutaneous injection.5,13,19,21,29,144,254,408,409
Following IM administration of interferon alfa in doses of 1 million to 198 million units, peak serum interferon alfa concentrations ranged from 18-1000 units/mL2,5,9,21,29,144,165,218,417,435 1-8 hours (range: 2-12 hours) after the injection.2,5,9,10,11,21,29,34,144,165,218,254,409,417,419,436 Dose-proportional increases in serum interferon alfa concentration were observed following IM doses of up to 198 million units;147,218,419 AUC also increased with increasing doses of interferon alfa,30,218 although route of administration did not have a consistent effect on this value.8,29,144,165,409 Limited data suggest that the time required to achieve peak serum drug concentrations following IM administration of interferon alfa may increase slightly with increasing doses up to 72 million units;218 however, this has not been a consistent finding.409,419 Following IM administration of recombinant interferon alfa-2a (no longer commercially available in the US) in patients with various solid and hematologic malignancies, serum interferon alfa concentrations achieved at 3, 4, and 8 hours were 14, 12, and 16 units/mL after 3-million-unit doses; 37, 38, and 46 units/mL with 9-million-unit doses; or 62, 108, and 182 units/mL with 18-million-unit doses.409 In patients with chronic lymphocytic leukemia or advanced non-Hodgkin's lymphoma, peak serum interferon alfa concentrations 4-8 hours after IM administration of 5 million or 50 million units of recombinant interferon alfa-2a ranged from 91-542 or from 1009-3725 units/mL, respectively.10,11
The serum concentration-time profile of interferon alfa following subcutaneous administration appears to be comparable to that following IM administration,2,5,9,21,29,144,254 although peak serum drug concentrations after subcutaneous injection are attained somewhat later.5,9,21,29 Following subcutaneous injection of recombinant interferon alfa-2a (no longer commercially available in the US) or alfa-2b in doses ranging from 1 million to 36 million units, mean peak serum interferon alfa concentrations ranged from 18-346 units/mL2,9,21,29,144 and were generally achieved in 6-8 hours (range: 3-12 hours).2,5,9,21,29,144,254
Following intralesional injection of interferon alfa-n3 into anogenital warts, systemic plasma concentrations of the drug were undetectable (detection limit of 3 units/mL);431 however, some systemic absorption apparently occurs since adverse systemic effects have been reported in patients receiving intralesional therapy.431 Following intralesional injection of 3 million units of interferon alfa-2b weekly per wart for 4 weeks, serum concentrations of the drug ranged from 5-40 units/mL.163 The drug also was absorbed systemically following intralesional injection of interferon alfa-2b or a mixture of naturally occurring human interferon alfa at dosages of 18-30 million units weekly in patients with malignant melanoma; peak serum concentrations of the drug occurred 6 hours after injection, achieving a median of 95 units/mL.1108 Some percutaneous absorption of interferon alfa also appears to occur following topical application of the drug, since adverse systemic effects have been reported rarely.1398
Interferon alfa can achieve high and sustained CSF concentrations following intrathecal†5,23,159,414,421,436,968 or intraventricular†30,421,436,969,970 administration. (See Pharmacokinetics: Distribution.) Following intraperitoneal† administration, interferon alfa reportedly is absorbed systemically, resulting in high, sustained serum concentrations after several weeks of therapy; interferon alfa was still detectable in serum 5 days following intraperitoneal administration,13 but intraperitoneal concentrations were 30-1000 times those achieved in serum.
Following topical application to the eye (into the lower conjunctival sac) of 0.25, 0.75, 2.5, or 5 million units of a buffered solution of interferon alfa, concentrations of the drug in the nasal cavity at 1 hour were 602, 1461, 1197, or 4360 units/mL, respectively; detectable concentrations were present for at least 8 hours following administration.1465 The extent of intraocular penetration of interferon alfa following topical application of the eye currently is not known.88,1465,1549
Distribution
Limited data on the tissue distribution of interferon in animals suggest that mixtures of naturally occurring human or animal interferons are widely and rapidly distributed into body tissues after parenteral administration, with the highest concentrations occurring in spleen, kidney, liver, and lung.8,15 Limited evidence also indicates interferon uptake and/or binding by other types of tissue or tumors.19,977 Although a similar pattern of tissue distribution was noted in animals given certain recombinant DNA-derived interferons (human interferon alfa-2c),28 animal studies in which recombinant interferon alfa-2a (no longer commercially available in the US) or alfa-2b13 were used suggest that the these interferons are not concentrated in any organ or that only the kidney, which appears to be the principal site of interferon metabolism,2,9,13,45,444,446,447,976,977 demonstrates substantial uptake of the drugs.13,436,437 (See Pharmacokinetics: Elimination.) Studies with radiolabeled recombinant interferon alfa-2a in patients with osteosarcoma indicate uptake of the drug by the liver and by tumor tissue;977 differences in peak plasma concentrations following administration of human leukocyte interferon suggest that interferon alfa binds to a greater degree to tumors of the lymph nodes and bone marrow than to breast tumors.19 Following IM or subcutaneous injection of human recombinant interferon alfa-2a into the shank muscle of animals, interferon alfa readily distributes into lymph tissue.978
Differences in volume of distribution and in other pharmacokinetic values among various recombinant interferons have been demonstrated in a few studies;437,972 however, the overall disposition of recombinant interferon alfa-2a in mice, dogs, monkeys, and humans appears to be similar (i.e., species independent).30,401,418,421 The volume of distribution of interferon alfa in humans reportedly approximates 20-60% of body weight;436 in healthy individuals who received 36 million units of recombinant interferon alfa-2a IV over 40 minutes, the volume of distribution at steady state (Vss) ranged from 0.23-0.75 L/kg (mean: 0.4 L/kg).29
Interferon alfa does not readily distribute into CSF following systemic administration of mixtures of naturally occurring human or recombinant interferons5,8,9,18,21,23,30,34,42,165,409,413,414,421 in animals or humans, although low concentrations have been detected in CSF following administration of large systemic doses.9,30,34,42,414,434 Following IM injection of a mixture of naturally occurring human leukocyte interferon, no interferon activity was detectable (i.e., concentration less than 20 units/mL)18 in CSF at 4 hours after a dose of 3 million units in an infant18 or at 6 and 8 hours after a dose of 30 million units in a 12-year-old boy.21 Using a radioimmunoassay (detection limit 2.5 units/mL), CSF interferon alfa concentrations of 3.1-3.8 units/mL were noted from 0.5-8 hours following a dose of recombinant interferon alfa-2b in a woman with disseminated breast cancer receiving 27 million units daily as a 30-minute IV infusion for 5 successive days every 3 weeks; corresponding serum interferon alfa concentrations ranged from 22-3065 units/mL.42 In a limited number of patients with amyotrophic lateral sclerosis, interferon alfa concentrations in CSF were undetectable (i.e., less than 2.6 units/mL) following IV infusion of a single 18-million units dose of recombinant interferon alfa-2a but ranged from 2.9-11.9 units/mL (550- to 1100-fold less than corresponding serum concentrations) following a dose of 50 million units; CSF concentrations were detectable after 1 hour and, in 2 patients, for at least 24 hours after the dose.30 In both animals and man, higher CSF concentrations of interferon alfa can be achieved by intrathecal†5,23,159,414,421,436,968 or intraventricular†30,421,436,969,970 administration. Distribution of interferon alfa into serum following injection into CSF occurs slowly; a stable serum concentration was maintained for 12-24 hours following intrathecal injection of 10 million units of human leukocyte interferon in monkeys.414 Intrathecal administration of interferon alfa in animals produced CSF interferon concentrations that were approximately 16- to 30-fold greater than corresponding serum concentrations.8,23,159,414,992,993,994 In a neonate who received 600,000 units of a mixture of naturally occurring human interferon alfa intrathecally once or twice daily for disseminated herpes simplex infection, CSF interferon alfa concentrations measured 12 or 24 hours after the dose ranged from 800-8000 units/mL.23 The presence of interferon alfa in CSF does not ensure penetration of the drug into parenchymal brain tissue;34,88,421,979,980,981,1549 virus has been recovered postmortem from the brain tissue of a patient with disseminated herpes simplex infection in whom relatively high CSF concentrations of interferon alfa were attained following intrathecal injection of the drug.23 However, survival was substantially greater in monkeys infected with rabies virus and treated with intrathecally administered human leukocyte interferon than in those not treated, suggesting that interferon does reach grey and white matter of the brain.159
It is not known whether interferon crosses the placenta in humans.88 Studies in mice indicate that murine interferon is distributed into milk;2,431,975 it is not known whether interferon is distributed into human milk.2,431
Elimination
Interferon alfa is rapidly cleared from plasma following rapid IV injection or IV infusion in animals or humans, while more prolonged concentrations are observed following IM or subcutaneous administration.2,5,8,13,21,28,29,32,215,286,436 In healthy individuals and patients with normal renal function, plasma concentrations of interferon alfa appear to decline in a biphasic manner.5,8,21,29,30,215,436,469,971 Limited data from studies in humans receiving recombinant interferon alfa-2a (no longer commercially available in the US) or recombinant interferon alfa-2b suggest that variability in the reported elimination half-life of interferon alfa may be related to route or method of administration,409,420,436 interindividual variability in drug disposition,420 and/or presence of disease.409,420,1549 However, the serum concentrations and clearance of partially purified human leukocyte interferon or recombinant interferon alfa-2a was not appreciably altered in several patients with chronic renal failure.9,150,410
Following a brief IV infusion, the terminal elimination half-life of recombinant interferon alfa-2a averaged 5.1 hours (range 3.7-8.5 hours) in healthy individuals9,29 and ranged from approximately 0.75-2 hours in a limited number of patients with disseminated cancer.409 Elimination half-life of recombinant interferon alfa-2a was more prolonged following continuous IV infusion for 14 days in a few patients with leukemia, ranging from 4.6-9.8 hours.420 In healthy individuals who received a 30-minute IV infusion of recombinant interferon alfa-2b, elimination half-life averaged approximately 2 hours (range: 0.5-2.9 hours).2,13,144,215,286 Elimination half-life of recombinant interferon alfa-2a or alfa-2b averaged approximately 2-3.5 hours following IM or subcutaneous administration in healthy individuals9,29 and approximately 2.6-11.5 hours following IM administration in patients with disseminated cancer.218,407,409,971
In a study using isolated, perfused rabbit kidneys, the plasma disappearance rate of recombinant interferon alfa was greater than that of a mixture of naturally occurring interferon alfa.45 Following a single, rapid IV injection or a 14-day continuous IV infusion of interferon alfa-2a, total body clearance of the drug from plasma was 1.9-3.6 or 0.6-1.4 mL/minute per kg, respectively.9,29,30,420 Although conflicting data have been reported,19 accumulation of interferon alfa appears to occur with multiple IM dosing.147,165,419
The metabolism of recombinant interferon alfa appears to be similar to that of mixtures of naturally occurring human interferon alfa in general.45,402,444,446,447 Interferon alfa appears to be metabolized principally in the kidney.9,13,28,29,32,43,45,46,215,436,444,446,447 Interferon alfa generally is undetectable or present only in trace quantities in urine,2,5,9,13,18,21,43,45,165,436,983 and the drug reappears in systemic circulation in negligible concentrations following its passage through the kidney;45,444,446 studies in which interferons have been detected in urine21,31,40,46,47 reported no correlation between urine and serum concentrations of the drug.21 In animals and humans, the total body clearance of recombinant interferon alfa exceeds the creatinine clearance, which also suggests that renal tubular secretion, extrarenal elimination, and/or renal and/or extrarenal catabolism contribute to elimination of the drug.9,29,32 Studies in isolated, perfused kidney preparations demonstrate that interferon alfa is freely filtered through the glomeruli.29,43,45,215,444,446,447 Approximately 90-96% of the drug is absorbed by the renal tubule, where it undergoes rapid proteolytic degradation at the brush border or in the lysosomes of the tubular epithelium.29,43,45,215,444,446,447 Studies of human leukocyte or recombinant interferons in isolated liver perfusate systems suggest that hepatic metabolism and subsequent biliary excretion is a minor pathway of elimination for interferon alfa.46,402,984
In a limited number of patients with chronic renal failure who received single, low doses (i.e., 3 million units) of partially purified or recombinant interferon alfa, the serum concentrations and clearance of the drugs were not substantially altered;9,150 however, it has been suggested that interferon alfa may accumulate in body fluids of patients with markedly depressed glomerular filtration rate (GFR) and creatinine clearance.45 Limited evidence in patients receiving recombinant interferon alfa-2a suggests that hemodialysis is not effective in removing interferon alfa from the body.150
Chemistry and Stability
Chemistry
Interferon alfa is a family of highly homologous, species-specific proteins and, occasionally, glycoproteins that possess complex antiviral, antineoplastic, and immunomodulating activities.2,8,47,70,255,259,261,456,648,714,717,740,906,1211,1240,1241,1339,1426,1464 Because of the relative species-specific activity of interferons,8,47,73,456,933,949,999,1000 interferons intended for human use are of human origin (e.g., prepared using donor-provided human cells such as leukocytes,3,431,433 using cultured human cell lines such as lymphoblastoid cells,456 or using recombinant techniques that employ human genes).2,47,215,1348 At least 23 structurally similar subtypes of human interferon alfa (e.g., interferon alfa-2a, interferon alfa-2b) have been identified.5,8,9,47,51,71,73,88,374,427,430,456,630,947,948,1339,1464,1549
Interferon alfa is commercially available in the US as interferon alfa-2b2 and interferon alfa-n3.3 Interferon alfa-2b is of recombinant DNA origin2 and interferon alfa-n3 is derived from human leukocytes.3 For additional information on interferon alfa-2b and interferon alfa-n3, see see Interferon Alfa 8:18.20.
Interferons are produced and secreted principally by peripheral blood leukocytes, fibroblasts, and epithelial cells in response to viral infection or certain other synthetic and biologic inducers (e.g., double-stranded RNA, certain bacteria and other microorganisms, endotoxin, surface glycoproteins).5,7,8,9,26,51,71,73,998,1001,1549 By definition, interferons exist as proteins or glycoproteins, are produced endogenously according to information encoded by species of interferon genes, and exert virus-nonspecific antiviral activity, at least in homologous cells, through cellular metabolic processes involving synthesis of RNA and proteins.8,424,425,426,428,429,526,1453,1461 In addition to interferon alfa, interferon beta and interferon gamma have been identified2,5,9,47,51,73,406,424,425,426,427,428,429,430,456,1339,1453 and are classified according to antigenic specificity and/or biologic properties.5,8,9,47,73,424,425,426,427,428,429,430,456,985,1339,1464 Interferon alfa and interferon beta have been referred to as type I interferons in part because of their general acid stability, and interferon gamma has been referred to as a type II interferon in part because of its general acid lability;2,5,8,73,424,426,428,429,1339,1549 however, some subtypes may not possess the acid stability profile indicated by this classification.8,424,426,428,429,986,1339 Although interferon alfa, interferon beta, and interferon gamma also have been referred to as leukocyte or lymphoblastoid interferon, fibroblast interferon, and lymphocyte or immune interferon, respectively,2,5,215,406,424,425,426,428,429,1339,1453 these descriptions are considered misnomers since interferons alfa and beta can both be produced by leukocytes and fibroblasts, and production of interferon gamma can be induced by mitogen-stimulated mechanisms.5,8,51,215,424,426,428,429
Human interferon alfa proteins generally contain 165 or 166 amino acids and have molecular weights ranging from 16,000-28,000 daltons,2,5,8,47,51,71,215,431,456,1041,1339,1348,1464 with most subtypes containing 166 amino acids and having molecular weights of 18,000-20,000.215,255,456,1339 While the precise subtype composition of interferon alfa-n3 (α-interferons, leukocyte interferon, HuIFN-α (Le)) currently is not known, interferon alfa proteins present in the mixture consist of approximately 166 amino acids each and have molecular weights ranging from 16,000-27,000 daltons.431,433 The precise subtype composition of interferon alfa-n1 (α-interferons, lymphoblastoid interferon, HuIFN-α (Ly); not commercially available in the US), which is a mixture of at least 8 interferon alfa proteins1348 but is derived from lymphoblastoid cells rather than from leukocytes,9,50,77,166,216,456,1453 also currently is not known.1348 Interferon alfa-2a (HuIFN-αA, Ro 22-8181; no longer commercially available in the US) and interferon alfa-2b (Sch 38500) are biosynthetic (recombinant DNA origin) forms of interferon alfa (rHuIFN-α) that consist of 165 amino acids.61,71,215,260,955,1041,1339,1453,1464 Interferons alfa-2a and alfa-2b have molecular weights of approximately 19,000 daltons and differ at position 23 in the amino acid sequence, with alfa-2a possessing a lysine group and alfa-2b an arginine group at this position.26,47,50,77,171,215,1041,1348,1464 The importance, if any, of this single amino acid difference has not been established, and it remains to be elucidated whether clinically important differences in therapeutic and/or toxicologic profiles exist.88,215,1144,1549 Compared with other interferon alfa subtypes, interferon alfa-2a and interferon alfa-2b both have a deletion at position 44 in the amino acid sequence.71,77,255,305,930,933,955,982 In addition, although 2 large molecular segments are identical in various interferon alfa subtypes, the amino acid sequences of the subtypes differ from one another by several amino acids and are 70-90% homologous.51,71,214,1348,1464 Interferon alfa-2c (not commercially available in the US) differs structurally from interferon alfa-2b by the presence of an arginine group rather than a histidine group at position 34 in the amino acid sequence.50,191,305 The structure-activity relationships for interferons have not been clearly established.78,550,551,552,988,989,990,991,1339,1575,1576 While both the amino and carboxy terminal regions of the molecules may be involved in eliciting antiviral activity, studies to determine which region(s) of the molecules confers various degrees of activity have yielded conflicting results.78,550,551,552,988,989,990,991,1339,1464,1575,1576 In addition, some evidence indicates that different regions may be involved in eliciting various activities of the drug.1575,1576
Interferon Alfa-2b
Interferon alfa-2b is prepared from cultures of genetically modified Escherichia coli using recombinant DNA technology.2,11,47,53,77,254,255,259,374,1041,1348,1464 The bacteria is modified by the addition of a plasmid that incorporates an interferon alfa-2b gene from human leukocytes for human interferon alfa synthesis.2,1041,1348 Because a single gene is used for the preparation, single molecular species (i.e., 2b) rather than a mixture of interferon alfa subtypes is present in commercially available preparations of interferon alfa-2b.2,10,88,138,215,1348 Trace amounts of residual E. coli protein may be produced during fermentation.47 Although tetracycline hydrochloride is included in the nutrient medium used during the fermentation process, it is undetectable in the final preparation of interferon alfa-2b.2
Potency of interferon alfa-2b is expressed in International Units (IU)2 as tested against the activity of specific international reference preparations of interferons established by the World Health Organization (WHO).9,47,88,1348,1464 Interferon alfa-2b (recombinant DNA origin) commercially available in the US has a specific activity that is approximately 2.6 million units/mg of protein as measured by high performance liquid chromatography (HPLC) assay.2
Interferon alfa-2b is commercially available in the US as a sterile powder for injection in single-dose vials2 or as a sterile solution in multiple-dose vials.2 The powder for injection occurs as a white to cream-colored lyophilized powder2 and contains dibasic and monobasic sodium phosphate as a buffer, glycine, and albumin human.2,215 Following reconstitution with the sterile water for injection diluent provided by the manufacturer, the injection occurs as a clear and colorless to light yellow solution.2 Commercially available solutions of interferon alfa-2b are clear and colorless and contain dibasic and monobasic sodium phosphate, edetate disodium, and polysorbate 80; m -cresol is added as a preservative.2
Stability
Commercially available interferon alfa-2b powder for injection in single-dose vials should be stored in a refrigerator at 2-8°C.2 Following reconstitution of the powder for injection with the sterile water for injection diluent provided by the manufacturer, the solution should be used immediately, but may be stored at 2-8°C for up to 24 hours.2
Commercially available interferon alfa-2b solution for injection in multiple-dose vials should be stored at 2-8°C and should not be frozen or exposed to heat.2 After the initial dose is administered, any solution remaining in the vial should be discarded after 1 month.2
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web]
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations ⬆ ⬇
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Interferon Alfa-2b (Recombinant DNA Origin)
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Parenteral | For injection | 10 million units | Intron® A (available as single-dose vials with sterile water for injection diluent) | Schering |
| | 18 million units | Intron® A (available as single-dose vials with sterile water for injection diluent) | Schering |
| | 50 million units | Intron® A (available as single-dose vials with sterile water for injection diluent) | Schering |
| Injection | 6 million units/mL (18 million units) | Intron® A (available as multiple-dose vials) | Schering |
| | 10 million units/mL (25 million units) | Intron® A (available as multiple-dose vials) | Schering |
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References ⬆
2. Schering Corporation. Intron® A (interferon alfa-2b, recombinant) for injection prescribing information. Whitehouse Station, NJ; 2014 Apr.
3. Hemispherx Biopharma. Alferon N injection® (interferon alfa-n3 [human leukocyte derived]) prescribing information. Philadelphia, PA; 2004 Jul.
5. Houglum JE. Interferon: mechanisms of action and clinical value. Clin Pharm . 1983; 2:20-8. [PubMed 6192965]
6. Farci P, Mandas A, Coiana A et al. Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med . 1994; 330:88-94. [PubMed 8259188]
7. Samanta H, Yoshie O, Schmidt H et al. Interferons as activators of gene expression: induction of mRNAs specifying major histocompatibility complex antigens, (2'-5') (A)7n synthetases and proteins of unknown function. In: Bertazzione U, Bollum M, Ghione M, eds. Contributions of modern biology to medicine. Sereno Symposium Publication No. 17. New York: Raven Press; 1985:89-97.
8. Borden EC, Edwards BS, Hawkins MJ et al. Interferons: biological response modification and pharmacology. In: Mihich E, ed. Biological response in cancer: progress toward potential applications. New York: Plenum Press; 1982:169-218.
9. Balmer CM. The new alpha interferons. Drug Intell Clin Pharm . 1985; 19:887-93. [PubMed 3910384]
10. Foon KA, Bottino GC, Abrams PG et al. Phase II trial of recombinant leukocyte A interferon in patients with advanced chronic lymphocytic leukemia. Am J Med . 1985; 78: 216-20. [PubMed 3970047]
11. Foon KA, Sherwin SA, Abrams PG et al. Treatment of advanced non-Hodgkin's lymphoma with recombinant leukocyte A interferon. N Engl J Med . 1984; 311:1148-52. [PubMed 6482933]
12. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000-Summary of a workshop. Gastroenterology . 2001; 120:1828-53. [PubMed 11375963]
13. Schering-Plough Corporation. Interferon backgrounder. Kenilworth, NJ; 1988 May.
14. Perrillo RP, Schiffer, Davis GL et al and the Hepatitis Interventional Therapy Group. A randomized, control trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N Engl J Med . 1990; 323:295-301. [PubMed 2195346]
15. Hanley DF, Wiranowska-Stewart M, Stewart WE. Pharmacology of interferons: I. Pharmacologic distinctions between human leukocyte and fibroblast interferons. Int J Immunopharmacol . 1979; 1:219-26. [PubMed 95249]
16. Wong DKH, Cheung AM, O'apos;Rourke K et al. Effect of alfa-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B: a meta-analysis. Ann Intern Med . 1993; 119:312-23. [PubMed 8328741]
17. Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep . 2010; 59(RR-12):1-110. [Web]
18. Larsson A, Forsgren M, Hard af Segerstad S et al. Administration of interferon to an infant with congenital rubella syndrome involving persistent viremia and cutaneous vasculitis. Acta Paediatr Scand . 1976; 65:105-10. [PubMed 1251716]
19. Gutterman JU, Blumenschein GR, Alexanian R et al. Leukocyte interferon-induced tumor regression in human metastatic breast cancer, multiple myeloma, and malignant lymphoma. Ann Intern Med . 1980; 93:399-406. [PubMed 6159812]
20. Genentech. Pegasys® (peginterferon alfa-2a) injection for subcutaneous use prescribing information. South San Francisco, CA; 2013 Jul.
21. Emodi G, Just M, Hernandez R et al. Circulating interferon in man after administration of exogenous human leukocyte interferon. J Natl Cancer Inst . 1975; 54:1045- 9. [PubMed 1127735]
22. McPherson TA, Tan YH. Phase I pharmacotoxicology study of human fibroblast interferon in human cancers. J Natl Cancer Inst . 1980; 65:75-9. [PubMed 6156261]
23. De Clercq E, Edy VG, De Vlieger H et al. Intrathecal administration of interferon in neonatal herpes. J Pediatr . 1975; 86:736-9. [PubMed 166151]
24. Cesario TC, Tilles JG. Inactivation of human interferon by body fluids. Tex Rep Biol Med . 1977; 35:443-8. [PubMed 616673]
25. Perez V, Tanno H, Villamil F et al. Recombinant interferon alfa-2b following prednisone withdrawal in the treatment of chronic type B hepatitis. J Hepatol . 1990; 11:S113-5. [PubMed 2079567]
26. USP DI: drug information for the health care professional. Johnson KW, ed. 10th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1990; 1B:1561-5.
27. Sokal EM, Conjeevaram HS, Roberts EA et al. Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial. Gastroenterology . 1998; 114:988-95. [PubMed 9558288]
28. Greischel A, Tanswell P, Busch U et al. Pharmacokinetics and biodistribution of recombinant human interferon-α2C in rat and marmoset. Arzneim Forsch . 1988; 38:1539-43.
29. Wills RJ, Dennis S, Spiegel H et al. Interferon kinetics and adverse reactions after intravenous, intramuscular, and subcutaneous injection. Clin Pharmacol Ther . 1984; 35:722-7. [PubMed 6713784]
30. Smith RA, Norris F, Palmer D et al. Distribution of alpha interferon in serum and cerebrospinal fluid after systemic circulation. Clin Pharmacol Ther . 1985; 37:85-8. [PubMed 3965239]
31. Williams SJ, Farrell GC. Inhibition of antipyrine metabolism by interferon. Br J Clin Pharmacol . 1986; 22:610-2. [PubMed 3790409]
32. Wills RJ, Soike KF. Pharmacokinetics of human recombinant interferon-αI after IV infusion and im injection in African green monkeys. J Interferon Res . 1988; 8:427-32. [PubMed 3171243]
34. Billiau A. Interferon therapy: pharmacokinetic and pharmacological aspects. Arch Virol . 1981; 67:121-33. [PubMed 6163417]
35. Anon. Interferon plus ribavirin for chronic hepatitis C. Med Lett Drugs Ther . 1999; 41:53-4. [PubMed 10368698]
36. McHutchison JG, Gordon SC, Schiffer et al for the Hepatitis Interventional Therapy Group. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med . 1998; 339:1485-92. [PubMed 9819446]
37. Poynard T, Marcellin P, Lee SS et al for the International Hepatitis Interventional Therapy Group (IHIT). Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet . 1998; 352:1426-32. [PubMed 9807989]
38. Davis GL, Esteban-Mur R, Rustgi V et al Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med . 1998; 339:1493-9.
39. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet . 2001; 358:958-65. [PubMed 11583749]
40. Bocci V, Russi M, Rita G. Recovery and identification of interferon in the rabbit urine. Experientia . 1967; 23:309-10. [PubMed 4964311]
41. Renton KW, Mannering GJ. Depression of hepatic cytochrome P-450-dependent monooxygenase systems with administered interferon inducing agents. Biochem Biophys Res Commun . 1976; 73:343-8. [PubMed 187194]
42. Martino S, Singhakowinta A. Serial interferon alpha2 levels in serum and cerebrospinal fluid. Cancer Treat Rep . 1984; 68:1057-8. [PubMed 6744344]
43. Sumpio BE, Ernstoff MS, Kirkwood JM. Urinary excretion of interferon, albumin, and β2-microglobulin during interferon treatment. Cancer Res . 1984; 44:3599-603. [PubMed 6378373]
44. Renton KW, Gray JD, Hall RI. Decreased elimination of theophylline after influenza vaccination. Can Med Assoc J . 1980; 123:288-90. [PubMed 7260771]
45. Bocci V, Pacini A, Muscettola M et al. The kidney is the main site of interferon catabolism. J Interferon Res. 1982; 2:309-14.
46. Bocci V, Pacini A, Bandinelli L et al. The role of the liver in the catabolism of human α- and β- interferon. J Gen Virol . 1982; 60:397-400. [PubMed 6180128]
47. WHO Expert Committee on Biological Standardization. World Health Organization Technical Report Series, 771. 38th Report; World Health Organization, Geneva, 1988:29-32,37-87.
48. Schering Corporation. PegIntron® (peginterferon alfa-2b) injection, for subcutaneous use prescribing information. Whitehouse Station, NJ; 2014 Jul.
49. Schering Corporation. Sylatron® (peginterferon alfa-2b) for injection, for subcutaneous use prescribing information. Whitehouse Station, NJ; 2013 Dec.
50. WHO. International nonproprietary names for pharmaceutical substances. WHO Chronicle. 1984; 38(Suppl):23.
51. DeVita VT, Hellman S, Rosenberg SA. Cancer—principles and practice of oncology. Philadelphia: Lippincott; 1989:2229-30.
52. Comanor L, Minor J, Conjeevaram HS et al. Impact of chronic hepatitis B and interferon-alpha therapy on growth of children. J Viral Hepat . 2001; 8:139-47. [PubMed 11264734]
53. Goldstein D, Laszlo J. The role of interferon in cancer therapy: a current perspective. Ca Cancer J Clin . 1988; 38:258-77. [PubMed 2458171]
54. Balkwill F, Taylor-Papadimitriou J. Interferon affects both G1 and S+G2 in cells stimulated from quiescence to growth. Nature . 1978; 274:798-800. [PubMed 683317]
55. Branca AA, Faltynek CR, D'Alessandro SB et al. Interaction of interferon with cellular receptors—internalization and degradation of cell-bound interferon. J Biol Chem . 1982; 257:13291-6. [PubMed 6292184]
61. Salmon SE, Durie BGM, Young L et al. Effects of cloned human leukocyte interferons in the human tumor stem cell assay. J Clin Oncol . 1983; 1:217-25. [PubMed 6686847]
62. Samid D, Chang EH, Friedman RM. Biochemical correlates of phenotypic reversion in interferon-treated mouse cells transformed by a human oncogene. Biochem Biophys Res Commun . 1984; 119:21-8. [PubMed 6200112]
63. Smyth JF. Guidelines for the use of Intron A (interferon alfa-2b) in clinical oncology: lessons from the laboratory. Cancer Treat Rev . 1988; 15(Suppl A):3-6. [PubMed 3342417]
64. Herberman RB, Ortaldo JR, Mantovani A et al. Effect of human recombinant interferon on cytotoxic activity of natural killer (NK) cells and monocytes. Cell Immunol . 1982; 67:160-7. [PubMed 6176335]
65. Jonak GJ, Knight E Jr. Selective reduction of c- myc mRNA in Daudi cells by human β interferon. Proc Natl Acad Sci USA . 1984; 81:1747-50. [PubMed 6584908]
66. Herberman RB, Ortaldo JR, Bonnard GD. Augmentation by interferon of human natural and antibody-dependent cell-mediated cytotoxicity. Nature . 1979; 277:221-3. [PubMed 95205]
67. Kiessling R, Gronberg A, Guevara L. On the complexity of interferon-mediated NK regulation. In: Bertazzione U, Bollum M, Ghione M, eds. Contributions of modern biology to medicine. Sereno Symposium Publication No. 17. New York: Raven Press; 1985:25-36.
68. Peterson LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med . 2002; 137:173-9. [PubMed 12160365]
69. Tomida M, Yamamoto Y, Hozumi M. Stimulation by interferon of induction of differentiation of human promyelocytic leukemia cells. Biochem Biophys Res Commun . 1982; 104:30-7. [PubMed 6176225]
70. Tovey MG. Interferon: immunomodulator and antitumor agent. In: Fudenberg H, Whiten HD, Ambrogi F, eds. Immunoregulation: new frontiers and advances. New York: Plenum Press; 1984:155-9.
71. Oldham RK. Biologicals for cancer treatment: interferons. Hosp Pract . 1985; 20:71-91.
72. Ho DD, Hartshorn KL, Rota TR et al. Recombinant human interferon alfa-A supresses HTLV-III replication in vitro. Lancet . 1985; 1:602-4. [PubMed 2857946]
73. Wagstaff J, Melief KJ. Lymphokines and cytokines. In: Pinedo HM, Longo DL, Chabner BL, eds. Cancer chemotherapy and biological response modifiers. New York: Elsevier; 1988:432-53.
75. Soslau G, Bogucki AR, Gillespie D et al. Phosphoproteins altered by antiproliferative doses of human interferon-β in a human bladder carcinoma cell line. Biochem Biophys Res Commun . 1984; 119:941-8. [PubMed 6424675]
76. Samuel CE, Knutson GS. Mechanism of interferon action- kinetics of decay of the antiviral state and protein phosphorylation in mouse fibroblasts treated with natural and cloned interferons. J Biol Chem . 1982; 257:11796-801. [PubMed 6181060]
77. Borden EC. Effects of interferons in neoplastic diseases of man. Pharmacol Ther . 1988; 37:213-29. [PubMed 2455301]
78. Zoon KC, Arnheiter H. Studies of the interferon receptors. Pharmacol Ther . 1984; 24:259-78. [PubMed 6205408]
79. Schultz RM. Macrophage activation by interferons. Lymphokine Rep . 1980; 1:63-97.
80. Spiegel RJ, Spicehandler JR, Jacobs SL et al. Low incidence of serum neutralizing factors in patients receiving recombinant alfa-2b interferon (Intron A). Am J Med . 1986; 80:223-8. [PubMed 3484902]
81. Atzpodien J, Korfer A, Franks CR. Home therapy with recombinant interleukin-2 and interferon-α2b in advanced human malignancies. Lancet . 1990; 336:1509-12. [PubMed 1979116]
82. Krown SE. Therapeutic options in renal-cell carcinoma. Semin Oncol . 1985; 12(Suppl 5):13-7. [PubMed 2417331]
83. Vallbracht A, Treuner J, Flehmig B et al. Interferon- neutralizing antibodies in a patient treated with human fibroblast interferon. Nature . 1981; 289:496-7. [PubMed 6162104]
84. Freund M, von Wussow P, Knuver-Hopf J et al. Treatment with natural human interferon alpha of a CML-patient with antibodies to recombinant interferon alpha-2b. Blut . 1988; 57:311-5. [PubMed 3196882]
85. von Wussow P, Hartmann F, Freund M et al. Leucocyte- derived interferon-alfa in patients with antibodies to recombinant ifn-α2b . Lancet . 1988; 1:882-3. [PubMed 2895387]
86. Oberg K, Alm G, Magnusson A et al. Treatment of malignant carcinoid tumors wih recombinant interferon alfa-2b: development of neutralizing interferon antibodies and possible loss of antitumor activity. J Natl Cancer Inst . 1989; 81:531-5. [PubMed 2466128]
87. Steis RG, Smith JW II, Urba WJ et al. Resistance to recombinant interferon alfa-2a in hairy-cell leukemia associated with neutralizing anti-interferon antibodies. N Engl J Med . 1988; 318:1409-13. [PubMed 3367950]
88. Manufacturer's comments (personal observations)
89. Bunn PA Jr, Ihde DC, Foon KA. The role of recombinant interferon alfa-2a in the therapy of cutaneous T-cell lymphomas. Cancer . 1986; 57:1689-95. [PubMed 3485012]
92. Weiskittel PD. West nile virus infection in a renal transplant recipient. Nephrol Nurs J . 2004; 31:327-9. [PubMed 15303427]
93. Sayao AL, Suchowersky O, Al-Khathaami A et al. Calgary experience with West Nile virus neurological syndrome during the late summer of 2003. Can J Neurol Sci . 2004; 31:194-203. [PubMed 15198443]
94. Kalil AC, Devetten MP, Singh S et al. Use of interferon-alpha in patients with West Nile encephalitis: report of 2 cases. Clin Infect Dis . 2005; 40:764-6. [PubMed 15714427]
95. Itri LM, Campion M, Dennin RA et al. Incidence and clinical significance of neutralizing antibodies in patients receiving recombinant interferon alfa-2a by intramuscular injection. Cancer . 1987; 59:668-74. [PubMed 10822468]
97. Lok ASF, McMahon BJ. Chronic hepatitis B: Update 2009. AASLD practice guidelines. Sep 2009. From AASLD website. [Web]
98. Trown PW, Kramer MJ, Dennin RA Jr et al. Antibodies to human leukocyte interferons in cancer patients. Lancet . 1983; 1:81-4. [PubMed 6129455]
99. Niro GA, Rosina F, Rizzetto M. Treatment of hepatitis D. J Viral Hepat . 2005; 12:2-9. [PubMed 15655042]
100. Rosina F, Pintus C, Meschievitz C et al. A randomized controlled trial of a 12-month course of recombinant human interferon-alpha in chronic delta (type D) hepatitis: a multicenter Italian study. Hepatology . 1991; 13:1052-6. [PubMed 2050321]
101. Di Marco V, Giacchino R, Timitilli A et al. Long-term interferon-alpha treatment of children with chronic hepatitis delta: a multicentre study. J Viral Hepat . 1996; 3:123-8. [PubMed 8871870]
102. Farci P, Roskams T, Chessa L et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology . 2004; 126:1740-9. [PubMed 15188169]
103. Killion JJ, Fan D, Bucana CD et al. Augmentation of antiproliferative activity of interferon alfa against human bladder tumor cell lines by encapsulation of interferon alfa within liposomes. J Natl Cancer Inst . 1989; 81:1387-92. [PubMed 2778824]
104. Renton KW, Singh G, Stebbing N. Relationship between the antiviral effects of interferons and their abilities to depress cytochrome P-450. Biochem Pharmacol . 1984; 33:3899-902. [PubMed 6508841]
105. Singh G, Renton KW. Inhibition of the synthesis of hepatic cytochrome P-450 by the interferon-inducing agent poly rI.rCi. Can J Physiol Pharmacol . 1984; 62:379-83. [PubMed 6733584]
106. Jonkman JHG, Nicholson KG, Farrow PR et al. Effects of α-interferon on theophylline pharmacokinetics and metabolism. Br J Clin Pharmacol . 1989; 27:795-802. [PubMed 2757895]
107. Williams SJ, Baird-Lambert JA, Farrell GC. Inhibition of theophylline metabolism by interferon. Lancet . 1987; 2:939-41. [PubMed 2444839]
108. Williams SJ, Baird-Lambert J, Cantrill EM et al. Interferon inhibits hepatic clearance of theophylline by a non competitive mechanism. Aust N Z J Med . 1987; 17(Suppl 1):128.
109. Taylor G, Marafino BJ Jr, Moore JA et al. Interferon reduces hepatic drug metabolism in vivo in mice. Drug Metab Dispos . 1985; 13:459-63. [PubMed 2863111]
110. Sorrell MF, Belongia EA, Costa J et al. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med . 2009; 150:104-10. [PubMed 19124811]
111. González-Peralta RP, Kelly DA, Haber B et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology . 2005; 42:1010-8. [PubMed 16250032]
112. Schering Corporation. Intron® A (interferon alfa-2b, recombinant) for injection medication guide. Whitehouse Station, NJ; 2011 Feb.
113. Aguet M, Blanchard B. High affinity binding of125I-labeled mouse interferon to a specific cell surface receptor: II. Analysis of binding properties. Virology . 1981; 115:249-61. [PubMed 6171930]
114. Aguet M. High-affinity binding of125I-labelled mouse interferon to a specific cell surface receptor. Nature . 1980; 284:459-61. [PubMed 6444699]
115. Schering Corporation. Intron® A (interferon alfa-2b, recombinant) for injection instructions for use. Whitehouse Station, NJ; 2011 Feb.
116. Faltynek CR, Princler GL, Rossio JL et al. Relationship of the clinical response and binding of recombinant interferon alfa in patients with lymphoproliferative diseases. Blood . 67:1077.
117. Aguet M, Gresser I, Hovanessian AG et al. Specific high affinity binding of [125I]-labeled mouse interferon to interferon resistant embryonal carcinoma cells in vitro. Virology . 1981; 114:585-8. [PubMed 6170161]
118. Aguet M, Groebke M, Dreiding P. Various human alpha subclasses cross-react with common receptors: their binding affinities correlate with their specific biological activities. Virology . 1984; 132:211-6. [PubMed 6320534]
119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. [Web]
120. Lin TI, Lenz O, Fanning G et al. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob Agents Chemother . 2009; 53:1377-85. [PubMed 19171797]
122. Foon KA, Maluish AE, Abrams PG et al. Recombinant leukocyte A interferon therapy for advanced hairy cell leukemia. Am J Med . 1986; 80:351-6. [PubMed 3953613]
123. Golomb HM. Interferons: present and future use in cancer therapy. J Clin Oncol . 1986; 4:123-5. [PubMed 2418165]
124. Golomb HM, Jacobs A, Fefer A et al. Alpha-2 interferon therapy of hairy cell leukemia: a multicenter study of 64 patients. J Clin Oncol . 1986; 4:900-5. [PubMed 3519880]
125. Golomb HM, Ratain MJ, Fefer A et al. Randomized study of the duration of treatment with interferon alfa-2B in patients with hairy cell leukemia. J Natl Cancer Inst . 1988; 80:369-73. [PubMed 3282078]
126. Golomb HM, Fefer A, Golde DW et al. Report of a multi- institutional study of 193 patients with hairy cell leukemia treated with interferon-alfa2b. Semin Oncol . 1988; 15(Suppl 5):7-9. [PubMed 3057646]
127. Grem JL, King SA, Cheson BD et al. Pentostatin in hairy cell leukemia: treatment by the special exception mechanism. J Natl Cancer Inst . 1989; 81:448-53. [PubMed 2783980]
128. Henderson ES, Han T. Current therapy of acute and chronic leukemia in adults. CA Cancer J Clin . 1986; 36:322-50. [PubMed 3096521]
129. Hoffmann V, Frey B. Long-term treatment of hairy cell leukemia with interferon alfa-2b. Cancer Treat Rev . 1988; 15(Suppl A):7-13. [PubMed 3342418]
130. Triantos C, Kalafateli M, Nikolopoulou V et al. Meta-analysis: antiviral treatment for hepatitis D. Aliment Pharmacol Ther . 2012; 35:663-73. [PubMed 22273482]
131. Jacobs AD, Champlin RE, Golde DW. Recombinant α-2- interferon for hairy cell leukemia. Blood . 1985; 65:1017-20. [PubMed 3884059]
132. Moormeier JA, Ratain MJ, Westbrook CA et al. Low-dose interferon alfa-2b in the treatment of hairy cell leukemia. J Natl Cancer Inst . 1989; 81:1172-4. [PubMed 2746669]
133. Michalevicz R, Aderka D, Frisch B et al. Interferon- beta induced remission in a hairy cell leukemia patient resistant to interferon-alfa. Leuk Res . 1988; 12:845-51. [PubMed 3199843]
134. Niederle N, Kummer G. The role of interferon in the management of patients with hairy cell leukemia and multiple myeloma. In: Berger HG, Buchler M, Rusfeld RA et al, eds. Cancer therapy—monoclonal antibodies, lymphokines: new developments in surgical oncology and chemotherapy and hormonal therapy. Berlin: Springer, Verlag; 1989.
135. Ozer H, Golomb HM, Zimmerman H et al. Cost-benefit analysis of interferon alfa-2b in treatment of hairy cell leukemia. J Natl Cancer Inst . 1989; 81:594-602. [PubMed 2495367]
136. Pagnucco G, Castelli G, Lazzarino M et al. Human lymphoblastoid interferon in the treatment of hairy cell leukaemia. Int J Immunother . 1988; IV:169-75.
137. Quesada JR, Reuben J, Manning JT et al. Alpha interferon for induction of remission in hairy-cell leukemia. N Engl J Med . 1984; 310:15-8. [PubMed 6689734]
138. Quesada JR, Gutterman JU, Hersh EM. Treatment of hairy cell leukemia with alpha interferons. Cancer . 1986; 57:1678-80. [PubMed 3948137]
139. Quesada JR, Hersh EM, Gutterman JU. Biologic therapy of hairy cell leukemia. Semin Oncol . 1984; 11(Suppl 2):507- 10. [PubMed 6505713]
140. Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet . 2011; 378:73-85. [PubMed 21511329]
141. Abbas Z, Khan MA, Salih M et al. Interferon alpha for chronic hepatitis D. Cochrane Database Syst Rev . 2011; :CD006002. [PubMed 22161394]
142. Golomb HM, Ratain MJ. Recent advances in the treatment of hairy-cell leukemia. N Engl J Med . 1987; 316:870-2. [PubMed 2434851]
143. Spiers ASD, Moore D, Cassileth PA et al. Remissions in hairy-cell leukemia with pentostatin (2'-deoxycoformycin). N Engl J Med . 1987; 316:825-30. [PubMed 2434850]
144. Spiegel RJ. Intron-A (interferon alfa-2b): clinical overview. Cancer Treat Rev . 1985; 12(Suppl B):5-16. [PubMed 3914355]
145. De Wit R, Schattenkerk JKME, Boucher CAB et al. Clinical and virological effects of high-dose recombinant interferon-α in disseminated AIDS-related Kaposi's sarcoma. Lancet . 1988; 2:1214-7. [PubMed 2903953]
146. Gelmann EP, Preble OT, Steis R et al. Human lymphoblastoid interferon treatment of Kaposi's sarcoma in the acquired immune deficiency syndrome: clinical response and prognostic parameters. Am J Med . 1985; 78:737-41. [PubMed 3838854]
147. Kurzrock R, Rosenblum MG, Quesada JR et al. Phase I study of a combination of recombinant interferon-alpha and recombinant interferon-gamma in cancer patients. J Clin Oncol . 1986; 4:1677-83. [PubMed 3095504]
148. Groopman JE, Gottlieb MS, Goodman J et al. Recombinant alpha-2 interferon therapy for Kaposi's sarcoma associated with the acquired immunodeficiency syndrome. Ann Intern Med . 1984; 100:671-6. [PubMed 6712031]
149. Kovacs JA, Deyton L, Davey R et al. Combined zidovudine and interferon-α therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1989; 111:280-7. [PubMed 2757312]
150. Hirsch MS, Tolkoff-Rubin NE, Kelly AP et al. Pharmacokinetics of human and recombinant leukocyte interferon in patients with chronic renal failure who are undergoing dialysis. J Infect Dis. 1983; 148:335.
151. Krigel RL. Kaposi sarcoma and alpha-interferon therapy. Ann Intern Med . 1989; 111:185-6. [PubMed 2742253]
152. Scadden DT, Groopman JE. Kaposi sarcoma and alpha- interferon therapy. Ann Intern Med . 1989; 111:186-7.
153. Nightingale SL. Interferon alfa approved for Kaposi's sarcoma. JAMA . 1989; 261:350. [PubMed 2909766]
154. Krown SE, Real FX, Vadhan-Raj S et al. Kaposi's sarcoma and the acquired immune deficiency syndrome: treatment with recombinant interferon alpha and analysis of prognostic factors. Cancer . 1986; 57:1662-5. [PubMed 3081247]
155. Lane HC, Kovacs JA, Feinberg J et al. Anti-retroviral effects of interferon-α in AIDS-associated Kaposi's sarcoma. Lancet . 1988; 2:1218-22. [PubMed 2903954]
156. Groopman JE, Scadden DT. Interferon therapy for Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1989; 110:335-7. [PubMed 2644884]
157. Sulis E, Floris C, Sulis ML et al. Interferon administered intralesionally in skin and oral cavity lesions in heterosexual drug addicted patients with AIDS-related Kaposi's sarcoma. Eur J Clin Oncol . 1989; 25:759-61.
158. Wickramasinghe L, Hindson TC, Wacks H. Treatment of neoplastic skin lesions with intralesional interferon. J Am Acad Dermatol . 1989; 20:71-4. [PubMed 2913082]
159. Hilfenhaus J, Weinmann E, Majer M et al. Administration of human interferon to rabies virus-infected monkeys after exposure. J Infect Dis . 1977; 135:846-9. [PubMed 404370]
160. Eron LJ, Judson F, Tucker S et al. Interferon therapy for condylomata acuminata. N Engl J Med . 1986; 315:1059- 64. [PubMed 3531860]
161. Gall SA, Hughes CE, Trofatter K. Interferon for the therapy of condyloma acuminatum. Am J Obstet Gynecol . 1985; 153:157-63. [PubMed 3898846]
162. Laraque D. Severe anogenital warts in a child with HIV infection. N Engl J Med . 1989; 320:1220-1. [PubMed 2710199]
163. Reichman RC, Oakes D, Bonnez W et al. Treatment of condyloma acuminatum with three different interferons administered intralesionally: a double-blind, placebo-controlled trial. Ann Intern Med . 1988; 108:675-9. [PubMed 3358568]
164. Sonnenfeld G, Harned CL, Thaniyavarn S et al. Type II interferon induction and passive transfer depress the murine cytochrome P-450 drug metabolism system. Antimicrob Agents Chemother . 1980; 17:969-72. [PubMed 6157362]
165. Jordan GW, Fried RP, Merrigan TC. Administration of human leukocyte interferon in herpes zoster: I. Safety, circulating antiviral activity, and host responses to infection. J Infect Dis . 1974; 130:56-62. [PubMed 4601181]
166. Weck PK, Buddin DA, Whisnant JK. Interferons in the treatment of genital human papillomavirus infections. Am J Med . 1988; 85(Suppl 2A):159-64. [PubMed 3044081]
167. Anon. Interferon for treatment of genital warts. Med Lett Drugs Ther . 1988; 30:70-2. [PubMed 3386579]
168. Friedman-Kien AE, Eron LJ, Conant M et al. Natural interferon alfa for treatment of condylomata accuminata. JAMA . 1988; 259:533-8. [PubMed 3336177]
169. Kirby P. Interferon and genital warts: much potential, modest progress. JAMA . 1988; 259:570-2. [PubMed 2447298]
170. Groopman JE. Therapeutic options in hairy-cell leukemia. Semin Oncol . 1985; 12(Suppl 5):30-4. [PubMed 3909417]
171. Ratain MJ, Vardiman JW, Golomb HM. The role of interferon in the treatment of hairy cell leukemia. Semin Oncol . 1986: XIII(Suppl 2):21-8.
172. Weck PK, Leventhal BG, Brand C et al. Detection and incidence of neutralizing antibodies to interferon-alpha-n1. J Interferon Res . 1989; 9(Suppl 1):S37-43. [PubMed 2553830]
173. Flandrin G, Sigaux F, Castaigne S et al. Quantitative analysis of bone marrow changes during the treatment of hairy cell leukemia with interferon alfa. Cancer Treat Rev . 1985; 12(Suppl B):17-22. [PubMed 3833326]
174. Hofmann V, Fehr J, Sauter C et al. Hairy cell leukemia: an immune deficient disease? Cancer Treat Rev . 1985; 12(Suppl B):33-7.
175. Gibson J, Cameron K, Gallagher K et al. Clinical response of hairy-cell leukaemia to interferon-α: results of an Australian study. 1988; 149:293-6.
176. Castaigne S, Sigaux F, Degos L et al. Hairy cell leukemia: follow-up after completion of alpha interferon treatment. Nouv Rev Fr Hematol . 1989; 31:321-5. [PubMed 2587199]
177. Sen GC. Biochemical pathways in interferon—action. Pharmacol Ther . 1984; 24:235-57. [PubMed 6205407]
178. Brünig K, Fülle HH, Dahmen E et al. Therapy of hairy cell leukemia with interferon. Onkologie . 1988; 4:159-65.
179. Thompson JA, Kidd P, Rubin E et al. Very low dose α- 2b interferon for the treatment of hairy cell leukemia. Blood . 1989; 73:1440-3. [PubMed 2713488]
180. Kloke O, May D, Wandl U et al. Zur Dosierung von Interferon alpha in der Induktions- und Erhaltungstherapie der Haarzellenleukamie. (German; with English abstract.) Onkologie . 1988; 11(Suppl 2):41-5.
181. Hasselbalch H, Braide I, Lisse I et al. Recombinant interferon-alfa-2b treatment of hairy-cell leukemia: experience with a low dose schedule. Eur J Haematol . 1988; 41:438- 44. [PubMed 3061836]
182. Ratain MJ, Golomb HM, Vardiman JW et al. Relapse after interferon alfa-2b therapy for hairy-cell leukemia: analysis of prognostic variables. J Clin Oncol . 1988; 6:1714-21. [PubMed 3054003]
183. Belldegrun A, Koo A, Bochner B et al. Immunotherapy for metastatic renal cell carcinoma: should pretherapy nephrectomy be performed? Proc Am Soc Clin Oncol . 1990; 9:149. Abstract No. 580.
184. Vertex Pharmaceuticals Incorporated. Incivek® (telaprevir) tablets prescribing information. Cambridge, MA; 2013 Oct.
185. Merck Sharp & Dohme Corporation. Victrelis® (boceprevir) capsules prescribing information. Whitehouse Station, NJ; 2014 Jul.
186. Ehmann WC, Silber R. Recombinant alpha-2 interferon for treatment of hairy cell leukemia without prior splenectomy. Am J Med . 1986; 80:1111-14. [PubMed 3728508]
187. Janssen Therapeutics. Olysio® (simeprevir) capsules prescribing information. Titusville, NJ; 2013 Nov.
188. Gilead Sciences, Inc. Sovaldi® (sofosbuvir) tablets prescribing information. Foster City, CA; 2013 Dec.
189. Anon. Interferon to treat two cancers. NZ Pharm . 1986; 6:57.
190. Kaplan JE, Benson C, Holmes KH et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep . 2009; 58(RR-4):1-207; quiz CE1-4. [Fulltext MMWR]
191. Hood LE. Interferon: getting in the way of viruses and tumors. Am J Nurs . 1987; 87:459-65. [PubMed 2436479]
192. Bennett CL, Westbrook CA, Gruber B et al. Hairy cell leukemia and mucormycosis: treatment with alpha-2 interferon. Am J Med . 1986; 81:1065-7. [PubMed 3799636]
193. Maziarz RT, Tepler I, Antin JH et al. Reversal of infection with mycobacterium avium intracellulare by treatment with alpha-interferon in a patient with hairy cell leukemia. Ann Intern Med . 1988; 109:292-4. [PubMed 3395039]
194. Keller BC, Fredericksen BL, Samuel MA et al. Resistance to alpha/beta interferon is a determinant of West Nile virus replication fitness and virulence. J Virol . 2006; 80:9424-34. [PubMed 16973548]
195. Chan-Tack KM, Forrest G. Failure of interferon alpha-2b in a patient with West Nile virus meningoencephalitis and acute flaccid paralysis. Scand J Infect Dis . 2005; 37:944-6. [PubMed 16308241]
196. Lewis M, Amsden JR. Successful treatment of West Nile virus infection after approximately 3 weeks into the disease course. Pharmacotherapy . 2007; 27:455-8. [PubMed 17316156]
197. Krigel RL, Slywotzky CM, Lonberg M et al. Treatment of epidemic Kaposi's sarcoma with a combination of interferon-alfa 2b and etoposide. J Biol Response Mod . 1988; 7:359-64. [PubMed 3049944]
198. Clemens M. Interferons and oncogenes. Nature . 1985; 313:531-2. [PubMed 2578626]
199. Skotnick AB, Wolska-Smolen T, Blicharski J et al. Human recombinant interferon-alfa-2 in the treatment of patients with hairy cell leukemia. Cancer Detect Prev . 1988; 12:511- 22. [PubMed 3180143]
200. Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol . 2005; 79:1343-50. [PubMed 15650160]
201. Davis LE, DeBiasi R, Goade DE et al. West Nile virus neuroinvasive disease. Ann Neurol . 2006; 60:286-300. [PubMed 16983682]
202. Rai KR, Davis R, Davey F et al. Splenectomy may be avoidable in patients (pts) with active hairy cell leukemia (HCL) who are responsive to alfa-2b interferon (AIF): a cancer and leukemia group B (CALGB) study. Proc Am Soc Clin Oncol . 1989; 8:A813.
203. Krown SE. Kaposi's sarcoma and AIDS: the role of interferons in treatment. Dev Med Virol . 1988; 4:62-74.
204. Anon. Treatment of AIDS-related Kaposi's sarcoma. Am J Hosp Pharm . 1989; 46:1211.
205. Krown S, Bhalla R, Niedzwiecki D et al. Interferon (IFN), beta-2 microglobulin (beta2-m) and neopterin (Neo) in AIDS-associated Kaposi's sarcoma (KS). Fifth International Conference on AIDS. The Scientific and Social Challenge. Montreal, Canada: 1989 June 4-9. Abstract.
206. Volberding PA, Mitsuyasu RT, Golando JP et al. Treatment of Kaposi's sarcoma with interferon alfa 2b (Intron® A). Cancer . 1987; 59:620-5. [PubMed 3492260]
207. Rios A, Mansell P, Newell G et al. The use of lymphoblastoid interferon HuIFN alpha (Ly) and vinblastine in the treatment of acquired immunodeficiency syndrome (AIDS) related Kaposi's sarcoma (KS). Proc Am Soc Clin Oncol . 1985; 4:6.
208. Krown SE, Real FX, Cunningham-Rundles S et al. Preliminary observations on the effect of recombinant leukocyte A interferon in homosexual men with Kaposi's sarcoma. N Engl J Med . 1983; 308:1071-6. [PubMed 6835320]
209. Rios A, Mansell PWA, Newell GR et al. Treatment of acquired immunodeficiency syndrome-related Kaposi's sarcoma with lymphoblastoid interferon. J Clin Oncol . 1985; 3:506-12. [PubMed 3872349]
210. Mayer-da-Silva A, Stadler R, Imcke E et al. Disseminated Kaposi's sarcoma in AIDS: histogenesis-related populations and influence of long-term treatment with rIFN-αA. J Invest Dermatol . 1987; 89:618-24. [PubMed 3680987]
211. Food and Drug Administration. Alpha interferon for venereal warts. FDA Drug Bull . 1988. 18:19-20. (IDIS 245506)
212. Gariglio M, Gribaudo G, Franco A et al. Inhibition of interferon-γ antiviral and antiproliferative activities by ras oncogene expression. J Natl Cancer Inst . 1989; 81:1014-20. [PubMed 2499691]
213. Keay S, Teng N, Eisenberg M et al. Topical interferon for treating condyloma acuminata in women. J Infect Dis . 1988; 158:934-9. [PubMed 2460568]
214. Revel M, Chebath J. Interferon-activated genes. Trends Biochem Sci . 1986; 11:166-70.
215. Schering. Intron® A: interferon alfa-2b, recombinant injection product monograph. Condyloma acuminatum. Kenilworth, NJ: 1988 Jun.
216. Balkwill FR. Interferons. Lancet . 1989; 1:1060- 3. [PubMed 2469921]
217. Bunn PA Jr, Foon KA, Ihde DC et al. Recombinant leukocyte A inteferon: an active agent in advanced cutaneous T- cell lymphomas. Ann Intern Med . 1984; 101:484-7. [PubMed 6332565]
218. Gutterman JU, Fine S, Quesada J et al. Recombinant leukocyte A interferon: pharmacokinetics, single-dose tolerance, and biological effects in cancer patients. Ann Intern Med . 1982; 96:549-56. [PubMed 6176159]
219. Anon. Interferon for treatment of hairy-cell leukemia. Med Lett Drugs Ther . 1986; 28:78-80. [PubMed 3736496]
220. Thompson JA, Brady J, Kidd P et al. Recombinant alpha-2 interferon in the treatment of hairy cell leukemia. Cancer Treat Rep . 1985; 69:791-3. [PubMed 4016788]
221. Naeim F, Jacobs AD. Bone marrow changes in patients with hairy cell leukemia treated by recombinant alpha2- interferon. Hum Pathol . 1985; 16:1200-5. [PubMed 4065882]
222. Gall SA, Hughes CE, Whisnant J et al. Therapy of resistant condyloma acuminata with lymphoblastoid interferon. J Cell Biochem . 1985; 27:(Suppl 9C):91.
223. Gall SA, Hughes CE, Mounts P et al. Efficacy of human lymphoblastoid interferon in the therapy of resistant condyloma acuminata. Obstet Gynecol . 1986; 67:643-51. [PubMed 3008054]
224. Hersey P, Hasic E, MacDonald M et al. Effects of recombinant leukocyte interferon (RIFN-alfa A) on tumor growth and immune responses in patients with metastatic melanoma. Br J Cancer . 1985; 51:815-26. [PubMed 3873953]
225. Quesada JR, Rios A, Swanson D et al. Antitumor activity of recombinant-derived interferon alpha in metastatic renal cell carcinoma. J Clin Oncol . 1985; 3:1522-8. [PubMed 4056843]
226. Reichman RC, Bonnez W, Greisberger C et al. Treatment of condyloma acuminatum with intralesionally administered interferons: a multicentered, placebo-controlled trial. Clin Res . 1986; 34:531A.
227. Alawattegama AB, Kinghorn GR. Bowenoid dysplasia in human papillomavirus-16 DNA positive flat condylomas during interferon-β treatment. Lancet . 1984; 1:1468. [PubMed 6145904]
228. Benedetti Panici P, Scambia G, Baiocchi G et al. Randomized clinical trial comparing systemic interferon with diathermocoagulation in primary multiple and widespread anogenital condyloma. Obstet Gynecol . 1989; 74:393-7. [PubMed 2761917]
229. Boot JM, Blog FB, Stolz E. Intralesional interferon alfa-2b treatment of condylomata acuminata previously resistant to podophyllum resin application. Genitourin Med . 1989; 65:50-3. [PubMed 2921053]
230. Tyring SK, Cauda R, Baron S et al. Condyloma acuminatum: epidemiological, clinical and therapeutic aspects. Eur J Epidemiol . 1987; 3:209-15. [PubMed 3308509]
231. Tyring SK. Treatment of condyloma acuminatum with interferon. Semin Oncol . 1988; 15(Suppl 5):35-40. [PubMed 2461596]
232. Tovey MG, Dron M, Mogensen KE et al. Isolation of Daudi cells with reduced sensistivity to interferon: II. On the mechanisms of resistance. J Gen Virol . 1983; 64:2649-53. [PubMed 6319552]
233. Ferenczy A, Mitao M, Nagai N et al. Latent papillomavirus and recurring genital warts. N Engl J Med . 1985; 313:784-8. [PubMed 2993887]
234. Schneider A, Papendick U, Gissmann L et al. Interferon treatment of human genital papillomavirus infection: importance of viral type. Int J Cancer . 1987; 15:610-4.
235. Krown SE. Interferons and interferon inducers in cancer treatment. Semin Oncol . 1986; 13:207-17. [PubMed 2424089]
236. Joshi AR, Sarkar FH, Gupta SL. Interferon receptors: cross-linking of human leukocyte interferon α-2 to its receptor on human cells. J Biol Chem . 1982; 257:13884-7. [PubMed 6292213]
237. Schering. Intron®-A: a new, highly effective treatment for hairy cell leukemia. Kenilworth, New Jersey; 1986 Jul.
238. Einhorn N, Ling P, Strander H. Systemic interferon alpha treatment of human condylomata acuminata. Acta Obstet Gynecol Scand . 1983; 62:285-7. [PubMed 6624402]
239. Castaigne S, Sigaux F, Cantell K et al. Interferon alpha in the treatment of hairy cell leukemia. Cancer . 1986; 57:1681-4. [PubMed 3948138]
240. Geffen JR, Klein RJ, Friedman-Klein A. Intralesional administration of large doses of human leukocyte interferon for the treatment of condylomata acuminata. J Infect Dis . 1984; 150:612-5. [PubMed 6491370]
241. Vance JC, Bart BJ, Hansen RC et al. Intralesional recombinant alpha-2 interferon for the treatment of patients with condyloma acuminatum or verruca plantaris. Arch Dermatol . 1986; 122:272-7. [PubMed 3954392]
242. Reichman RC, Oakes D, Bonnez W et al. Treatment of condyloma acuminatum with three different interferon-α preparations administered parenterally: a double-blind, placebo- controlled trial. J Infect Dis . 1990; 162:1270-6. [PubMed 2172401]
243. Holmes R, Whiteside MG, Schwarz MA et al. Treatment of hairy cell leukemia with increasing doses of recombinant alpha A interferon. Aust N Z J Med . 1988; 18:557-62. [PubMed 3196242]
244. Weck PK, Brandsma JL, Whisnant JK. Interferons in the treatment of human papillomavirus diseases. Cancer Metastasis Rev . 1986; 5:139-65. [PubMed 2435427]
245. Androphy EJ. Papillomaviruses and interferon. In: Papillomaviruses: Ciba Foundation Symposium 120. New York: John Wiley & Sons; 1986:221-34.
246. Worman CP, Catovsky D, Beavan PC et al. Interferon is effective in hairy-cell leukaemia. Br J Haematol . 1985; 60:759-63. [PubMed 3875366]
248. Quesada JR, Hersh EM, Manning J et al. Treatment of hairy cell leukemia with recombinant α-interferon. Blood . 1986; 68:493-7. [PubMed 3730612]
249. Quesada JR, Hersh EM, Reuben J et al. Treatment of hairy cell leukemia (HCL) with recombinant-DNA derived interferon alpha (RIFN(ALPHA)A). Proc Am Soc Clin Oncol . 1985; 4:222.
250. Ratain MJ, Golomb HM, Bardawil RG et al. Durability of responses to interferon alfa-2b in advanced hairy cell leukemia. Blood . 1987; 69:872-7. [PubMed 3814819]
251. Cheson BD, Martin A. Clinical trials in hairy cell leukemia: current status and future directions. Ann Intern Med . 1987; 106:871-8. [PubMed 3555204]
252. Ratain MJ, Golomb HM, Vardiman JW et al. Treatment of hairy cell leukemia with recombinant alpha2 interferon. Blood . 1985; 65:644-8. [PubMed 3971043]
253. Choudhury C, Raman C, Gallagher MT et al. Restoration of natural killer cell activity and immune competence against Histoplasma capsulatum in hairy-cell leukemia following treatment with recombinant alpha interferon. Curr Ther Res . 1989; 45:179-87.
254. Koeller JM. Biological response modifiers: the interferon alfa experience. Am J Hosp Pharm . 1989; 46(Suppl 2):S11-5. [PubMed 2481396]
255. Borden EC. Progress toward therapeutic application of interferons, 1979-1983. Cancer . 1984; 54:2770-6. [PubMed 6208992]
256. Stiehm ER, Kronenberg LH, Rosenblatt HM et al. Interferon: immunobiology and clinical significance. Ann Intern Med . 1982; 96:80-93. [PubMed 617,2066]
257. Craig JB. Biological response modifiers in the therapy of malignant disease: current status and future prospects. Schumpert Med Q . 1988; 7:88-107.
258. Smalley RV, Oldham RK. Phase 1 trials of biological response modifiers. Drugs Exp Clin Res . 1986; XII:31-9.
259. Goldstein D, Laszlo J, Rudnick S. Interferon therapy in cancer. In: Oldham RK, ed. Principles of cancer biotherapy. New York: Raven Press, Ltd. 1987:247-72.
260. Spiegel RJ. Intron® A (interferon alfa-2b): clinical overview and future directions. Semin Oncol . 1986; XIII(Suppl 2):89-101.
261. Goldstein D, Laszlo J. Interferon therapy in cancer: from imaginon to interferon. Cancer Res . 1986; 46:4315- 29. [PubMed 2425950]
262. Lotze MT, Rosenberg SA. The immunologic treatment of cancer. Ca Cancer J Clin . 1988; 38:68-95. [PubMed 2450624]
263. Balkwill FR, Smyth JF. Interferons in cancer therapy: a reappraisal. Lancet . 1987; 2:317-9. [PubMed 2441217]
264. Brouty-Boye D, Wybier-Franqui J, Calvo C et al. Reversibility of the transformed and neoplastic phenotype: IV. Effects of long-term interferon treatment of C3H/10T½ cells transformed by methylcholanthrene and SV40 virus. Int J Cancer . 1984; 34:107-12. [PubMed 6204950]
265. World Health Organization. Progress in the development and use of antiviral drugs and interferon: report of a WHO scientific group. Geneva: World Health Organization; 1987.
266. Janssen JTP, de Pauw BE, Holdrinet RSG. Treatment of hairy-cell leukaemia with recombinant human α2- interferon. Lancet . 1984; 1:1025-6.
267. Aach RD. The treatment of chronic type B viral hepatitis. Ann Intern Med . 1988; 109:89-91. [PubMed 3289432]
268. Hoofnagle JH. Antiviral treatment of chronic type B hepatitis. Ann Intern Med . 1987; 107:414-5. [PubMed 2441635]
269. Anon. Chemotherapy and hepatitis B. Lancet . 1989; 2:1136-7. [PubMed 2572853]
270. Koretz RL, Baker M. New drug treatments for chronic liver disease: will this medical marriage last? Hosp Ther . 1989; 14:37-49.
271. Godefroid RJ. α-interferon in treating chronic hepatitis B virus infection. Drug Intell Clin Pharm . 1986; 20:234. [PubMed 3956385]
272. Spiegel RJ. Additional indications for interferon therapy: basal cell carcinoma, carcinoid, and chronic active hepatitis. Semin Oncol . 1988; 15(Suppl 5):41-5. [PubMed 3057643]
273. Galvani D, Griffiths SD, Cawley JC. Interferon for treatment: the dust settles. BMJ . 1988; 296:1554-6. [PubMed 2456124]
274. Main J, Thomas HC. Treatment of chronic hepatitis B infection. Pharmacol Ther . 1990; 45:373-81. [PubMed 2405441]
275. Alexander G, Williams R. Antiviral treatment in chronic infection with hepatitis B virus. BMJ . 1986; 292:915-7. [PubMed 2421818]
276. Alter MJ, Sampliner RE. Hepatitis C—and miles to go before we sleep. N Engl J Med . 1989; 321:1538-40. [PubMed 2509918]
277. Di Bisceglie AM, Martin P, Kassianides C et al. Recombinant interferon alfa therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. N Engl J Med . 1989; 321:1506-10. [PubMed 2509917]
278. Zorsky P, Siegel RS. Hairy-cell leukemia. Drug Ther . 1986; 16:137-9, 143.
279. Alexander GJM, Williams R. Natural history and therapy of chronic hepatitis B virus infection. Am J Med . 1988; 85(Suppl 2A):143-6. [PubMed 3044078]
280. Liaw YF, Lin SM, Sheen IS et al. Treatment of chronic type B hepatitis in Southeast Asia. Am J Med . 1988; 85(Suppl 2A):147-9. [PubMed 3044079]
281. Mazzella G, Saracco G, Rizetto M et al. Human lymphoblastoid interferon for the treatment of chronic hepatitis B: a randomized controlled trial. Am J Med . 1988; 85(Suppl 2A):141-2. [PubMed 3044077]
282. Zoon K, Zur Nedden D, Arnheiter H. Specific binding of human α interferon to a high affinity cell surface binding site on bovine kidney cells. J Biol Chem . 1982; 257:4695-7. [PubMed 6175643]
283. Garcia G, Smith CI, Weissberg JI et al. Adenine arabinoside monophosphate (vidarabine phosphate) in combination with human leukocyte interferon in the treatment of chronic hepatitis B: a randomized, double-blinded, placebo-controlled trial. Ann Intern Med . 1987; 107:278-85. [PubMed 2441633]
284. Perrillo RP, Regenstein FG, Peters MG et al. Prednisone withdrawal followed by recombinant alpha interferon in the treatment of chronic type B hepatitis: a randomized, controlled trial. Ann Intern Med . 1988; 109:95-100. [PubMed 3289433]
285. Alexander GJM, Brahm J, Fagan EA et al. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection. Lancet . 1987: 2:66-9.
286. Smyth JF, Balkwill FR, Cavalli F et al. Interferons in oncology: current status and future directions. Eur J Cancer Clin Oncol . 1987; 23:887-9. [PubMed 2443361]
289. Lisker-Melman M, Webb D, Di Bisceglie AM et al. Glomerulonephritis caused by chronic hepatitis B virus infection: treatment with recombinant human alpha-interferon. Ann Intern Med . 1989; 111:479-83. [PubMed 2774373]
293. Kakumu S, Arao M, Yoshioka K et al. Pilot study of recombinant human alpha-interferon for chronic non-A, non-B hepatitis. Am J Gastroenterol . 1989; 84:40-5. [PubMed 2521421]
294. Schvarcz R, Weiland O, Wejstal R et al. A randomized controlled open study of interferon alpha-2b treatment of chronic non-A, non-B posttransfusion hepatitis: no correlation of outcome to presence of hepatitis C virus antibodies. Scand J Infect Dis . 1989; 21:617-25. [PubMed 2482536]
295. Coppens JP, Cornu C, Lens E et al. Prospective trial of recombinant leucocyte interferon in chronic hepatitis B: a 10- month follow-up study. Liver . 1989; 9:307-13. [PubMed 2685491]
296. Weiland O, Schvarcz R, Wejstal R et al. Interferon alpha-2b treatment of chronic posttransfusion non-A, non-B hepatitis: interim results of a randomized controlled open study. Scand J Infect Dis . 1989; 21:127-32. [PubMed 2499037]
297. Hoofnagle JH, Peters M, Mullen KD et al. Randomized, controlled trial of recombinant human alpha-interferon in patients with chronic hepatitis B. Gastroenterol . 1988; 95:1318-25.
298. Figlin RA. Biotherapy with interferon—1988. Semin Oncol . 1988; 15(Suppl 6):3-9. [PubMed 2462749]
299. Figlin RA. Biotherapy in clinical practice. Semin Hematol . 1989; 26(Suppl 3):15-24. [PubMed 2477904]
300. Spiegel RJ. Clinical overview of alpha interferon: studies and future directions. Cancer . 1987; 59:626-31. [PubMed 3542185]
301. Talpaz M, Kantarjian H, McCredie K et al. Therapy of chronic myelogenous leukemia. Cancer . 1987; 59:664-7. [PubMed 10822467]
302. Fahey JL, Sarna G, Gale RP et al. Immune interventions in disease. Ann Intern Med . 1987; 106:257-74. [PubMed 2432815]
303. Bergsagel DE, Haas RH, Messner HA. Interferon alfa-2b in the treatment of chronic granulocytic leukemia. Semin Oncol . 1986; XIII(Suppl 2):29-34.
304. Champlin R, Gale RP, Foon KA et al. Chronic leukemias: oncogenes, chromosomes, and advances in therapy. Ann Intern Med . 1986; 104:671-88. [PubMed 3008618]
305. Roth MS, Foon KA. Alpha interferon in the treatment of hematologic malignancies. Am J Med . 1986; 81:871-82. [PubMed 3535496]
306. Fauci AS, Rosenberg SA, Sherwin SA et al. Immunomodulators in clinical medicine. Ann Intern Med . 1987; 106:421-33. [PubMed 2433978]
307. Talpaz M, Kantarjian HM, McCredie K et al. Hematologic remission and cytogenetic improvement induced by recombinant human interferon alphaA in chronic myelogenous leukemia. N Engl J Med . 1986; 314:1065-9. [PubMed 3457264]
308. Opalka B, Kloke O, Bartram CR et al. Elimination by interferon-alpha of malignant clone in chronic myeloid leukaemia. Lancet . 1989; 1:1334. [PubMed 2566865]
309. Talpaz M. Activity of alpha-interferons in chronic myelogenous leukaemia. Br J Clin Pract . 1988; 42(Suppl 62):13-5.
310. Ozer H. Biotherapy of chronic myelogenous leukemia with interferon. Semin Oncol . 1988; 15(Suppl 5):14-20. [PubMed 2461592]
311. Ozer H, Mick R, Testa J et al. Subcutaneous alpha- interferon (AIFN) shows substantial activity in untreated chronic phase Philadelphia chromosome positive (ph+) chronic myelogenous leukemia (CML). Proc Am Soc Clin Oncol . 1988; 7:A684.
312. Talpaz M, Kantarjian HM, Kurzrock R et al. Therapy of chronic myelogenous leukemia: chemotherapy and interferons. Semin Hematol . 1988; 25:62-73. [PubMed 2450402]
313. Gutterman JU. The role of interferons in the treatment of hematologic malignancies. Semin Hematol . 1988; 25(Suppl 3):3-8. [PubMed 2459780]
314. Jacobs P, Le Roux IM, Wood L et al. Recombinant alpha- interferon as salvage therapy in multiple myeloma: a pilot study. S Afr Med J . 1989; 76:100-2. [PubMed 2762938]
315. Buzaid AC, Durie BG. Management of refractory myeloma: a review. J Clin Oncol . 1988; 6:889-905. [PubMed 2452861]
316. Cooper MR. Interferons in the management of multiple myeloma. Semin Oncol . 1988; 15(Suppl 5):21-5. [PubMed 3057642]
317. Bonnem EM. The therapy of multiple myeloma with the interferons. Cancer Treat Rev . 1988; 15(Suppl A):35-41. [PubMed 2449280]
318. Quesada JR, Alexanian R, Hawkins M et al. Treatment of multiple myeloma with recombinant α-interferon. Blood . 1986; 67:275-8. [PubMed 3942826]
319. Cooper MR. Interferons in the treatment of multiple myeloma. Semin Oncol . 1986; XIII(Suppl 2):13-20.
320. Barlogie B, Epstein J, Selvanayagam P et al. Plasma cell myeloma—new biological insights and advances in therapy. Blood . 1989; 73:865-79. [PubMed 2465790]
321. Costanzi JJ, Cooper MR, Scarffe JH et al. Phase II study of recombinant alpha-2 interferon in resistant multiple myeloma. J Clin Oncol . 1985; 3:654-9. [PubMed 3998782]
325. Anon. Effect of interferon alpha-2B in advanced multiple myeloma. J Intern Med . 1990; 227:45-8. [PubMed 2299297]
326. Costanzi JJ, Pollard RB. The use of interferon in the treatment of multiple myeloma. Semin Oncol . 1987; 14(2 Suppl 2):24-8. [PubMed 3296211]
327. Cooper MR, Welander CE. Interferons in the treatment of multiple myeloma. Semin Oncol . 1986; 13:334-40. [PubMed 2429367]
328. Costanzi JJ, Pollard RB. The use of interferon in the treatment of multiple myeloma. In: Baron S et al, eds. The interferon system. A current review to 1987. Austin, TX: University of Texas Press; 1987:497-505.
329. Cox EB, Laszlo J, Krown S et al. Phase II study of human lymphoblastoid interferon in patients with multiple myeloma. J Biol Response Mod . 1988; 7:318-25. [PubMed 3392554]
330. Ohno R. Interferons in the treatment of multiple myeloma. Int J Cancer . 1987; 1(Suppl):14-20.
331. Krown SE. Therapeutic options in renal-cell carcinoma. Semin Oncol . 1985; 12(Suppl 5):13-7. [PubMed 2417331]
332. Sarna G, Figlin R, De Kernion J. Interferon in renal cell carcinoma. Cancer . 1987; 59:610-2. [PubMed 3542184]
333. Quesada JR. Biologic response modifiers in the therapy of metastatic renal cell carcinoma. Semin Oncol . 1988; 15:396-407. [PubMed 2457256]
334. Krown SE. Interferon treatment of renal cell carcinoma: current status and future prospects. Cancer . 1987; 59:647-51. [PubMed 10822464]
335. DeKernion JB, Sarna G, Figlin R et al. The treatment of renal cell carcinoma with human leukocyte alpha-interferon. J Urol . 1983; 130:1063-6. [PubMed 6644883]
336. Grosh WW. Renal cell carcinoma: treatment with interferon. Compr Ther . 1987; 13:34-9. [PubMed 2438082]
337. Kirkwood JM, Ernstoff M. Melanoma: therapeutic options with recombinant interferons. Semin Oncol . 1985; 12(Suppl 5):7-12. [PubMed 2417333]
338. Kirkwood JM, Ernstoff M. Potential applications of the interferons in oncology: lessons drawn from studies of human melanoma. Semin Oncol . 1986; XIII(Suppl 2):48-56.
339. Creagan ET, Ahmann DL, Frytak S et al. Three consecutive phase II studies of recombinant interferon alfa-2a in advanced malignant melanoma: updated analyses. Cancer . 1987; 59:638-46. [PubMed 10822463]
340. Legha SS. Current therapy for malignant melanoma. Semin Oncol . 1989; 16(1 Suppl 1):34-44. [PubMed 2465575]
341. Steis RG, Foon KA, Longo DL. Current and future uses of recombinant interferon alpha in the treatment of low-grade non- Hodgkin's lymphoma. Cancer . 1987; 59:658-63. [PubMed 10822466]
342. Kaplan EH, Rosen ST, Norris DB et al. Phase II study of recombinant human interferon gamma for treatment of cutaneous T- cell lymphoma. J Natl Cancer Inst . 1990; 82:208-12. [PubMed 2104937]
343. Wagstaff J, Scarffe JH, Crowther D. Interferon in the treatment of multiple myeloma and the non-Hodgkin's lymphomas. Cancer Treat Rev . 1985; 12(Suppl B):39-44. [PubMed 2421896]
344. Alcalay J, David M, Lotem M et al. Interferon and T- cell lymphoma. Ann Intern Med . 1987; 107:428. [PubMed 3619235]
345. Otto U, Conrad S, Schneider AW et al. Combined therapy with TNF-alpha and IFN-alpha-2a: a promising approach to treatment of metastatic renal cell carcinoma. Proc Am Soc Clin Oncol . 1990; 9:147.
346. Foon KA, Roth MS, Bunn PA Jr. Alpha interferon treatment of low-grade B-cell non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, and chronic lymphocytic leukemia. Semin Oncol . 1986; XIII(Suppl 2):35-42.
347. Canellos GP. Interferon in the treatment of malignant lymphoma. Semin Oncol . 1985; 12(Suppl 5):25-9. [PubMed 2417332]
348. Foon KA, Roth MS, Bunn PA Jr. Interferon therapy of non-Hodgkin's lymphoma. Cancer . 1987; 59:601-4. [PubMed 3492259]
349. Merck Sharp & Dohme Corporation. Rebetol® (ribavirin) capsules and oral solution prescribing information. Whitehouse Station, NJ; 2013 Nov.
350. Urba WJ, Hartmann LC, Watson T et al. Low- versus high- dose interferon alfa-2a in relapsed indolent non-Hodgkin's lymphoma. J Natl Cancer Inst . 1990; 82:235-8. [PubMed 2296053]
351. Belldegrun AS, Franklin JR, O'Donnell MA et al. Superficial bladder cancer: the role of interferon-α. J Urol . 1998; 159:1793-801. [PubMed 9598463]
352. Rajala P, Liukkonen T, Raitanen M et al. Transurethral resection with perioperative instillation of interferon-α or epirubicin for the prophylaxis of recurrent primary superficial bladder cancer: a prospective randomized multicenter study—Finnbladder III. J Urol . 1999; 161:1133-6. [PubMed 10081854]
353. Portillo J, Martin B, Hernandez R et al. Results at 43 months' follow-up of a double-blind, randomized, prospective clinical trial using intravesical interferon alpha-2b in the prophylaxis of stage pT1 transitional cell carcinoma of the bladder. Urology . 1997; 49:187-90. [PubMed 9037279]
354. Jimenez-Cruz JF, Vera-Donoso CD, Leiva O et al. Intravesical immunoprophylaxis in recurrent superficial bladder cancer (Stage T1): multicenter trial comparing bacille Calmette-Guerin and interferon-alpha. Urology . 1997; 50:529-35. [PubMed 9338727]
355. Raitanen MP, Lukkarinen O. A controlled study of intravesical epirubicin with or without alpha 2b-interferon as prophylaxis for recurrent superficial transitional cell carcinoma of the bladder. Finnish Multicentre Study Group. Br J Urol . 1995; 76:697-701. [PubMed 8535711]
356. Torti FM, Shortliffe LD, Williams RD et al. Alpha- interferon in superficial bladder cancer: a Northern California Oncology Group study. J Clin Oncol . 1988; 6:476-83. [PubMed 3280742]
357. Welander CE. Use of interferon in the treatment of ovarian cancer as a single agent and in combination with cytotoxic drugs. Cancer . 1987; 59:617-9. [PubMed 3802026]
358. Berek JS, Markman M, Blessing JA et al. Intraperitoneal alpha-interferon alternating with cisplatin in residual ovarian carcinoma: a phase II Gynecologic Oncology Group study. Gynecol Oncol . 1999; 74:48-52. [PubMed 10385550]
359. Berek JS, Markman M, Stonebraker B et al. Intraperitoneal interferon-alpha in residual ovarian carcinoma: a phase II gynecologic oncology group study. Gynecol Oncol . 1999; 75:10-4. [PubMed 10502418]
360. Berek JS, Hacker NF, Lichtenstein A et al. Intraperitoneal recombinant alpha-interferon for 'salvage' immunotherapy in stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Cancer Res . 1985; 45:4447-53. [PubMed 4028027]
361. Kuzel TM, Gilyon K, Springer E. Interferon alfa-2a combined with phototherapy in the treatment of cutaneous T-cell lymphoma. J Natl Cancer Inst . 1990; 82:203-7. [PubMed 2296050]
366. Lundquist PG, Haglund S, C et al. Interferon therapy in juvenile laryngeal papillomatosis. Otolaryngol Head Neck Surg . 1984; 92:386-91. [PubMed 6207477]
367. McCabe BF, Clark KF. Interferon and laryngeal papillomatosis: the Iowa experience. Ann Otol Rhinol Laryngol . 1983; 92:2-7. [PubMed 6824274]
368. Haglund S, Lundquist PG, Cantell K et al. Interferon therapy in juvenile laryngeal papillomatosis. Arch Otolaryngol . 1981; 107:327-32. [PubMed 6164359]
369. Lodemann E, Kornhuber B, Gerein V et al. (2'- 5')oligo(A) synthetase as a monitor of interferon action in juvenile laryngeal papillomatosis. J Interferon Res . 1984; 4:283-90. [PubMed 6747349]
372. Goepfert H, Sessions RB, Gutterman JU et al. Leukocyte interferon in patients with juvenile laryngeal papillomatosis. Ann Otol Rhinol Laryngol . 1982; 91:431-6. [PubMed 6180672]
374. Kirkwood JM, Ernstoff MS. Interferons in the treatment of human cancer. J Clin Oncol . 1984; 2:336-52. [PubMed 6323641]
376. Quesada JR, Talpaz M, Rios A et al. Clinical toxicity of interferons in cancer patients: a review. J Clin Oncol . 1986; 4:234-43. [PubMed 2418169]
378. Groopman JE. Biology and therapy of epidemic Kaposi's sarcoma. Cancer . 1987; 59:633-7. [PubMed 10822462]
379. Mitsuyasu R, Volberding P, Jacobs A et al. High dose alpha-2 recombinant interferon (IFN) in the therapy of epidemic Kaposi's sarcoma (KS) in acquired immune deficiency (AIDS). Proc Am Soc Clin Oncol . 1984; 3:51.
380. Real FX, Oettgen HF, Krown SE. Kaposi's sarcoma and the acquired immunodeficiency syndrome: treatment with high and low doses of recombinant leukocyte A interferon. J Clin Oncol . 1986; 4:544-51. [PubMed 3958767]
381. Volberding PA, Mitsuyasu R. Recombinant interferon alpha in the treatment of acquired immune deficiency syndrome—related Kaposi's sarcoma. Semin Oncol . 1985; 12:2-6. [PubMed 3909416]
382. Mitsuyasu RT, Lee KJ. T-lymphocyte colony assay (CFU-T) in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS). Exp Hematol . 1984; 12:442.
383. Mitsuyasu RT, Taylor JMG, Glaspy J et al. Heterogeneity of epidemic Kaposi's sarcoma: implications for therapy. Cancer . 1986; 57:1657-61. [PubMed 3081246]
384. Taylor J, Afrasiabi R, Fahey JL et al. Prognostically significant classification of immune changes in AIDS with Kaposi's sarcoma. Blood . 1986; 67:666-71. [PubMed 3081065]
385. Abrams DI, Volberding PA. Alpha interferon therapy of AIDS-associated Kaposi's sarcoma. Semin Oncol . 1986; XIII(Suppl 2):43-7.
386. Krown SE. The role of interferon in the therapy of epidemic Kaposi's sarcoma. Semin Oncol . 1987; 14(Suppl 3):27-33. [PubMed 2440110]
387. Fahey JL, Taylor J, Afrasiabi R et al. AIDS and Kaposi sarcoma. In: Reif AE, Mitchell MS, eds. Immunity to cancer. New York: Academic Press; 1985:347-61.
388. Mitsuyasu R, Afrasiabi R, Taylor J et al. Immunologic prognostic variable in patients with AIDS and Kaposi's sarcoma (KS). Proc Am Soc Clin Oncol . 1985; 4:1.
389. Mitsuyasu RT, Afrasiabi R, Taylor J et al. Prognostic immunologic variables in epidemic Kaposi's sarcoma (KS). International conference on acquired immunodeficiency syndrome (AIDS). Atlanta, GA: 1985 April 14-17. Abstract.
390. Shuler JD, Holland GM, Miles SA et al. Kaposi sarcoma of the conjunctiva and eyelids associated with the acquired immunodeficiency syndrome. Arch Ophthalmol . 1989; 107:858-62. [PubMed 2471496]
391. Vadhan-Raj S, Wong G, Gnecco C et al. Immunological variables as predictors of prognosis in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome. Cancer Res . 1986; 46:417-25. [PubMed 2415251]
392. Lonberg M, Odajnyk C, Krigel R et al. Sequential and simultaneous alpha 2 interferon (IFN) and VP16 in epidemic Kaposi's sarcoma (EKS). Proc Am Soc Clin Oncol . 1985; 4:2.
393. Preble OT, Rook AH, Steis R et al. Interferon-induced 2'-5' oligoadenylate synthetase during interferon-alpha therapy in homosexual men with Kaposi's sarcoma: marked deficiency in biochemical response to interferon in patients with acquired imunodeficiency syndrome. J Infect Dis . 1985; 152:457-65. [PubMed 2993441]
394. Krown SE, Gold JW, Real FX et al. Interferon alpha-2A +/- vinblastine (VLB) in AIDS-associated Kaposi's sarcoma (KS/AIDS): therapeutic activity, toxicity and effects on HTLV-III/LAV viremia. J Interferon Res . 1986; 6(Suppl 1):3.
395. Fischl M, Lucas S, Gorowski E et al. Interferon alpha- N1 wellferon (WFN) in Kaposi's sarcoma: single agent or combination with vinblastine (VLB). J Interferon Res . 1986; 6(Suppl 1):4.
398. Krown SE, Bundow B, Gansbacher W et al. Interferon-α (IFN-α) plus zidovudine (ZDV) in AIDS-associated Kaposi's sarcoma (AIDS/KS): an ongoing phase I trial. Proc Am Soc Clin Oncol . 1988; 7:1.
400. DeVita VT Jr, Broder S, Fauci AS et al. Developmental therapeutics and the acquired immunodeficiency syndrome. Ann Intern Med . 1987; 106:568-81. [PubMed 2435201]
401. Wills RJ, Spiegel HE, Soike KF. Pharmacokinetics of recombinant alpha A interferon following I.V. infusion and bolus, I.M., and P.O. administrations to African monkeys. J Interferon Res . 1984; 4:399-409. [PubMed 6491397]
402. Bocci V, Mogensen KE, Muscettola M et al. Degradation of human125I-interferon alpha by isolated perfused rabbit kidney and liver. J Lab Clin Med . 1983; 101:857- 63. [PubMed 6854125]
403. Kadmon Pharmaceuticals, LLC. Ribasphere® (ribavirin) capsules prescribing information. Warrendale, PA; 2012 Dec.
406. Budavari S, ed. The Merck index. l1th ed. Rahway, NJ: Merck & Co, Inc; 1989:790-1.
407. Sherwin SA, Knost JA, Fein S et al. A multiple-dose phase I trial of recombinant leukocyte A interferon in cancer patients. JAMA . 1982; 248:2461-6. [PubMed 6752447]
408. Kirkwood JM, Ernstoff MS, Davis CA et al. Comparison of intramuscular and intravenous recombinant alpha-2 interferon in melanoma and other cancers. Ann Intern Med . 1985; 103:32-6. [PubMed 4003987]
409. Bornemann LD, Spiegel HE, Dziewanowska ZE et al. Intravenous and intramuscular pharmacokinetics of recombinant leukoctye A interferon. Eur J Clin Pharmacol . 1985; 28:469-71. [PubMed 4029251]
410. Cheeseman SH, Rubin RH, Stewart JA et al. Controlled clinical trial of prophylactic human-leukocyte interferon in renal transplantation. N Engl J Med . 1979; 300:1345-9. [PubMed 220536]
411. Ho DD, Hartshorn KL, Rota TR et al. Recombinant human interferon alfa-A suppresses HTLV-III replication in vitro. Lancet . 1985; 1:602-4. [PubMed 2857946]
412. Strander H, Cantell K, C et al. Clinical and laboratory investigations on man: systemic administration of potent interferon to man. J Natl Cancer Inst . 1973; 51:733-42. [PubMed 4355215]
413. Priestman TJ. Initial evaluation of human lymphoblastoid interferon in patients with advanced malignant disease. Lancet . 1980; 2:113-8. [PubMed 6157064]
414. Habif DV, Lipton R, Cantell K. Interferon crosses blood-cerebrospinal fluid barrier in monkeys (38790). Proc Soc Exp Biol Med . 1975; 149:287-9. [PubMed 1144440]
415. Roche Laboratories. Product information on Roferon®- A. Nutley, NJ; 1986 Jul.
416. Merigan TC, Rand KH, Pollard RB et al. Human leukocyte interferon for the treatment of herpes zoster in patients with cancer. N Engl J Med . 1978; 298:891-7.
417. Witter F, Barouki F, Griffin D et al. Biologic response (antiviral) to recombinant human interferon alpha 2a as a function of dose and route of administration in healthy volunteers. Clin Pharmacol Ther . 1987; 42:567-75. [PubMed 2445516]
418. Gibson DM, Cotler S, Speigel HE et al. Pharmacokinetics of recombinant leukocyte A interferon following various routes and modes of administration to the dog. J Interferon Res . 1985; 5:403-8. [PubMed 4056487]
419. Quesada JR, Gutterman JU. Clinical study of recombinant DNA-produced leukocyte interferon (clone A) in an intermittent schedule in cancer patients. J Natl Cancer Inst . 1983; 70:1041-6. [PubMed 6190033]
420. Wills RJ, Spiegel HE. Continuous intravenous infusion pharmacokinetics of interferon to patients with leukemia. J Clin Pharm . 1985; 25:616-9.
421. Collins JM, Riccardi R, Trown P et al. Plasma and cerebrospinal fluid pharmacokinetics of recombinant interferon alpha A in monkeys: comparison of intravenous, intramuscular, and intraventricular delivery. Cancer Drug Delivery . 1985; 2:247-53. [PubMed 4063949]
422. Turek LP, Byrne JC, Lowy DR et al. Interferon induces morphologic reversion with elimination of extrachromosomal viral genes in bovine papillomavirus-transformed mouse cells. Proc Natl Acad Sci USA . 1982; 79:7914-8. [PubMed 6185955]
423. ViiV Healthcare. Retrovir® (zidovudine) tablets, capsules, and syrup prescribing information. Research Triangle Park, NC; 2012 May.
424. Stewart WE II, Blacock JE, Burke DC et al. Interferon nomenclature. J Immunol . 1980; 125:2353. [PubMed 6159407]
425. Stewart WE II. Interferon nomenclature recommendations. J Infect Dis . 1980; 142:643. [PubMed 6160187]
426. Stewart WE II, Blacock JE, Burke DC et al. Interferon nomenclature. Int J Immunopharmacol . 1980; 2:363-4. [PubMed 6162809]
427. The Interferon Nomenclature Committee. Interferon nomenclature. J Interferon Res . 1983; 3:377-8. [PubMed 6200548]
428. Stewart WE II, Blacock JE, Burke DC et al. Interferon nomenclature. Eur J Immunol . 1980; 10:660. [PubMed 6156851]
429. Stewart WE II, Blacock JE, Burke DC et al. Interferon nomenclature. Nature . 1980; 286:110. [PubMed 6157097]
430. The Interferon Nomenclature Committee. Interferon nomenclature. Arch Virol . 1983; 77:282-5.
431. Purdue Frederick Company. Alferon® N injection (interferon alfa-n3 [human leukocyte derived]) product information. Norwalk, CT; 1989 Nov.
433. Interferon Sciences. Summary basis of approval: Alferon® N injection (interferon alfa-n3 [human leukocyte derived]). Reference No.: 85-577. New Brunswick, NJ. (undated)
434. Rohatiner AZS, Balkwill FR, Griffin DB et al. A phase I study of human lymphoblastoid interferon administered by continuous intravenous infusion. Cancer Chemother Pharmacol . 1982; 9:97-102. [PubMed 7172412]
435. Knost JA, Sherwin SA, Abrams PG et al. The treatment of cancer patients with human lymphoblastoid interferon: a comparison of two routes of administration. Cancer Immunol Immunotherapy . 1983; 15:144-8.
436. Wills RJ, Smith RA. Pharmacokinetics of interferons. In: Smith RA, ed. Interferon treatment of neurologic disorders. New York: Marcel Dekker; 1988:103-33.
437. Bohoslawec O, Trown PW, Wills RJ. Pharmacokinetics and tissue distribution of recombinant human alpha A, D, A/D(Bg1), and I interferons and mouse alpha-interferon in mice. J Interferon Res . 1986; 6:207-13. [PubMed 3745986]
438. Barrett TJ, Silbar JD. Genital warts - a venereal disease. JAMA . 1954; 333-4.
439. Hairy cell leukemia treatment. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute. Accessed 2012 Nov 14.
440. Kaposi Sarcoma Treatment. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute. Accessed 2012 Nov 14.
441. Chronic myelogenous leukemia treatment. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute. Accessed 2012 Nov 14.
442. Adult non-Hodgkin lymphoma treatment. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute. Accessed 2012 Nov 14.
443. Renal cell cancer treatment. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute. Accessed 2012 Nov 14.
444. Bocci V, Pacini A, Muscettola M et al. Renal filtration, absorption, and catabolism of human alpha interferon. J Interferon Res . 1981; 1:347-52. [PubMed 6180066]
445. Bocci V, Pacini A, Muscettola M et al. Renal metabolism of rabbit serum interferon. J Gen Virol . 1981; 55:297- 304. [PubMed 6169795]
446. Bino T, Edery H, Gertler A et al. Involvement of the kidney in catabolism of human leukocyte interferon. J Gen Virol . 1982; 59:39-45. [PubMed 6175730]
447. Bino T, Madar Z, Gertler A et al. The kidney is the main site of interferon degradation. J Interferon Res . 1982; 2:301-8. [PubMed 7119510]
448. Bladder cancer treatment. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute. Accessed 2012 Nov 14.
449. Ovarian epithelial cancer treatment. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute. Accessed 2012 Nov 14.
450. Melanoma treatment. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute. Accessed 2012 Nov 14.
451. Abrams PG, McClamrock E, Foon KA. Evening administration of alpha interferon. N Engl J Med . 1985; 312:443-4. [PubMed 3969101]
452. Bocci V. Administration of interferon at night may increase its therapeutic index. Cancer Drug Delivery . 1985; 2:313-8. [PubMed 2415233]
453. Mora JS, Kao KP, Munsat TL. Indomethacin reduces the side effects of intrathecal interferon. N Engl J Med . 1984; 310:126-7. [PubMed 6197650]
454. Foon KA, Dougher G. Increased growth of eyelashes in a patient given leukocyte A interferon. N Engl J Med . 1984; 311:1259. [PubMed 6493282]
455. Dinarello CA, Bernheim HA, Duff GW et al. Mechanisms of fever induced by recombinant human interferon. J Clin Invest . 1984; 74:906-13. [PubMed 6590569]
456. WHO Expert Committee on Biological Standardization. Requirements for human interferons prepared from lymphoblastoid cells. Geneva: World Health Organization, Technical Report Series, no. 786; 1989:72-93.
457. Kauppila A, Cantell K, Janne O et al. Serum sex steroid and peptide hormone concentrations, and endometrial estrogen and progestin receptor levels during administration of human leukocyte interferon. Int J Cancer . 1982; 29:291-4. [PubMed 6175589]
459. Groopman JE, Broder S. Cancer in AIDS and other immunodeficiency states. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer—principles and practice of oncology. Philadelphia: Lippincott; 1988:1964-5.
460. Krown SE. AIDS and Kaposi's sarcoma. In: Gresser I, ed. Interferon 7. London and New York: Academic Press; 1986:198-203.
461. Scott GM. The toxic effects of interferon in man. In: Gresser I, ed. Interferon 5. London and New York: Academic Press; 1983:87-99.
462. Selby P, Kohn J, Raymond J et al. Nephrotic syndrome during treatment with interferon. BMJ . 1985; 290:1180. [PubMed 3921145]
463. Averbuch SD, Austin HA III, Sherwin SA et al. Acute interstitial nephritis with the nephrotic syndrome following recombinant leukocyte A interferon therapy for mycosis fungoides. N Engl J Med . 1984; 310:32-5. [PubMed 6689738]
464. Scott GM, Secher DS, Flowers D et al. Toxicity of interferon. BMJ . 1981; 282:1345-8. [PubMed 6165428]
465. Oldham RR. Toxic effects of interferon. Science . 1983; 219:902. [PubMed 6186027]
466. Mirro J Jr, Kalwinsky D, Whisnant J et al. Coagulopathy induced by continuous infusion of high doses of human lymphoblastoid interferon. Cancer Treat Rep . 1985; 69:315-7. [PubMed 3856479]
467. Eggermont AM, Welmar W, Marquet RL et al. Phase II trial of high-dose recombinant leukocyte alpha-2 interferon for metastatic colorectal cancer without previous systemic treatment. Cancer Treat Rep . 1985; 69:185-7. [PubMed 3882227]
468. Creagan ET, Ahmann DL, Green SJ et al. Phase II study of recombinant leukocyte A interferon (rIFN-αA) in disseminated malignant melanoma. Cancer . 1984; 54:2844-9. [PubMed 6498762]
469. Deyton LR, Walker RE, Kovacs JA et al. Reversible cardiac dysfunction associated with interferon alfa therapy in AIDS patients with Kaposi's sarcoma. N Engl J Med . 1989; 321:1246-9. [PubMed 2638573]
470. Cohen MC, Huberman MS, Nesto RW. Recombinant alpha2 interferon-related cardiomyopathy. Am J Med . 1988; 85:549-51. [PubMed 3177405]
471. Sarna G, Figlin R, Callaghan M. α (human leukocyte) interferon as treatment for non-small cell carcinoma of the lung: a phase II trial. J Biol Response Mod . 1983; 2:343-7. [PubMed 6315898]
472. Budd GT, Bukowski RM, Miketo L et al. Phase-I trial of ultrapureTM human leukocyte interferon in human malignancy. Cancer Chemother Pharmacol . 1984; 12:39-42. [PubMed 6690072]
473. Grunberg SM, Kempf RA, Itri LM et al. Phase II study of recombinant alpha interferon in the treatment of advanced non- small cell carcinoma lung. Cancer Treat Rep . 1985; 69:1031-2. [PubMed 4028036]
474. Cooper MR, Fefer A, Thompson J et al. Alpha-2- interferon/melphalan/prednisone in previously treated patients with multiple myeloma: a phase I-II trial. Cancer Treat Rep . 1986; 70:473-6. [PubMed 3698041]
475. Martino S, Ratanatharathorn V, Karanes C et al. Reversible arrhythmias observed in patients treated with recombinant alpha 2 interferon. J Cancer Res Clin Oncol . 1987; 113:376-8. [PubMed 3597523]
479. Renault PF, Hoofnagle JH, Park Y et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med . 1987; 147:1577-80. [PubMed 3307672]
480. McDonald EM, Mann AH, Thomas HC. Interferons as mediators of psychiatric morbidity: an investigation in a trial of recombinant α-interferon in hepatitis-B carriers. Lancet . 1987; 2:1175-7. [PubMed 2890808]
482. Adams F, Quesada JR, Gutterman JU. Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer. JAMA . 1984; 252:938-41. [PubMed 6748198]
483. Mattson K, Niiranen A, Laaksonen R et al. Psychometric monitoring of interferon neurotoxicity. Lancet . 1984; 1:275-6. [PubMed 6143011]
484. Katz JA, Mahoney DH, Steuber CP et al. Human leukocyte alpha interferon-induced transient neurotoxicity in children. Invest New Drugs . 1988; 6:115-20. [PubMed 3170131]
485. Bernsen PLJA, Wong-Chung RE, Janssen JTP. Neuralgic amyotrophy and polyradiculopathy during interferon therapy. Lancet . 1985; 1:50.
486. Bernsen PLJA, Wong Chung RE, Vingerhoets HM et al. Bilateral neurologic amyotrophy induced by interferon treatment. Arch Neurol . 1988; 45:449-51. [PubMed 2451493]
487. Gastineau DA, Habermann TM, Hermann RC. Severe neuropathy associated with low-dose recombinant interferon-alpha. Am J Med . 1989; 87:116. [PubMed 2741970]
488. Larrey D, Marcellin P, Freneaux E et al. Exacerbation of multiple sclerosis after the administration of recombinant human interferon alfa. JAMA . 1989; 261:2065. [PubMed 2494361]
489. Coyle JT. Multiple sclerosis and human interferon alfa. JAMA . 1989; 262:2684. [PubMed 2624644]
490. AUSTIMS Research Group. Interferon-α and transfer factor in the treatment of multiple sclerosis: a double-blind placebo-controlled trial. J Neurol Neurosurg Psychiatry . 1989; 52:566-74. [PubMed 2659737]
491. Ruutiainen J, Panelius M, Cantell K. Toxic effects of interferon administered intrathecally. BMJ . 1983; 286:940. [PubMed 6403145]
492. Johnson DH, Hande KR, Hainsworth JD et al. Neurotoxicity of interferon. Cancer Treat Rep . 1983; 67:958-61. [PubMed 6194882]
493. Smedley H, Katrak M, Sikora K et al. Neurological effects of recombinant human interferon. BMJ . 1983; 286:262-4. [PubMed 6402063]
494. Rohatiner AZS, Prior PF, Burton AC et al. Central nervous system toxicity of interferon. Br J Cancer . 1983; 47:419-21. [PubMed 6830692]
495. Davidson HS, Schilsky RL, Golomb HM. Gonadal and sexual function following treatment of hairy cell leukemia with recombinant alpha 2 interferon (IFN). Proc Am Soc Clin Oncol . 1985; 4:232.
498. Bevan PC. Interferon-induced parotitis and epididymitis. Lancet . 1985; 2:561. [PubMed 2863587]
499. Ronnblom LE, Alm GV, Oberg KE. Possible induction of systemic lupus erythematosus by interferon-α treatment in a patient with a malignant carcinoid tumour. J Intern Med . 1990; 227:201-10. [PubMed 2313228]
500. Fer MF, Bottino GC, Sherwin SA et al. Atypical tumor lysis syndrome in a patient with T cell lymphoma treated with recombinant leukocyte interferon. Am J Med . 1984; 77:953-6. [PubMed 6333818]
501. Shlohara T, Kobayashi M, Kimiaki A et al. Psoriasis occurring predominantly on warts: possible involvement of interferon alfa. Arch Dermatol . 1988; 124:1816-21. [PubMed 3190257]
502. Bjerke JR, Livden JK, Degre M et al. Interferon in suction blister fluid from psoriatic lesions. Br J Dermatol . 1983; 108:295-9. [PubMed 6187354]
503. Dreno B, Huart A, Billaud E et al. Alpha-interferon therapy and cutaneous vascular lesions. Ann Intern Med . 1989; 111:95-6. [PubMed 2786685]
505. Rasokat H, Bendick C, Nemmer U et al. Aseptic necrosis of the skin after subcutaneous injection of interferon alpha. (German; with English abstract.) Dtsch Med Wochenschr . 1989; 114:458-60.
506. Herrman J, Gabriel F. Membranoproliferative glomerulonephritis in a patient with hairy-cell leukemia treated with alpha-II interferon. N Engl J Med . 1987; 316:112. [PubMed 3785357]
507. Burman P, , Oberg K et al. Autoimmune thyroid disease in interferon treated patients. Lancet . 1985; 2:100-1. [PubMed 2861513]
508. Fentiman IS, Balkwill FR, Thomas BS et al. An autoimmune aetiology for hypothyroidism following interferon therapy for breast cancer. Eur J Cancer Clin Oncol . 1988; 24:1299-303. [PubMed 2460358]
509. Schultz M, Muller R, Von Zur Muhlen A et al. Induction of hyperthyroidism by interferon-α-2b. Lancet . 1989; 1:1452. [PubMed 2567459]
510. Fentiman IS, Thomas BS, Balkwill FR et al. Primary hypothyroidism associated with interferon therapy of breast cancer. Lancet . 1985; 1:1166. [PubMed 2860373]
512. Vento S, DiPerri G, Garofano T et al. Hazards of interferon therapy for HBV-seronegative chronic hepatitis. Lancet . 1989; 2:926. [PubMed 2571851]
515. Kramer P, Ten Kate FWJ, Bijnen AB et al. Recombinant leucocyte interferon A induces steroid-resistant acute vascular rejection episodes in reanl transplant recipients. Lancet . 1984; 1:989-91. [PubMed 6143968]
516. Abdi EA, Nguyen GK, Ludwig RN et al. Pulmonary sarcoidosis following interferon therapy for advanced renal cell carcinoma. Cancer . 1987; 59:896-900. [PubMed 3815268]
517. Akard LP, Hoffman R, Elias L et al. Alpha-interferon and immune hemolytic anemia. Ann Intern Med . 1986; 105:306. [PubMed 3729223]
518. Braathen LR, Stavem P. Autoimmune haemolytic anaemia associated with interferon alfa-2a in patient with mycosis fungoides. BMJ . 1989; 298:1713. [PubMed 2503190]
519. McLaughlin P, Talpaz M, Quesada JR et al. Immune thrombocytopenia following α-interferon therapy in patients with cancer. JAMA . 1985; 254:1353-4. [PubMed 4021013]
520. Abdi EA, Brien W, Venner PM. Autoimmune thrombocytopenia: first report. Scand J Haematol . 1986: 36:515-9.
521. Farkkila M, Iivanainen M. Thrombocytopenia and interferon. BMJ . 1988; 296:642. [PubMed 3126937]
522. Cottler-Fox M, Torrisi J, Sptizer TR et al. Increased toxicity of total body irradiation in patients receiving interferon for leukaemia. Lancet . 1990; 335:174.
523. Real FX, Krown SE, Nisce LZ et al. Unexpected toxicity from radiation therapy in two patients with Kaposi's sarcoma receiving interferon. J Biol Response Mod . 1985; 4:141-6. [PubMed 3998765]
524. Ernstoff MS, Kirkwood JM. Changes in the bone marrow of cancer patients treated with recombinant interferon alpha-2. Am J Med . 1984; 76:593-6. [PubMed 6711573]
525. Riordan T, Lewin I, Oliver MH. Rapid diagnosis of psittacosis. Lancet . 1990; 335:471-2. [PubMed 1968188]
526. Knost JA, Sherwin S, Abrams P et al. Increased steroid dependence after recombinant leucocyte interferon therapy. Lancet . 1981; 2:1287-8. [PubMed 6171695]
528. Quesada JR, Hawkins M, Horning S et al. Collaborative phase I-II study of recombinant DNA-produced leukocyte interferon (clone A) in metastatic breast cancer, malignant lymphoma, and multiple myeloma. Am J Med . 1984; 77:427-32. [PubMed 6548079]
529. Dukes PP, Izadi P, Ortega JA et al. Inhibitory effects of interferon on mouse megakaryocytic progenitor cells in culture. Exp Hematol . 1980; 8:1048-56. [PubMed 6162661]
531. Ortega JA, Ma A, Shore NA et al. Suppressive effect of interferon on erythroid cell proliferation. Exp Hematol . 1979; 7:145-50. [PubMed 446582]
533. Higashi Y, Sokawa Y. Microinjection of interferon and 2',5'-oligoadenylate into mouse L cells and their effects on virus growth. J Biochem . 1982; 91:2021-8. [PubMed 6181054]
534. Vengris VE, Stollar BD, Pitha PM. Interferon externalization by producing cell before induction of antiviral state. Virology . 1975; 65:410-7. [PubMed 165620]
535. Farrell PJ, Sen GC, Dubois MF et al. Interferon action: two distinct pathways for inhibition of protein synthesis by double stranded RNA. Proc Natl Acad Sci USA . 1978; 75:5893-7. [PubMed 282611]
536. Baglioni C. Interferon-induced enzymatic activities and their role in the antiviral state. Cell . 1979; 17:255- 64. [PubMed 455463]
537. Roberts WK, Hovanessian A, Brown RE et al. Interferon- mediated protein kinase and low-molecular-weight inhibitor of protein synthesis. Nature . 1976; 264:477-80. [PubMed 1004583]
538. Hovanessian AG, Brown RE, Kerr IM. Synthesis of low molecular weight inhibitor of protein synthesis with enzyme from interferon-treated cells. Nature . 1977; 268:537-40. [PubMed 560630]
539. Lengyl P. Biochemistry of interferons and their actions. Ann Rev Biochem . 1982; 51:251-282. [PubMed 6180680]
540. Farrell PJ, Balkow K, Hunt T et al. Phosphorylation of initiation factor elF-2 and the control of reticulocyte protein synthesis. Cell . 1977; 11:187-200. [PubMed 559547]
541. Samuel CE. Mechanism of interferon action: phosphorylation of protein synthesis initiation factor eIF-2 in interferon treated cells by a ribosome associated kinase processing site specificity similar to hemin-regulated rabbit reticulcyte kinase. Proc Natl Acad Sci USA . 1979; 76:600-4. [PubMed 284384]
542. Lebleu B, Sen GC, Shaila S et al. Interferon, double- stranded RNA, and protein phosphorylation. Proc Natl Acad Sci USA . 1976; 73:3107-11. [PubMed 1067606]
543. Nilsen TW, Baglioni C. Mechanism for discremination between viral and host mRNA in interferon-treated cells. Proc Natl Acad Sci USA . 1979; 76:2600-4. [PubMed 223150]
544. Hovanessian AG, Kerr IM. The (2'-5') oligoadenylate (pppA2'-5'A2'-5'A) synthetase and protein kinase(s) from interferon-treated cells. Eur J Biochem . 1979; 93:515-26. [PubMed 217683]
545. Morant R, Richner J, Evers P et al. Interleukin-2 (rIL- 2) and interferon-alpha combination immunotherapy in patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol . 1990; 9:141.
546. Zilberstein A, Kimchi A, Schmidt A et al. Isolation of two interferon-induced translational inhibitors: a protein kinase and an oligo-isoadenylate synthetase. Proc Natl Acad Sci USA . 1978; 75:4734-8. [PubMed 283387]
547. West DK, Baglioni C. Induction of interferon in HeLa cells of a protein kinase activated by double-stranded RNA. Eur J Biochem . 1979; 101:461-8. [PubMed 520308]
548. Kimchi A, Shulman L, Schmidt A et al. Kinetics of the induction of three translation-regulatory enzymes by interferon. Proc Natl Acad Sci USA . 1979; 76:3208-12. [PubMed 226962]
549. Samuel CE, Knutson GS. Mechanism of interferon action. Kinetics of induction of the antiviral state and protein phosphorylation in mouse fibroblasts treated with natural and cloned interferons. J Biol Chem . 1982; 257:11791-5. [PubMed 6181059]
550. Rehberg E, Kelder B, Hoal EG et al. Specific molecular activities of recombinant and hybrid leukocyte interferons. J Biol Chem . 1982; 257:11497-502. [PubMed 6288687]
551. Streuli M, Hall A, Boll W et al. Target cell specificity of two species of human interferon-alpha produced in Escherichia coli and of hybrid molecules derived from them. Proc Natl Acad Sci USA . 1981; 78:2848-52. [PubMed 6166941]
552. Weck PK, Apperson S, May L et al. Comparison of the antiviral activities of various cloned human interferon-alpha subtypes in mammalian cell cultures. J Gen Virol . 1981; 57:233-7. [PubMed 6172550]
553. Kerr IM, Brown RE. pppA2'p5'A2'p5'A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cells. Proc Natl Acad Sci USA . 1978; 75:256-60. [PubMed 272640]
554. Kimchi A, Shulman L, Schmidt A et al. Kinetics of the induction of three translation-regulatory enzymes by interferon. Proc Natl Acad Sci USA . 1979; 76:3208-12. [PubMed 226962]
555. Falcoff R, Falcoff E, Sanceau J et al. Influence of preincubation of on the development of the inhibition of protein synthesis in extracts from interferon treated mouse L cells action on tRNA. Virology . 1978; 86:507-15. [PubMed 208258]
556. Clemens MJ, Williams BR. Inhibition of cell-free protein synthesis by pppA2'p5-A2'p5'A: a novel oligonucleotide synthesized by interferon-treated L cell extracts. Cell . 1978; 13:565-72. [PubMed 657268]
557. Baglioni C, Minks MA, Maroney PA. Interferon action may be mediated by activation of a nuclease by pppA2'p5'A2'p5'A. Nature . 1978; 273:684-7. [PubMed 208001]
558. Lengyel P. In: Gresser I, ed. Interferon 1981. Vol. 3. New York: Raven Press; 1981:77-99.
559. Ratner L, Wiegand RC, Farrell PJ et al. Interferon, double-stranded RNA and RNA degradation: fractionation of the endocnuclease INT system into two macromolecular components; role of a small molecule in nuclease activation. Biochem Biophys Res Commun . 1978; 81:947-54. [PubMed 566549]
561. Slattery E, Ghosh N, Samanta H et al. Interferon, double-stranded RNA, and RNA degradation: activation of an endonuclease by (2'-5')An . Proc Natl Acad Sci USA . 1979; 76:4778-82. [PubMed 291897]
564. Pratt WB, Fekety R. The antimicrobial drugs. New York: Oxford University Press; 1986:447-60.
565. Schmidt A, Zilberstein A, Shulman L et al. Interferon action: isolation of nuclease F, a translation inhibitor activated by interferon-induced (2'-5') oligo-isoadenylate. FEBS Lett . 1978; 95:257-64. [PubMed 720619]
566. Williams BRG, Golgher RR, Kerr IM. Activation of a nuclease by ppp2'p5'A2'p5'A in intact cells. FEBS Lett . 1979: 105:47-52.
568. Chebath J, Benech P, Hovanessian A et al. Four different forms of interferon-induced 2',5'-oligo(A) synthetase identified by imunoblotting in human cells. J Biol Chem . 1987; 262:3852-7. [PubMed 2434505]
569. Williams BRG, Kerr IM. The 2-5A (pppA2' p5' p5' A) system in interferon-treated and control cells. Trends Biochem Sci . 1980; 5:138-40.
570. Baglioni C, Nilsen TW. In: Gresser I, ed. Interferon 5. New York: Academic Press; 1988:23-42.
571. Schmidt A, Chernajovsky Y, Shulman L et al. An interferon-induced phosphodiesterase degrading (2'-5') oligoisoadenylate and the C-C-A terminus of tRNA. Proc Natl Acad Sci USA . 1979; 76:4788-92. [PubMed 228264]
572. Minks MA, Benvin S, Maroney PA et al. Metabolic stability of (2'-5') oligo (A)-dependent endonuclease in extracts of interferon-treated and control HeLa cells. Nucleic Acid Res . 1979; 6:767-80. [PubMed 424314]
573. Baglioni C. The molecular mediators of interferon action In: Came PE, Carter WE. eds; Interferons and their applications. Springer Verlag; NY. 1984; 153-68.
574. Nilsen TW, Baglioni C. Mechanism for discrimination between viral and host mRNA in interferon treated cells. Prac Natl Acad Sci USA . 1979; 76:2000-4.
575. Shatkin AJ. Reovirus mRNA: transcription and translation. Cell . 1977; 7:305-13.
576. Samuel C. Molecular mechanisms of interferon action. In: Stringfellow D, ed. Clinical applications of interferons and their inducers. 2nd ed. Marcel Dekker NY. 1986; 1-18.
579. Revel M. The interferon system in man: nature of interferon molecules and mode of action. In: Becker Y, ed. Antiviral drugs and interferon. New York: Martin Nijhoff; 1984:357-433.
580. Taylor J. Inhibition of interferon action by actinomycin. Biochem Biophys Res Commun . 1964; 14:447- 51. [PubMed 4158168]
581. Lockhart RZ. The necessity for cellular RNA and protein synthesis for viral inhibition from interferon. Biochem Biophys Res Commun . 1964; 15:513-8.
582. Friedman RM. Sonnabend JA. Inhibition of interferon action by puromycin. J Immunol . 1965; 95:696-703. [PubMed 5841055]
583. Borden EC, Ball LA. Interferons: biochemical, cell growth inhibitory and immunological effects. In: Brown EB, ed. Progress in hematology. Vol. 12. Grune and Stratton, New York; 1981:299-339.
584. Meurs E, Hovanessian AG, Montagnier L. Interferon- mediated antiviral state in human MRC5 cells in the absence of detectable levels of 2-5A synthetase and protein kinase. J Interferon Res . 1981; 1:219-32. [PubMed 6180053]
585. Hovanessian AG, Meurs E, Montagnier L. Lack of systematic correlation between the interferon mediated antiviral state and the levels of 2-5A synthetase and protein kinase in three different types of murine cells. J Interferon Res . 1981; 1:179-90. [PubMed 6286803]
586. Maheshwari RK, Banerjee DK, Waechter CJ et al. Interferon treatment inhibits glycosylation of a viral protein. Nature . 1980; 287:454-6. [PubMed 6159539]
587. Wood JN, Hovanessian AG. Interferon enhances 2-5A synthetase in embryonal carcinoma cells. Nature . 1979; 282:74-6. [PubMed 503189]
588. Ball LA. Molecular mechanisms of interferon action. Med Pediatr Oncol . 1981; 9:83-8. [PubMed 6162086]
589. Hollenberg MD, Cuatrecasas P. Methods for the biochemical identification of insulin receptors. In: Blecher M, ed. Methods in receptor research, Part II. New York: Marcel Dekker; 1976:429-78.
594. Pottathil R, Chandrabose K, Cuatrecassas P et al. Establishment of the interferon-mediated antiviral state: possible role of superoride dismutase. Proc Natl Acad Sci USA . 1981; 78:3343-7. [PubMed 6167983]
595. Tovey MG, Gresser I, Rochette-Egly C et al. Indomethacin and aspirin do not inhibit the antiviral or anti- proliferative action of interferon. J Gen Virol . 1982; 63:505-8. [PubMed 6185629]
596. Stotter H, Haas G, Lotze ML et al. Pretreatment of renal cell cancer (RCC) with alpha interferon (IFNa) and interleukin-2 (IL-2) prior to nephrectomy. Proc Am Soc Clin Oncol . 1990; 9:133.
597. Tovey MG, Rochette-Egly C. Rapid increase guanosine 3'5' cyclic monophosphate in interferon treated mouse LVP cells. Relationship to development of the anti-viral state and inhibition of cell multiplication. Virology . 1981; 115:272-81. [PubMed 6171931]
598. Tovey MG, Rochette-Egly C, Castagna M. Effect of interferon on concentration of cyclic nucleotides in cultured cells. Proc Natl Acad Sci USA . 1979; 76:3890-3. [PubMed 226987]
599. Gordon J, Minks MA. The interferon renaissance: molecular aspects of induction and action. Microbiol Rev . 1981; 45:244-66. [PubMed 6167846]
600. Baglione C, Nelson TW. The action of interferon at the molecular level. Am Sci . 1981; 69:392-9. [PubMed 6169297]
603. Gupta SL, Grazidei WD III, Weideli H et al. Selective inhibition of viral protein accumulation in interferon-treated cells: nondiscriminate inhibition of the translation of added viral and cellular messenger RNAs in their extracts. Virology . 1974; 57:49-63. [PubMed 4206536]
604. Carter WA, Swartz H, Gillespie DH. Independent evolution of antiviral and growth modulating activities of interferon. J Biol Response Mod . 1985; 4:447-59. [PubMed 2416881]
605. Krueger LJ, Terry RW, Sussman AJ et al. Interferon-induced growth modulation: low dose maintenance of the antiproliferative response. J Interferon Res . 1984; 4:29-40. [PubMed 6715912]
606. Gresser I, Tovey MG. Antitumor effects of interferon. Biochim Biophys Acta . 1978; 516:231-47. [PubMed 365241]
610. Lindahl P, Gresser I, Leary P et al. Interferon treatment of mice: enhanced expression of histocompatibility antigens on lymphoid cells. Proc Natl Acad Sci USA . 1976; 73:1284-7. [PubMed 1063409]
611. Brouty-Boye D. Inhibitory effect of interferons on cell multiplication. Lymph Rep . 1980; 1:99-
612. Tovey MG, Rochette-Egly C, Castagna M. Effects of interferon on concentrations of cyclic nucleotides in cultured cells. Proc Natl Acad Sci USA . 1979; 76:3890-3. [PubMed 226987]
613. Tovey MG, Brouty-Boye D. The use of the chemostat to study the relationship between cell growth rate, viability, and the effect of interferon on L1210 cells. Exp Cell Res . 1979; 118:383. [PubMed 367800]
614. Brouty-Boye D, Tovey MG. Inhibition by interferon of thymidine uptake in cheomostat cultures of L1210 cells. Intervirology . 1978; 9:243. [PubMed 304053]
615. Brouty-Boye D, Gresser I. Studies on the reversibility of the transformed and neoplastic phenotype. I. Progressive reversion of the phenotype of x-ray transformed C3h/10T½ cells under prolonged treatment with interferon. Int J Cancer . 1981; 28:165-73. [PubMed 6172389]
616. Lee SH, Chiu H, Sabo W et al. Importance of treatment regimen of interferon as an antitumor agent. Cancer Res . 1983; 43:4172-5. [PubMed 6347366]
617. Kempf RA, Grunberg SM, Daniels JR et al. Recombinant interferon alpha-2 (INTRON A) in a phase II study of renal cell carcinoma. J Biol Response Mod . 1986; 5:27-35. [PubMed 3958753]
618. Gresser I, Maury C, Brouty-Boye D. On the mechanism of the antitumor effect of interferon in mice. Nature . 1972; 239:167-8. [PubMed 4561966]
619. Belardelli F, Gresser I, Maury C et al. Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells: I. Int J Cancer . 1982; 30:813-20. [PubMed 6186614]
620. Broxmeyer HE, Lu L, Platzer E et al. Comparative analysis of the influences of human gamma, alpha, and beta interferons on human multipotential (CFU-GEMM), erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) progenitor cells. J Immunol . 1983; 131:1300-5. [PubMed 6193183]
621. Taylor JL, Sabran JL, Grossberg SE. The cellular effects of interferon. In: Came PE, Carter WA. eds. Interferons and their applications. New York: Springer-Verlag; 1984:169-204.
622. Balkwill FR, Moodie EM, Freedman V et al. Human interferon inhibits the growth of established human breast tumours in the nude mouse. Int J Cancer . 1982; 30:231-5. [PubMed 6182113]
623. Horoszewicz JS, Leong SS, Carter WA. Non-cycling tumor cells are sensitive targets for the antiproliferative activity of human interferon. Science . 1979; 206:1091-3. [PubMed 493995]
624. Creasy AA, Bartholomew JC, Merigan TC. Role of G0-G1 arrest in the inhibition of tumor cell growth by interferon. Proc Natl Acad Sci USA . 1980; 77:1471-5. [PubMed 6154934]
625. Balkwill FR. Interferons. In: Cytokines in cancer chemotherapy. New York: Oxford University Press. 1989.
626. Kimchi A. Autocrine interferon and the suppression of the c- myc nuclear oncogene. Interferon . 1987; 8:86-110.
627. Gresser I. How does interferon inhibit tumor growth? In: Gresser I. ed. Interferon. Vol. 6. Academic Press: New York; 1985:93-126.
628. Paulnock DM, Borden EC. Modulation of immune functions by interferon. Immunity to cancer. New York: Academic Press; 1985:545-559.
629. Stewart WE, Blanchard DK. Interferons, cytotatic and immunomodulatory effects. Immunity to cancer. New York: Academic Press; 1985:295-307.
630. Toy JL. The interferons. Clin Exp Immunol . 1983; 54:1-13. [PubMed 6193915]
631. Pegg AE, McCann PP. Polyamine metabolism and function. Am J Physiol . 1982; 243:212-21.
632. d'Hooghe MC, Brouty-Boye D, Malaise EP et al. Interferon and cell division: XXI. Prolongation by interferon of the intermiotic time of mouse mammary tumor cells in vitro: microcinematographic analysis. Exp Cell Res . 1977; 105:73-7. [PubMed 837997]
633. Evinger M, Rubinstein M, Pestka S. Antiproliferative and antiviral activities of human leukocyte interferons. Arch Biochem Biophys . 1981; 210:319-29. [PubMed 6170263]
634. Pfeffer LM, Murphy JS, Tamm I. Interferon effects on the growth and division of human fibroblasts. Exp Cell Res . 1979; 121:111-20. [PubMed 446522]
635. Macieira-Coelho A, Brouty-Boye D, Thomas MT et al. Interferon and cell division: III. Effect of interferon on the division cycle of L1210 cells in vitro. J Cell Biol . 1971; 48:415-9. [PubMed 5551661]
636. Lundgren E, Larsson I, Miorner H et al. Effects of leukocyte and fibroblast interferon on events in the fibroblast cell cycle. J Gen Virol . 1979; 42:589-95. [PubMed 430031]
637. Gresser I. On the varied biologic effects of interferon. Cell Immunol . 1977; 34:406-15. [PubMed 589672]
638. Einhorn S, Strander H. Is interferon tissue specific? Effect of human leukocyte and fibroblast interferons on the growth of lymphoblastoid and osteosarcoma cell lines. J Gen Virol . 1977; 35:573-7. [PubMed 267737]
639. Strander H, Einhorn S. Effect of human leukocyte interferon on the growth of human osteosarcoma cells in tissue culture. Int J Cancer . 1977; 15:468-73.
640. Gresser I, Thomas MT, Brouty-Boye D. Effect of interferon treatment of L1210 cells in vitro on tumour and colony formation. Nature New Biol . 1971; 231:20-1. [PubMed 5282845]
641. Gresser I, Brouty-Boye D, Thomas MT et al. Interferon and cell division: I. Inhibition of the multiplication of mouse leukemia L1210 cells in vitro by interferon preparations. Proc Natl Acad Sci USA . 1970; 66:1052-8. [PubMed 4319881]
642. Gresser I, Thomas MT, Brouty-Boye D et al. Interferon and cell division: V. Titration of the anticellular action of interferon preparations. Proc Soc Exp Biol Med . 1971; 137:1258-61. [PubMed 4333094]
643. Gresser I, Brouty-Boye D, Thomas MT et al. Interferon and cell division: II. Influence of various experimental conditions on the inhibition of L1210 cell multiplication in vitro by interferon preparations. J Natl Cancer Inst . 1970; 45:1145-53. [PubMed 5488061]
644. Willson JKV, Bittner G, Borden EC. Antiproliferative activity of human interferon against ovarian cancer cells grown in human tumor stem cell assay. J Interferon Res . 1984:4:441-7.
645. Huang KY, Donahoe RM, Gordon FB et al. Enhancement of phagocytosis by interferon-containing preparations. Infect Immun . 1971; 4:581-8. [PubMed 4343410]
646. Jett JR, Mantovani A, Herberman RB. Augmentation of human monocyte-mediated cytolysis by interferon. Cell Immunol . 1980; 54:425-34. [PubMed 6158375]
647. Thomas HC, Ikeda T, Caruso L. Symposium developments in the treatment of malignant and viral disorders with recombinant interferon. Osaka, Japan: 1985 June 22.
648. Giacomini P, Aguzzi A, Pestka S et al. Modulation by recombinant DNA leukocyte (alpha) and fibroblast (beta) interferons of the expression and shedding of HLA- and tumor- associated antigens by human melanoma cells. J Immunol . 1984; 133:1649-55. [PubMed 6747299]
649. Herlyn M, Guerry D, Koprowski H. Recombinant gamma- interferon induces changes in expression and shedding of antigens asscoiated with normal human melanocytes, nevus cells, and primary and metastatic melanoma cells. J Immunol . 1985; 134:4226-30. [PubMed 2985706]
650. Greiner JW, Hand PH, Noguchi P et al. Enhanced expression of surface tumor-associated antigens on human breast and colon tumor cells after recombinant human leukocyte alpha- interferon treatment. Cancer Res . 1984; 44:3208-14. [PubMed 6744259]
651. Oldham RK, Smalley RV. Immunotherapy: the old and the new. J Biol Response Mod . 1983; 2:1-37. [PubMed 6196449]
652. Keay S, Grossberg SE. Interferon inhibits the conversion of 3T3-L1 mouse fibroblasts into adipocytes. Proc Natl Acad Sci USA . 1980; 77:4099-103. [PubMed 6159626]
653. Grossberg SE, Keay S. The effects of interferon on 3T3- L1 cell differentiation. Ann NY Acad Sci . 1980; 350:294- 300. [PubMed 6165283]
654. Fisher PB, Miranda AF, Babiss LE et al. Opposing effects of interferon produced in bacteria and of tumor promoters on myogenesis in human myoblast cultures. Proc Natl Acad Sci USA . 1983; 80:2961-5. [PubMed 6574466]
655. Einat M, Resnitzky D, Kimchi A. Close link between reduction of c-myc expression by interferon and G0/G1 arrest. Nature . 1985; 313:597- 600. [PubMed 3881681]
656. Tominaga S, Lengyel P. Beta-interferon alters the pattern of proteins secreted from quiescent and platelet derived growth-factor treated BALB/c 3T3 cells. J Biol Chem . 1985; 260:1975-8. [PubMed 3882683]
657. Tominaga S, Tominaga K, Lengyel P. Characteristics of 30-, 63-, and 89-kilodalton proteins whose secretion from mouse fibroblasts is altered by beta interferon. J Biol Chem . 1985; 260:16406-10. [PubMed 4066715]
658. Borden EC. Interferons: rationale for clinical trials in neoplastic disease. Ann Intern Med . 1979; 91:472-9. [PubMed 382941]
659. Yaron M, Yaron I, Gurari-Rotman D et al. Stimulation of prostaglandin E production in cultured human fibroblasts by poly(I)-poly(C) and human interferon. Nature . 1977; 267:457-9. [PubMed 876363]
660. Fitzpatrick FA, Stringfellow DA. Virus and interferon effects on cellular prostaglandin biosynthesis. J Immunol . 1980; 125:431-7. [PubMed 6155405]
661. Pottathil R, Chandrabose KA, Cuatrecasas P et al. Establishment of the interferon-mediated antiviral state: role of fatty acid cyclooxygenase. Proc Natl Acad Sci USA . 1980; 77:5437-40. [PubMed 6159647]
662. Brunda MJ, Herberman RB, Holden HT. Inhibition of murine natural killer cell activity by prostaglandins. J Immunol . 1980; 124:2682-7. [PubMed 6154736]
663. Chirigos MA, Schultz RM, Stylos WA. Interaction of interferon, macrophage, and lymphocyte tumoricidal activity with prostaglandin effect. Ann NY Acad Sci . 1980; 350:91-101. [PubMed 6165308]
664. Friedman RM, Pastan I. Interferon and cyclic-3'5' adenosine monophosphate: potentiation of antiviral activity. Biochem Biophys Res Commun . 1969; 36:735-40. [PubMed 4309119]
665. Weber JM, Stewart RB. Cyclic AMP potentiation of interferon antiviral activity and effect of interferon on cellular cyclic AMP levels. J Gen Virol . 1975; 28:363- 72. [PubMed 170377]
666. Melodosi MF, Friedman RM, Kohn LD. An interferon induced increase in cAMP levels precedes the establishment of the antiviral state. Biochem Biophys Res Commun . 1977; 79:239-46. [PubMed 200241]
667. Fuse A, Kuwata T. Inhibition of DNA synthesis and alteration of cyclic adenosine 3',5'-monophosphate levels in RSa cells by human leukocyte interferon. J Natl Cancer Inst . 1978; 60:1227-32. [PubMed 206702]
668. Tovey MG, Rochette-Egly C. The effect of interferon on cyclic nucleotides. Ann NY Acad Sci . 1980; 350:266-78. [PubMed 6165281]
669. Borden EC, McBain JA, Leonhardt PH. Effects of amphotericin B and its methyl ester on the antiviral activity of poly(I):poly(C). Antimicrob Agents Chemother . 1979; 16:203-9. [PubMed 225986]
670. Bourgeade MF, Chany C. Inhibition of interferon action by cytochalasin B, colchicine, and vinblastine. Proc Soc Exp Biol Med . 1976; 153:501-4. [PubMed 1034933]
671. Bourgeade MF, Chany C, Merigan TC. Type I and type II interferons: differential antiviral actions in transformed cells. J Gen Virol . 1980; 46:449-54. [PubMed 6155431]
673. Duran Garcia E, Santolaya R, Requena T. Treatment of malignant melanoma. Am Pharmacother . 1999; 33:730-8.
674. Tovey MG. Interferon and cyclic neucleotides. In: Gresser I, ed. Interferon 4. London and New York: Academic Press; 1982:23-46.
675. Pastan IH, Johnson GS, Anderson WB. Role of cyclic nucleotides in growth control. Annu Rev Biochem . 1975; 44:491-522. [PubMed 166606]
676. Schneck J, Rager-Zisman B, Rosen OM et al. Genetic analysis of the role of cAMP in mediating effects of interferon. Proc Natl Acad Sci USA . 1982; 79:1879-83. [PubMed 6177003]
677. Tovey MG, Rochette-Egly C. Rapid increase in guanosine 3',5' cyclic monophosphate in interferon treated mouse leuk L1210 cells: relationship to development of the antiviral state and inhibition of cell multiplication. Virology . 1981; 115:272-81. [PubMed 6171931]
678. Richman RA, Weiss JP, Roberts SB et al. The effect of serum and multiplication stimulating activity on L6 myoblast grwoth: the lack of correlation with cyclic nucleotide changes. J Cell Physiol . 1980; 103:63-9. [PubMed 6253507]
679. Dumont SE, Greengard P, Robson GA, eds. Advances in cyclic nucleotide research. New York: Raven Press; 1981:429-42.
680. Burstin SJ, Renger HC, Basilico C. Cyclic AMP levels in temperature sensitive SV40 transformed cell lines. J Cell Physiol . 1974; 84:69-73. [PubMed 4367529]
681. Kram R, Mamont P, Tomkins GM. Pleiotropic control by adenosine 3':5'-cyclic monophosphate: a model for growth control in animal cells. Proc Natl Acad Sci USA . 1973; 70:1432-6. [PubMed 4351178]
682. Willingham MC, Johnson GS, Pastan I. Control of DNA synthesis and mitosis in 3T3 cells by cyclic AMP. Biochem Biophys Res Commun . 1972; 48:743-8. [PubMed 4344274]
683. Forti RL, Mitchell WM, Hubbard WC et al. Pleiotropic activities of human interferons are mediated by multiple response pathways. Proc Natl Acad Sci USA . 1984; 81:170. [PubMed 6320163]
684. Yaron M, Yaron I, Wiletzki C et al. Interrelationship between stimulation of prostaglandin E and hyaluronate production by poly(I) poly(O) and interferon in synovial fibroblast culture. Arthritis Rheum . 1978; 21:694-8. [PubMed 736999]
686. Faltynek CR, Baglioni C. Interferon induction of antiviral state. In: Pfeffer LM, ed. Mechanism of interferon action. Vol 1. Boca Raton, Fl: CRC Press; 1987:99-110.
687. Stringfellow DA. PG restoration of the interferon response of hyporeactive animals. Science . 1978; 201:376-8. [PubMed 208154]
688. Stringfellow DA. Antiviral and interferon-inducing properties of interferon inducers administered with prostaglandins. Antimicrob Agents Chemother . 1980; 17:455-60. [PubMed 6158913]
689. Strayer DR, Carter WA. Agents which modulate the activity of interferon. Handb Exp Pharmacol . 1984; 71:385-402.
691. Schultz RM, Pavlidis NA, Stylos WA et al. Cytotoxic activity of interferon-treated macrophages studied by various inhibitors. Cancer Treat Rep . 1978; 62:1889-92. [PubMed 728906]
692. Targan SA. The dual interaction of PGE2 (PGE2) and interferon (IFN) on NR lytic activation: enhanced capacity of effector-target hylic interactors (recycling) and blockage of pre NR recruitment. J Immunol . 1981; 127:1424-8. [PubMed 6168691]
693. Dinarello CA, Mier JW. Current concepts: lymphokines. N Engl J Med . 1987; 317:940-5. [PubMed 2442611]
694. Johnston RB Jr. Current concepts: immunology. Monocytes and macrophages. 1988; 318:747-52.
695. Higgins PG, Phillpotts RJ, Scott GM et al. Intranasal interferon as protection against experimental respiratory coronavirus infection in volunteers. Antimicrobial Agents Chemother . 1983; 24:713-5.
696. Cooper MD. Current concepts: B lymphocytes. N Engl J Med . 1987; 317:1452-6. [PubMed 3317043]
697. Gresser I, Tovey MG. Antitumor effects of interferon. Biochem Biophys Acta . 1978; 516:231. [PubMed 365241]
698. Kataoka T, Matsuura N, Oh-hashi F et al. Treatment regimen and host T-cell-dependent therapeutic effect of inteferon in mouse solid tumors. Cancer Res . 1985; 45:3548-53. [PubMed 2410097]
699. Blomgren H, Einhorn S. Lymphokine production by PHA- stimulated human lymphocytes is enhanced by interferon. Int Arch Allergy Appl Immunol . 1981; 66:173-8. [PubMed 6169650]
700. Hersey P, Hasic E, MacDonald M et al. Effects of recombinant leukocyte interferon (rIFN-alpha A) on tumor growth and immune responses in patients with metastatic melanoma. Br J Cancer . 1985; 51:815-26. [PubMed 3873953]
701. Neefe JR, Sullivan JE, Ayoob M et al. Augmented immunity in cancer patients treated with alpha-interferon. Cancer Res . 1985; 45:874-8. [PubMed 3967248]
702. DeMaeyer-Guignard J, DeMaeyer E. Immunomodulation by interferons:recent developments. In: Gresser I. ed. Interferon Academic Press. New York; 1985; 6:69-86.
703. Balkwill FR, Moodie EM, Freedman V et al. Human interferon inhibits the growth of established human breast tumours in the nude mouse. Int J Cancer . 1982; 30:231-5. [PubMed 6182113]
704. Horoszewicz JS, Leong SS, Ito M et al. Human fibroblast interferon in human neoplasia: clinical and laboratory study. Cancer Treat Rep . 1978; 62:1899-1906. [PubMed 728909]
705. Balkwill F, Taylor-Papadimitriou J, Fantes KH et al. Human lymphoblastoid interferon can inhibit the growth of human breast cancer xenografts in athymic (nude) mice. Eur J Cancer . 1980; 16:569-573. [PubMed 6156841]
708. Fast LD, Hansen JA, Newman W. Evidence for T cell nature and heterogeneity within natural killer (NK) and antibody dependent cellular cytotoxicity (ADCC) effectors: a comparison with cytolytic lymphocytes (CTL). J Immunol . 1981; 127:448-52. [PubMed 6788841]
709. Neville ME. Human killer cells and natural killer cells: distinct subpopulations of Fc receptor-bearing lymphocytes. J Immunol . 1980; 125:2604-9. [PubMed 6776195]
710. Ortaldo JR, McDermott RP, Bonnard GD et al. Cytotoxicity from cultured cells: analysis of precursors involved in generation of human cells mediating natural and antibody- dependent-cell-mediated cytotoxicity. Cell Immunol . 1979; 48:356-8. [PubMed 315834]
711. Perussia B, Trinchieri G, Cerottii JC. Functional studies of Fc receptor-bearing human lymphocytes: effect of treatment with proteolytic enzymes. J Immunol . 1979; 123:681-7. [PubMed 572388]
712. Kay HD, Bonnard GD, West WW et al. A functional comparison of human Fc-receptor-bearing lymphocytes active in natural cytotoxicity and antibody-dependent-cell- mediated toxicity. J Immunol . 1977; 118:2058-66. [PubMed 325136]
713. Parrillo JE, Fauci AS. Comparison of the effector cells in human spontaneous cellular cytotoxicity and antibody-dependent cellular cytotoxicity: differential sensitivity of effector cell to in vivo and in vitro corticosteroids. Scand J Immunol . 1978; 8:99-107. [PubMed 705262]
714. Masucci MG, Szigeti R, Klein E et al. Effect of interferon-β1 from E. coli on some cell functions. Science . 1980; 209: 1431-35. [PubMed 6158096]
715. Foon K, Doroshow J, Bonnem E et al. A prospective randomized trial of alpha 2B-interferon/gamma-interferon or the combination in advanced metastatic renal cell carcinoma. J Biol Response Mod . 1988; 7:540-5. [PubMed 3145964]
716. Ortaldo JR, Pestka S, Slease RB et al. Augmentation of human K-cell activity with interferon. Scand J Immunol . 1980; 12:365-9. [PubMed 6162197]
717. Herberman RB, Djeu JY, Ortaldo JR et al. Role of interferon in the augmentation of natural and antibody-dependent cell-mediated cytotoxicity. Cancer Treat Rep . 1978; 62:1893-96. [PubMed 728907]
718. Attallah AM, Folks T. Interferon enhanced human natural killer and antibody-dependent cell-mediated cytotoxic activity. Int Arch Allergy Appl Immunol . 1979; 60:377-82. [PubMed 574126]
719. Heron I, Hoakland M, Moller-Larsen A et al. The effect of interferon on lymphocyte-mediated effector cell functions: selective enhancement of natural killer cells. Cell Immunol . 1979; 42:183-7. [PubMed 155499]
720. Kimber I. Moore M. Selective enhancement of human mononuclear leukocyte cytotoxic function by interferon. Scand J Immunol . 1981; 13:375-81. [PubMed 6171028]
722. Trinchieri G, Santoli D. Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus transformed cells: enhancement of human natural killer cell activity by interferon and antagonistic inhibition of susceptibility of target cells to lysis. J Exp Med . 1978; 147:1314-33. [PubMed 650156]
724. Gisler RH, Lindahl P, Gresser I. Effects of interferon on antibody synthesis in vitro. J Immunol . 1974; 113:438-44. [PubMed 4602660]
725. Johnson HM, Smith BG, Baron S. Inhibition of the primary in vitro antibody response by interferon preparations. J Immunol . 1975; 114:403-9. [PubMed 1090660]
726. Johnson HM, Baron S. The nature of the suppressive effect of interferon and interferon inducers on the in vitro immune response. Cell Immunol . 1976; 25:106-15. [PubMed 786465]
727. Sonnenfeld G, Mandel AD, Merigan TC. Time and dosage dependence of immunoenhancement by murine type II interferon preparations. Cell Immunol . 1977; 34:193-206. [PubMed 338162]
728. Virelizier JL, Chan EL, Allison AC. Immunosuppressive effects of lymphocyte (type II) and leucocyte (type I) interferon on primary antibody responses in vivo and in vitro. Clin Exp Immunol . 1977; 30:299-304. [PubMed 203424]
729. Friedman RM. Interferon: a primer. New York: Academic Press: 1981.
730. Sonnenfeld G, Mandel AD, Merigan TC. Time and dosage dependence of immunoenhancement by murine type II interferon preparations. Cell Immunol . 1978; 40:285-93. [PubMed 363280]
731. Parker MA, Mandel AD, Wallace JH et al. Modulation of the human in vitro antibody response by human leukocyte interferon preparations. Cell Immunol . 1981; 58:64-9.
732. Brodeur BR, Merigan TC. Mechanism of the suppressive effect of interferon on antibody synthesis in vivo. J Immunol . 1975; 114:1323-8. [PubMed 163863]
733. Brodeur BR, Merigan TC. Suppresive effect of interferon on the humoral immune response to sheep red blood cells in mice. J Immunol . 1974; 113:1319-25. [PubMed 4607133]
734. Braun W, Levy HB. Interferon preparations as modifiers of immune responses. Proc Soc Exp Biol Med . 1972; 141:769-73. [PubMed 4566752]
735. Chester TJ, Paucker K, Merigan TC. Suppression of mouse antibody producing spleen cells by various interferon preparations. Nature . 1973; 246:92-4. [PubMed 4585853]
736. Vignaux F, Gresser I, Fridman WH. Effect of virus-induced interferon on the antibody response of suckling and adult mice. Eur J Immunol . 1980; 10:767-72. [PubMed 6159214]
737. Ngan J, Lee SHS, Kind LS. The suppressive effect of interferon on the ability of mouse spleen cells synthesizing IgE to sensitize rat skin for heterologous adoptive cutaneous anaphylaxis. J Immunol . 1976; 117:1063-6. [PubMed 977941]
738. Ida S, Hooks JJ, Siraganian RP et al. Enhancement of IgE-mediated histamine release from human basophils by viruses: role of interferon. J Exp Med . 1977; 145:892-906. [PubMed 67173]
739. Hernandez-Asenio M, Hooks JJ, Ida S et al. Interferon- induced enhancement of of IgE-mediated histamine release from human basophils requires RNA synthesis. J Immunol . 1979; 122:1601-3. [PubMed 87438]
740. Fellous M, Kamoun M, Gresser I et al. Enhanced expression of HLA antigens and beta 2-microglobulin on interferon-treated human lymphoid cells. Eur J Immunol . 1979; 9:446-52. [PubMed 91516]
741. Heron I, Hoakland M, Berg K. Proc Natl Acad Sci USA . 1978; 75:6215.
742. Yoshie O, Schmidt H, Reddy ES et al. Mouse interferons enhance the accumulation of a human HLA RNA and protein in transfected mouse and hamster cells. J Biol Chem . 1982; 257:13169-72. [PubMed 6183260]
743. Klotzbucher A, Mittnacht S, Kirchner et al. Different effects of IFN gamma and IFN alpha/beta on immediate early gene expression of HSV-1. Virology . 1990; 179:487-91. [PubMed 2171221]
744. Herlyn M, Guerry D, Koprowski H. Recombinant gamma- interferon induces changes in expression and shedding of antigens associated with normal human melanocytes, nevus cells, and primary and metastatic melanoma cells. J Immunol . 1985; 134:4226-30. [PubMed 2985706]
745. Greiner JW, Hand PH, Noguchi P et al. Enhanced expression of surface tumor-associated antigens on human breast and colon tumor cells after recombinant human leukocyte alpha- interferon treatment. Cancer Res . 1984; 44:3208-14. [PubMed 6744259]
746. Greiner JW, Fisher PB, Pestka S et al. Differential effects of recombinant human leukocyte interferons on cell surface antigen expression. Cancer Res . 1986; 46:4984- 90. [PubMed 2944575]
747. Vignaux F, Gresser I. Differential effects of interferon on the expression of H-2K, H-2D, and Ia antigens on mouse lymphocytes. J Immunol . 1977; 118:721-3. [PubMed 839076]
748. Lonai P, Steinman L. Physiological regulation of antigen binding to T cells: role of a soluble macrophage factor and of interferon. Proc Natl Acad Sci USA . 1977; 74:5662-6. [PubMed 414224]
749. Lindahl P, Leary P, Gresser I. Enhancement by interferon of the expression of surface antigens on murine leukemia L1210 cells. Proc Natl Acad Sci USA . 1973; 70:2785-8. [PubMed 4517933]
750. Lucero MA, Magdelenat H, Fridman WH et al. Comparison of effects of leukocyte and fibroblast interferon on immunological parameters of cancer patients. Eur J Cancer Clin Oncol . 1982; 18:243-51. [PubMed 6178592]
751. Kohzoh I, Ng AK, Glassy MC et al. Differential effect of interferon on the expression of tumor-associated antigens and histocompatibility antigens on human melanoma cells: relationship to susceptibility to immune lysis mediated by monoclonal antibodies. J Immunol . 1981; 127:505-8. [PubMed 6166672]
752. Fellous M, Nir U, Wallach D et al. Interferon-dependent induction of mRNA for the major histocompatibility antigens in human fibroblasts and lymphoid cells. Proc Natl Acad Sci USA . 1982; 79:3082-6. [PubMed 6179076]
753. Hrushesky WJ, Murphy GP. Current status of the therapy of advanced renal carcinoma. J Surg Oncol . 1977; 9:277- 88. [PubMed 327158]
754. Heron I, Hokland M, Berg K. Enhanced expression of beta2-microglobulin and HLA antigens on human lymphoid cells by interferon. Proc Natl Acad Sci USA . 1978; 75:6215-9. [PubMed 83651]
756. Schultz RM, Cirigos MA, Heine UI. Functional and morphologic characteristics of interferon-treated macrophages. Cell Immunol . 1978; 35:84-91. [PubMed 620429]
757. Huang KY, Donahoe RM, Gordon FB et al. Enhancement of phagocytosis by interferon containing preparations. Infect Immun . 1971; 4:581-8. [PubMed 4343410]
758. Imanishi J, Yokota Y, Kishida T et al. Phagocytosis- enhancing effect of human leukocyte interferon preparation of human peripheral monocytes in vitro. Acta Virol . 1975; 19:52-8. [PubMed 235198]
759. Hamburg SI, Manejias RE, Rabinovitch M. Macrophage activation: increased ingestion of IgG-coated erythrocytes after administration of interferon inducers to mice. J Exp Med . 1978; 147:593-8. [PubMed 624908]
760. Hamburg SI, Cassell GH, Rabinovitch M. Relationship between enhanced macrophage phagocytic activity and the induction of interferon by Newcastle disease virus in mice. J Immunol . 1980; 124:1360-4. [PubMed 6965692]
761. Alexander P, Evans R. Endotoxin and double stranded RNA render macrophages cytotoxic. Nature New Biol . 1971; 232:76-8. [PubMed 5285341]
762. Fidler IJ, Roblin RO, Poste G. In vitro tumoricidal activity of macrophages against virus-transformed lines with temperature-dependent transformed phenotypic characteristics. Cell Immunol . 1978; 38:131-46. [PubMed 208781]
763. Hibbs JB Jr, Lambert LH Jr, Remington JS. Control of carcinogenesis: a possible role for the activated macrophage. Science . 1972; 177:998-1000. [PubMed 5055947]
764. Keller R. Modulation of cell proliferation by macrophages: a possible function apart from cytotoxic tumour rejection. Br J Cancer . 1974; 30:401-15. [PubMed 4469193]
765. Hibbs JB Jr. Macrophage nonimmunologic recognition: target cell factors related to contact inhibition. Science . 1973; 180:868-70. [PubMed 4350403]
768. Heron I, Berg K. Human leukocyte interferon: analysis of effect on MLC and effector cell generation. Scand J Immunol . 1979; 9:517-26. [PubMed 156947]
769. Kadish AS, Tansey FA, Yu GSM et al. Interferon as a mediator of human lymphocyte suppression. J Exp Med . 1980; 151:637-50. [PubMed 6444662]
770. Johnson HM. Cyclic AMP regulation of mitogen-induced interferon production and mitogen suppression of immune response. Nature . 1977; 265:154-5. [PubMed 189202]
771. Johnson HM, Stanton GJ, Baron S. Relative ability of mitogens to stimulate production of interferon by lymphoid cells and to induce suppression of the in vitro immune response. Proc Soc Exp Biol Med . 1977; 138-41.
772. Einhorn S, Blomgren H. Enhancement of the human mixed lymphocyte culture response by pretreating the stimulating cells with interferon. Int Arch Allergy Appl Immunol . 1980; 62:126-32. [PubMed 6154651]
773. Heron I, Hokland M, Berg K. Enhanced expression of β2-microglobulin and HLA antigens on human lymphoid cells by interferon. Proc Natl Acad Sci USA . 1978; 75:6215-9. [PubMed 83651]
774. Fridman WH, Gresser I, Bandu MT et al. Interferon enhances the expression of Fc gamma receptors. J Immunol . 1980; 124:2436-41. [PubMed 6154103]
775. Bolhuis RLH, Hokland M, Olesen BK et al. Modulation of cytolytic activity of T3 — natural killer cell derived from clones by interferon. Proceedings of the 14th International Chemotherapy Conference. 1985. Abstract No. WS-2-6.
776. Vanky F, Argov S. Human tumor-lymphocyte interaction in vitro: VII. Blastogenesis and generation of cytotoxicity against autologous tumor biopsy cells are inhibited by interferon. Int J Cancer . 1980; 26:405-11. [PubMed 6166574]
777. Brenan M, Zinkernagel RM. Influence of one virus infection on a second concurrent primary in vivo antiviral cytotoxic T-cell response. Infect Immun . 1983; 41:470-5. [PubMed 6192082]
778. Heron I, Berg K, Cantell K. Regulatory effect of interferon on T cells in vitro. J Immunol . 1976; 117:1370-3. [PubMed 135810]
779. Zarling JM, Sosman J, Eskra L et al. Enhancement of T cell cytotoxic responses by purified human fibroblast interferon. J Immunol . 1978; 121:2002-4. [PubMed 309487]
780. Ausiello C, Hokland P, Heron I. Interferon-induced augmentation of cytotoxic killer cell generation in mixed lymphocyte cultures: analysis of the effector cell product. Scand J Immunol . 1980; 13:263-70.
781. Vanky FT, Argov SA, Einhorn SA et al. Role of alloantigens in natural killing: allogeneic but not autologous tumor biopsy cells are sensitive for interferon-induced cytotoxicity of human blood lymphocytes. J Exp Med . 1980; 151:1151-65. [PubMed 6154767]
782. Hirsh MS, Ellis DA, Black PH et al. Immunosuppressive effects of an interferon preparation in vivo. Transplantation . 1973; 17:234-6.
783. DeMaeyer E, DeMaeyer-Guignard J, Vandeputte M. Inhibition by interferon of delayed-type hypersensitvity in mice. Proc Natl Acad Sci USA . 1975; 72:1753-7. [PubMed 168573]
784. DeMaeyer-Guianard J, Cachard A, DeMaeyer E. Delayed- type hypersensitivity to sheep red blood cells: inhibition of sensitization by interferon. Science . 1975; 190:574-6. [PubMed 1188355]
785. Epstein LB. The effects of interferons on the immune response in vitro and in vivo. In: Stewart W., ed. Interferons and their actions. CRC Press: Cleveland, OH; 1977:91-132.
786. DeMaeyer E, DeMaeyer-Guignard J. Immunoregulatory action of type I interferon in the mouse. Ann NY Acad Sci . 1980; 350:1-11.
787. Masucci MG, Szigeti R, Klein E et al. Effect of interferon-α1 from E coli on some cell functions. Science . 1980; 209:1431-5. [PubMed 6158096]
788. Szigeti R, Masucci MG, Masucci G et al. Inteferon suppresses antigen- and mitogen-induced leukocyte migration inhibition. Nature . 1980; 288:594-6. [PubMed 6160404]
789. Dinh PN, Beladi I, Rosztoczy I et al. Modulation of lymphokine production by interferon. J Interferon Res . 1980; 1:23-30. [PubMed 6180042]
792. Einhorn S, Blomgren H, Strander H. Interferon and spontaneous cytotoxicity in man: II. Studies in patients receiving exogenous leukocyte interferon. Acta Med Scand . 1978; 204:477-83. [PubMed 282781]
794. Edwards BS, Hawkins MJ, Borden EC. Comparative in vivo and in vitro activation of human natural killer cells by two recombinant alpha-interferons differing in antiviral activity. Cancer Res . 1984; 44:3135-9. [PubMed 6586292]
796. Edwards BS, Hawkins MJ, Borden EC. Correlation between in vitro and systemic effects of native and recombinant interferons-alpha on human natural killer cell cytotoxicity. J Biol Response Mod . 1983; 2:409-17. [PubMed 6644345]
798. Djeu JY, Huang KY, Herberman RB. Augmentation of mouse natural killer cell activity and induction of interferon by tumor cells in vivo. J Exp Med . 1980; 151:781-9. [PubMed 6154760]
799. Silva A, Bonavida B, Targan S. Mode of action of interferon-mediated modulation of natural killer cell cytotoxic activity: recruitment of pre-NK cells and enhanced kinetics of lysis. J Immunol . 1980; 125:479-84. [PubMed 6156205]
800. Flexman JP, Shellam GR. Mechanism of stimulation of natural killer-cell cytotoxicity by interferon and an interferon- inducer in the rat. Immunology . 1981; 44:311-20. [PubMed 6170575]
801. Targan S, Dorey F. Interferon activation of "pre- spontaneous killer" (pre-SK) cells and alteration of kinetics of lysis of both "pre-SK" and active SK cells. J Immunol . 1980; 124:2157-61. [PubMed 6154092]
802. Laszlo J, Huang AT, Brenckman WD et al. Phase I study of pharmacological and immunological effects of human lymphoblastoid interferon given to patients with cancer. Cancer Res . 1983; 43:4458-66. [PubMed 6603265]
803. Sherwin SA, Knost JA, Fein S et al. A multiple-dose phase I trial of recombinant leukocyte interferon in cancer patients. JAMA . 1982; 248:2461-6. [PubMed 6752447]
804. Edwards BS, Merritt JA, Fuhlbrigge RC et al. Low doses of interferon alpha result in more effective natural killer cell activation. J Clin Invest . 1985; 75:1908-13. [PubMed 4008643]
805. Maluish AE, Ontaldo JR, Conlon JC et al. Depression of natural killer cytotoxicity after in vivo administration of recombinant leukocyte interferon. J Immunol . 1983; 80:2961-5.
808. Einhorn S, Ahre A, Blomgren H et al. Interferon and naturl killer activity in multiple myeloma. Lack of correlation between interferon-induced enhancement of natural killer activity and clinical response to human interferon-α. Int J Cancer . 1982; 30:167-72. [PubMed 6182111]
809. Pope GR, Hadam MR, Eisenburg J et al. Kinetics of natural cytotoxicity in patients treated with human fibroblast interferon. Cancer Immunol Immunother . 1981; 11:1-6.
810. Maluish AE, Leavitt R, Sherwin S et al. Effecgs of recombinant interferon-α on immune function in cancer patients. J Biol Response Mod . 1984; 2:470-81.
811. Maluish AE, Ortaldo Jr, Sherwin S et al. Changes in immune function in patients receiving natural leukocyte interferon. J Biol Response Mod . 1983; 2:418-22. [PubMed 6644346]
812. Spinn CA, Dahey JL, Durhos-Smith D et al. Suppression of NC cell acytotoxicity in the peripheral blood of patients receiving interferon therapy. J Biol Response Mod . 1983; 2:458-9. [PubMed 6644350]
813. Lotzova E, Savary CA, Gutterman JU et al. Regulation of natural killer cell cytotoxicity by recombinant leukocyte interferon clone A. J Biol Response Mod . 1983; 2:482- 98. [PubMed 6644351]
814. Silver HKB, Connors JM, Salinas FA. Prospectively randomized toxicity study of high-dose versus low-dose treatment strategies for lymphoblastoid interferon. Cancer Treat Rep . 1985; 69:743-50. [PubMed 4016785]
815. Paulnock DM, Borden EC. Modulation of immune functions by interferons. In: Immunity to cancer. New York: Academic Press; 1985:545-59.
816. Einhorn S, Blomgren H, Strander H. Interferon and spontaneous cytotoxicity in man: I. Enhancement of the spontaneous cytotoxicity of peripheral lymphocytes by human leukocyte interferon. Int J Cancer . 1978; 22:405-12. [PubMed 700895]
817. Trinchieri G, Granato D, Perussia B. Interferon-induced resistance of fibroblasts to cytolysis mediated by natural killer cells: specificity and mechanism. J Immunol . 1981; 126:335-40. [PubMed 7451975]
818. Welsh R, Karre K, Hansson M et al. Interferon-mediated protection of normal and tumor target cells against lysis by mouse natural killer cells. J Immunol . 1981; 126:219-25. [PubMed 6161162]
819. Moore M, White WJ, Potter MR. Modulation of target cell susceptibility to human natural killer cells by interferon. Int J Cancer . 1980; 25:565-72. [PubMed 6154661]
820. Hansson M, Kiessling R, Andersson B et al. Effect of interferon and interferon inducers on the NK sensitivity of normal mouse thymocytes. J Immunol . 1980; 125:2225-31. [PubMed 6159402]
821. Dubreuil M, Sportza L, D'Addario M et al. Inhibition of HIV-1 transmission by interferon and 3'-azido-3'- deoxythymidine during de novo infection of promonocytic cells. Virology . 1990; 179:388-94. [PubMed 1699354]
822. Trinchieri G, Santoli D, Koprowski H. Spontaneous cell- mediated cytotoxicity in humans: role of interferon and immunoglobulins. J Immunol . 1978; 120:1849-55. [PubMed 659880]
824. Ortaldo JR, Mantovani A, Hobbs D et al. Effects of several species of human leukocyte interferon on cytotoxic activity of NK cells and monocytes. Int J Cancer . 1983; 31:285-9. [PubMed 6826252]
825. Smekens-Etienne M, Goldstein J, Ooms HA et al. Variation of (2'-5')oligo(adenylate) synthetase activity during rat-liver regeneration. Eur J Biochem . 1983; 130:269-73. [PubMed 6825692]
826. Schattner A, Merlin G, Wallach D et al. Monitoring of interferon therapy by assay of 2'-5' oligoisoadenylate synthetase in human peripheral white blood cells. J Interferon Res . 1981; 1:587-94. [PubMed 6180091]
829. Silverman RH, Watling D, Balkwill FR et al. The ppp(A2'p)nA and protein kinase systems in wild-type and interferon resistant Daudi cells. Eur J Biochem . 1982; 126:333-41. [PubMed 6181993]
830. Burke DC, Graham CF, Lehman JM. Appearance of interferon inducibility and sensitivity during differentiation of murine teratocarcinoma cells in vitro. Cell . 1978; 13:243-8. [PubMed 627035]
831. Hovanessian AG, Wood JN. Anticellular and antiviral effects of pppA(2'p5'A)n . Virology . 1980; 101:81-90. [PubMed 6243832]
832. Sreevalsan T. Effects of interferons on cell physiology. In: Friedman RM, ed. Interferon — mechanisms of production and action. New York: Elsevier; 1984:3.
833. Kimchi A, Shure H, Revel M. Regulation of lymphocyte mitogenesis by (2'-5') oligo-isoadenylate. Nature . 1979; 282:849-51. [PubMed 514363]
834. Kimchi A, Shure H, Revel M. Anti-mitogenic function of interferon induced (2'-5') oligo(adenylate) and growth- related variations in enzymes that synthesize and degrade this oligonucleotide. Eur J Biochem . 1981; 114:5-10. [PubMed 6163628]
835. Hovanessian AG, Wood J, Meurs E et al. Incresed nuclease activity in cells treated with pppA2'p5'A2'P5'A. Proc Natl Acad Sci USA . 1979; 76:3261-5. [PubMed 114998]
836. Kimchi A, Schulman L, Schmidt A et al. Kinetics of induction of three regulatory enzymes by interferon. Proc Natl Acad Sci USA . 1979; 76:3208-12. [PubMed 226962]
837. Krishnan I, Baglioni C. Increased levels of 2'-5' oligo(A) polymerase activity in human lymphoblastoid cells treated with glucocorticoids. Proc Natl Acad Sci USA . 1980; 77:6506-10. [PubMed 6161367]
838. Jacobsen H, Krause D, Friedman RM et al. Induction of ppp(A2'p)nA-dependent RNAase in murine JLS-V9R cells during growth inhibition. Proc Natl Acad Sci USA . 1983; 80:4954-8. [PubMed 6576368]
839. Stark GR, Dower WJ, Schimke RT et al. 2-5 A synthetase: assay, distribution, and variation with growth or hormone status. Nature . 1979; 278:471-3. [PubMed 450053]
840. Kimchi A, Shure H, Lapidot Y et al. Antimitogenic effects of interferon and (2'-5')-oligoadenylate in synchronized 3T3 fibroblasts. FEBS Lett . 1981; 134:212- 6. [PubMed 6171460]
841. Krown SE. Interferons in malignancy: biological products or biological response modifiers? J Natl Cancer Inst . 1988; 80:306-9.
842. Giacomini P, Fraioli R, Nistico P et al. Modulation of the antigenic phenotype of early-passage human melanoma cells derived from multiple autologous metastases by recombinant human leukocyte, fibroblast and immune interferon. Int J Cancer . 1990; 46:539-45. [PubMed 2118485]
844. Gerwert D, Shah S, Clemens MJ. Inhibition of cell division by interferons: changes in the transport of thymidine in human lymphoblastoid (Daudi) cells. Eur J Biochem . 1981; 116:487-92. [PubMed 6167441]
845. Gendelman HE, Baca L, Turpin JA et al. Restriction of HIV replication in infected T cells and monocytes by interferon- alpha. AIDS Res Hum Retroviruses . 1990; 6:1045-9. [PubMed 2121192]
846. Brouty-Boye D. Acquisition of tolerance to the antiproliferative activity of interferon by x-ray transformed C3H/10T½ cells under prolonged treatment with interferon. Int J Cancer . 1982; 30:193-5. [PubMed 6182112]
848. Nilsen TW, Wood DL, Baglioni C. Virus-specific effects of interferon in embryonal carcinoma cells. Nature . 1980; 286:178-80. [PubMed 6157099]
849. Horisberger MA, Haller O, Arnheiter H. Interferon- dependent genetic resistance to influenza virus in mice: virus replication in macrophages is inhibited at an early step. J Gen Virol . 1980; 50:205-10. [PubMed 6160200]
850. Haller O, Arnheiter H, Gresser I et al. Virus specific interferon action. Protection of newborn Mx carriers against lethal infection with influenza virus. J Exp Med . 1981; 154:199-203. [PubMed 6166723]
851. Banerjee AK. 5'-terminal cap structure in eucaryotic meme and dosage dependence of immunoenhancement by murine type II interferon preparations. Cell Immunol . 1977; 34:193-206. [PubMed 338162]
852. Sen GC, Shaila S, Lebleu B et al. Impairment of reovirus mRNA methylation in extracts of interferon-treated Ehrlich ascites tumor cells: further characteristics of the phenomenon. J Virol . 1977; 21:69-83. [PubMed 556782]
853. Desrosiers RC, Lengyel P. Impairment of reovirus mRNA "cap" methylation in interferon- treated mouse L929 cells. Biochim Biophys Acta . 1979; 562:471-80. [PubMed 454611]
854. Kroath H, Janda HG, Hiller G et al. Methylation of vaccinia virus-specific mRNA in the interferon-treated chick cell. Virology . 1979; 92:572-7. [PubMed 425328]
855. Kahana G, Yakobson E, Revel M et al. Increased methylation of RNA in SV40-infected interferon treated cells. Virology . 1981; 112:109-118. [PubMed 6166121]
856. In: Gresser I, ed. Interferon I. London and New York: Academic Press; 1979:102-63.
857. Sidky YA, Borden EC. Inhibition of angiogenesis by interferons: effects on tumor-and lymphocyte induced vasucular responses. Cancer Res . 1987; 47:5155-61. [PubMed 2441862]
858. Harfast B, Huddlestone JR, Casali P et al. Interferon acts directly on human B-lymphocytes to modulate immunoglobulin synthesis. J Immunol . 1981; 127:2146-50. [PubMed 6170691]
859. Cohen GL, Falkson CI. Current treatment options for malignant melanoma. Drugs . 1998; 55:791-9. [PubMed 9617594]
861. Rubin BY, Gupta SL. Differential efficacies of type I and type II interferons as antiviral and antiproliferative agents. Proc Natl Acad Sci USA . 1980; 77:5928-32. [PubMed 6160587]
862. Ennis FA, Meager A, Beare AS et al. Interferon induction and increased natural killer-cell activity in influenza infections in man. Lancet . 1981; 2:891-3. [PubMed 6170850]
863. Krown SE, Mintzer D, Cunningham-Rundles S et al. High- dose human lymphoblastoid interferon in metastatic colorectal cancer: clinical results and modification of biological responses. Cancer Treat Rep . 1987; 71:39-45. [PubMed 3791267]
865. Kerr IM. The 2-5A system: a personal view. J Interferon Res . 1987: 7:505-510.
867. Herberman RB, Hiserodt J, Vujanovic N et al. Lymphokine-activated killer cell activity: characteristics of effector cells and their progenitors in blood and spleen. Immunol Today . 1987; 8:178-81. [PubMed 25290217]
868. Barlozzari T, Leonhardt J, Wiltrout RH et al. Direct evidence for the role of LGL in the inhibition of experimental tumor metastases. J Immunol . 1985; 134:2783-9. [PubMed 3871818]
869. Barlozzari T, Reynolds CW, Herberman RB. In vivo role of natural killer cells: involvement of large granular lymphocytes in the clearance of tumor cells in anti-asialo GM1- treated rats. J Immunol . 1983; 131:1024-7. [PubMed 6863925]
870. Hanna N. Inhibition of experimental tumor metastasis by selective activation of natural killer cells. Cancer Res . 1982; 42:1337-42. [PubMed 6277482]
871. Wiltrout RH, Talmadge JE, Herberman RB. In: Herberman RB, Wiltrout RH, Gorelik E, eds. Immune responses to metastases. CRC Press. Boca Raton, FL; 1987.
872. Brunda MJ, Rosenbaum D, Stern L. Inhibition of experimentally-induced murine metastases by recombinant alpha interferon: correlation between the modulatory effect of interferon treatment on natural killer cell activity and inhibition of metastases. Int J Cancer . 1984; 34:421-6. [PubMed 6480158]
873. Gresser I, Bourali-Maury C. Inhibition by interferon preparations of a solid malignant tumor and pulmonary metastases in mice. Nature . 1972; 236:78-9. [PubMed 4623141]
874. Zarling JM, Eskra L, Borden EC et al. Activation of human natural killer cells cytotoxic for human leukemia cells by purified interferon. J Immunol . 1979; 123:63-70. [PubMed 286738]
875. Mantovani A, Allavena P, Sessa C et al. Natural killer activity of lymphoid cells isolated from human ascitic ovarian tumors. Int J Cancer . 1980; 25:573-82. [PubMed 6154662]
876. Rubinstein M, Levy WP, Moschera JA et al. Human leukocyte interferon: isolation and characterization of several molecular forms. Arch Biochem Biophys . 1981; 210:307-18. [PubMed 6170262]
877. Locardi C, Petrini C, Boccoli G et al. Increased human immunodeficiency virus (HIV) expression in chronically infected U937 cells upon in vitro differentiation by hydroxyvitamin D3: roles of interferon and tumor necrosis factor in regulation of HIV production. J Virol . 1990; 64:5874-82. [PubMed 1700829]
879. Timonen T, Ortaldo JR, Herberman RB. Analysis by a single cell cytotoxicity assay of natural killer (NK) cell frequencies among human large granular lymphocytes and of the effects of interferon on their activity. J Immunol . 1980; 128:2514-21.
891. Ho DD, Rota TR, Kaplan JC et al. Recombinant human interferon alfa-A suppresses HTLV-III replication in vitro. Lancet . 1985; 1:602-4. [PubMed 2857946]
892. Ho M. Interferon for the treatment of infections. Ann Rev Med . 1987; 38:51-9. [PubMed 2437854]
893. Winston DJ, Eron LJ, Ho M et al. Recombinant interferon alpha-2a for treatment of herpes zoster in immunosuppressed patients with cancer. Am J Med . 1988; 85:147-151. [PubMed 3041829]
894. Arvin AM, Feldman S, Merigan TC. Human leukocyte interferon in the treatment of varicella in children with cancer: a preliminary controlled study. Antimicrob Agents Chemother . 1978; 13:605-7. [PubMed 352259]
895. Arvin AM, Kushner JH, Feldman S et al. Human leukocyte interferon for the treatment of varicella in children with cancer. N Engl J Med . 1982; 306:761-5. [PubMed 6174864]
896. Hartshorn KL, Sandstrom EG, Neumeyer D et al. Synergistic inhibition of human T-cell lymphotropic virus type III replication in vitro by phosphonoformate and recombinant alpha-A interferon. Antimicrobial Agents Chemother . 1986; 30:189-91.
897. Kornbluth RS, Oh PS, Munus JR et al. The role of interferons in the control of HIV replication in macrophages. Clin Immunol Immunopathol . 1990; 54:200-19. [PubMed 1688522]
898. Palmisano L. Immunomodulatory treatment of HIV infection. Serono Symposium Publication No. 59. New York: Raven Press; 1989:73-87.
899. Williams BRG, Fish EN. Interferon and viruses: in vitro studies. In: Taylor-Papadimitriou J. ed. Interferons: their impact in biology and medicine. New York: Oxford University Press; 1985:40-60.
900. Silverman RH, Cayley PJ, Knight M et al. Control of the ppp(a2'ap)nA system in HeLa cells. Effects of interferon and virus infection. Eur J Biochem . 1982; 124:131-8. [PubMed 6177533]
901. Munoz A, Garcia RA, Perez-Aranda A et al. Potentiation by levamisole, methisoprinol, and adenine or adenosine of the inhibitory activity of human interferon against encephalomyocarditis virus. Antimicrob Agents Chemother . 1986; 30:192-5. [PubMed 2428301]
902. Munoz A, Carrasco L. Protein synthesis and membrane integrity in interferon-treated HeLa cells infected with encephalomyocarditis virus. J Gen Virol . 56(Part 1):153- 62.
903. Munoz A, Carrasco L. Effect of interferon treatment on blockade of protein synthesis induced by poliovirus infection. Eur J Biochem . 1983; 137:623-9. [PubMed 6198175]
904. Munoz A, Harvey R, Carrasco L. Cellular RNA is not degraded in interferon-treated HeLa cells after poliovirus infection. FEBS Lett . 1983; 16:87-92.
905. Munoz A, Carrasco L. Action of human lymphoblastoid interferon on HeLa cells infected with RNA-containing animal viruses. J Gen Virol . 1984; 65(Part 2):377-90. [PubMed 6319580]
906. Whitaker-Dowling P, Younger JS. Antiviral effects of interferons in different virus-host cell systems. In: Pfeffer LM, ed. Mechanisms of interferon actions. CRC Press: Boca Raton FL; 1987:83-98.
907. Marcus PI, Engelhardt DL, Hunt JM et al. Interferon action: inhibition of vesicular stomatitis virus RNA synthesis induced by virion-bound polymerase. Science . 1971; 174:593-8. [PubMed 4329841]
908. Joklik WK, Merigan TC. Concerning the mechanism of action of interferon. Proc Natl Acad Sci USA . 1966; 56:558-65. [PubMed 5229977]
909. Metz DH, Esteban M, Danielescu G. The effect of interferon on the formation of virus polyribosomes in L cells infected with vaccinia virus. J Gen Virol . 1975; 27:197- 209. [PubMed 806660]
910. Metz DH, Estaban M. Interferon inhibits viral protein synthesis in L cells infected with vaccinia virus. Nature . 1972; 238:385-8. [PubMed 4559581]
911. Stewart WE. Mechanism of antiviral action of interferons. In: Stewart WE, ed. The interferon system. 2nd ed. New York: Springer Verlag; 1981:196-222.
912. Hayden FG, Albrecht JK, Kaiser DL et al. Prevention of natural colds by contact prophylaxis with intranasal alpha2-interferon. N Engl J Med . 1986; 314:71-5. [PubMed 3001519]
914. Douglas RM, Moore BW, Miles HB et al. Prophylactic efficacy of intranasal alpha2interferon against rhinovirus infections in the family setting. N Engl J Med . 1986; 314:65-70. [PubMed 3001518]
915. Hoofnagle JH, Mullen K, Peters M et al. Treatment of chronic delta hepatitis with recombinant human alpha interferon. Prog Clin Biol Res . 1987; 234:291-8. [PubMed 3628383]
916. Rosina F, Saracco G, Lattore V et al. Alpha 2 recombinant interferon in the treatment of chronic hepatitis delta virus (HDV) hepatitis. Prog Clin Biol Res . 1987; 234:299-304. [PubMed 3628384]
917. Okita K, Kaneko T. The potential of interferons in malignant disease. Drugs . 1990; 39:1-6. [PubMed 1690107]
919. Sonnavend JA, Friedman RA. Mechanism of interferon action. In: Finter NB, ed. Frontiers of biology: interferons and interferon inducers. 2nd ed. New York: American Elsevier; 1973:201-38.
920. Yacobson E, Revel M, Winocour E. Inhibition of simian virus 40 replication by interferon treatment late in the lytic cycle. Virology . 1977; 80:225-8. [PubMed 195396]
921. Metz DH. Interferon and inteferon inducers. In: Simmonds AB, ed. Advances in drug action. New York: Academic Press; 1975:101-56.
922. Strander HA. Interferon in the treatment of human papilloma virus. Med Clin North Am . 1986; (May Supplement):19-23. [PubMed 2426533]
923. Quesada JR. Role of interferons in the therapy of metastatic renal cell carcinoma. Urology . 1989; 34(Suppl 4):80-3. [PubMed 2678687]
924. Kashima H, Leventhal B, Dedo H et al. Inteferon alfa-N1 (Wellferon) in juvenile onset recurrent respiratory papillomatosis: results of a randomized study in twelve collaborative institutions. Laryngoscope . 1988; 98:334- 40. [PubMed 3278186]
925. Content J. The antiviral effect of interferon on cells. In: Billiau A. ed. Interferon: general and applied aspects. New York: Elsevier; 1984; 125-38.
926. Stitz L, Schellekens H. Influence of input multiplicity of infection on the antiviral activity of interferon. J Gen Virol . 1980; 46:205-10. [PubMed 6243342]
927. Ito Y, Montagnier L. Heterogeneity of the sensitivity of vesicular stomatitis virus to interferons. Infect Immunity . 1977; 18:23-7.
928. Ahl R, Rump A. Assay of bovine interferons in cultures of the porcine cell line IB-RS-2. Infect Immunity . 1976; 14:603-6.
929. Allen PT, Schellenkens H, Van Griensven LJ et al. Differential sensitivity of Rauscher murine leukaemia virus (MuLV-R) to interferons in two interferon-responsive cell lines. J Gen Virol . 1976; 31:429-35. [PubMed 58965]
930. Streuli M, Nagata S, Weissmann C. At least three human type α interferons: structure of α2. Science . 1980; 209:1343-7. [PubMed 6158094]
931. Rios A, Mansell P, Newell G et al. The use of lymphoblastoid interferon (HuIFNα[Ly]) and vinblastine in the treatment of acquired immunodeficiency syndrome (AIDS) related Kaposi's Sarcoma (KS). Proc Am Soc Clin Oncol . 1985; 4:6.
932. Figlin RA, deKernlon JB, Maldazys J et al. Treatment of renal cell carcinoma with α(human leukocyte) interferon and vinblastine in combination: a phase I-II trial. Cancer Treat Rep . 1985; 69:263-7. [PubMed 3978656]
933. Weissman C, Weber H. The interferon genes. In: Progress in nucleic acid research and molecular biology. Vol. 33. San Diego, CA: Academic Press; 1986:251-301.
935. Swanson DA, Quesada JR. Interferon therapy for metastatic renal cell carcinoma. Semin Surg Oncol . 1988; 4:174-7. [PubMed 3142007]
936. Krown SE. Clinical trials of interferons in human malignancy. In: Pfeffer L. Mechanisms of interferons' actions. Boca Raton, FL; CRC Press; 1987:143-78.
937. Torrisi J, Berg C, Bonnem E et al. The combined use of interferon and radiotherapy in cancer management. Semin Oncol . 1986; 13(Suppl 2):78-83. [PubMed 3764443]
938. Torrisi J, Berg C, Harter K et al. Phase I combined modality clinical trial of alpha-2-interferon and radiotherapy. Int J Radiat Oncol Biol Phys . 1986; 12:1453-6. [PubMed 3759573]
939. Mattson LR, Holsti A, Niiranen L et al. Human leukocyte interferon as part of a combined treatment for previously untreated small cell lung cancer. J Biol Response Mod . 1985; 4:8-17. [PubMed 2984340]
940. Ortaldo JR, McCoy JL. Protective effects of interferon in mice previously exposed to lethal irradiation. Radiat Res . 1980; 81:262-6. [PubMed 7360883]
941. Dritschilo A, Mossman K, Gray M et al. Potentiation of radiation injury by interferon. Am J Clin Oncol . 1982; 5:79-82. [PubMed 6177232]
942. Nederman T, Benediktsson G. Effects of interferon on growth rate and radiation sensitivity of cultured, human glioma cells. Acta Radiol Oncol Radiat Phys Biol . 1982; 21:231- 4.
943. Namba M, Yamamoto S, Tanaka H et al. In vitro and in vivo studies on potentiation of cytotoxic effects of anticancer drugs or cobalt 60 gamma ray by interferon on human neoplastic disease. Cancer . 1984; 54:2262-7. [PubMed 6207909]
944. Kyle G, Woolley P, Kumar S et al. Antiproliferative effects of human recombinant interferon in combination with radiation and chemotherapeutic drugs in five human cell lines. Proc Am Soc Clin Oncol . 1985; 26:327.
945. Gould MN, Kakria RC, Olson S et al. Radiosensitization of human bronchogenic carcinoma cells by interferon beta. J Interferon Res . 1984; 4:123-8. [PubMed 6715911]
946. Mossman KL, Hill LT, Dritschilo A. Utility of interferons in clinical radiotherapy. J Natl Med Assoc . 1982; 74:1083-7. [PubMed 6184481]
947. Goddel DV, Leung DW, Dull TJ et al. The structure of eight distinct cloned human leukocyte interferon cDNAs. Nature . 1981; 290:20-6. [PubMed 6163083]
948. Nagata S, Mantei N, Weissmann C. The structure of one of the eight or more distinct chromosomal genes for human interferon. Nature . 1980; 287:401-8. [PubMed 6159536]
949. Gresser I, Bandu MT, Brouty-Boye D et al. Pronounced antiviral activity of human interferon on bovine and porcine cells. Nature . 1974; 251:543-5. [PubMed 4371444]
950. Levine M, Jones M. Interferon and drug metabolism. Clin Pharm . 1983; 2:210-1. [PubMed 6192966]
951. Bauman JH, Fuentes RJ. Interferon and drug metabolism. Clinical Pharmacy . 1983; 2:211.
952. el Azhary R, Renton KW, Mannering GJ. Effect of interferon inducing agents (polyriboinosinic acid- polyribocytidylic acid and tilorone) on the heme turnover of hepatic cytochrome P-450. Mol Pharmacol . 1980; 17:395-9. [PubMed 7393215]
953. Parkinson A, Lasker J, Kramer MJ et al. Effects of three recombinant human leukocyte interferons on drug metabolism in mice. Drug Metab Dispos . 1982; 10:579-85. [PubMed 6130903]
954. Singh G, Renton KW, Stebbing N. Homogeneous interferon from E. coli depresses hepatic cytochrome P-450 and drug biotransformation. Biochem Biophys Res Commun . 1982; 106:1256-61. [PubMed 6180750]
955. Weissmann C, Nagata S, Boll W et al. Structure and expression of human IFN-alpha genes. Philos Trans R Soc Lond B . 1982; 299:7-28.
957. Lane HC, Falloon J, Walker RE et al. Zidovudine in patients with human immunodeficiency virus (HIV) infection and Kaposi's sarcoma: a phase II randomized, placebo-controlled trial. Ann Intern Med . 1989; 111:41-50. [PubMed 2735626]
958. Walker RE, Parker RI, Kovacs JA et al. Anemia and erythropoiesis in patients with acquired immunodeficiency syndrome (AIDS) and Kaposi sarcoma treated with zidovudine. Ann Intern Med . 1988; 108:372-6. [PubMed 3422548]
959. Richman DD, Fischl MA, Grieco MH et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med . 1987; 317:192-7. [PubMed 3299090]
960. Krown SE. Approaches to interferon combination therapy in the treatment of AIDS. Semin Oncol . 1990; 17:(1 Suppl 1):11-5. [PubMed 2405490]
961. Berman E, Duigou-Osterndorf R, Krown SE et al. Synergistic cytotoxic effect of azidothymidine and recombinant interferon alpha on normal human bone marrow progenitor cells. Blood . 1989; 74:1281-6. [PubMed 2765664]
962. Hartshorn KL, Vogt MW, Chou TC et al. Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant alpha A interferon. Antimicrob Agents Chemother . 1987; 31:168-72. [PubMed 3471180]
963. Dickson D. Death halts interferon trials in France. Science . 1982; 218:772. [PubMed 6182613]
968. Nagai M. [Local chemotherapy of cancer: intrathecal administration]. Gan To Kagaku Ryoho . 1989; 16:156-64. [PubMed 2465738]
969. Ho M, Nash C, Morgan CW et al. Interferon administered in the cerebrospinal space and its effect on rabies in rabbits. Infect Immun . 1974; 9:286-93. [PubMed 4816460]
970. Smith RA, Kingsbury D, Alksne A et al. Distribution of interferon in cerebrospinal fluid after systemic intrathecal and intraventricular administration. Ann Neurol . 1982; 12:81.
971. Shah I, Band J, Samson M et al. Pharmacokinetics and tolerance of intravenous and intramuscular recombinant alpha 2 interferon in patients with malignancies. Am J Hematol . 1984; 17:363-71. [PubMed 6594039]
972. Tokazewski-Chen SA, Marafino BJ Jr, Stebbing N. Effects of nephrectomy on the pharmacokinetics of various cloned human interferons in the rat. J Pharm Exp Ther . 1983; 227:9- 15.
973. Rubinstein S, Familletti PC, Pestka S. Convenient assay for interferons. J Virol . 1981; 37:755-8. [PubMed 6163873]
974. Horning SJ, Levine JF, Miller RA et al. Clinical and immunologic effects of recombinant leukocyte A interferon in eight patients with advanced cancer. JAMA . 1982; 247:1718-22. [PubMed 6174742]
975. Schafer TW, Lieberman M, Cohen M et al. Interferon administered orally: protection of neonatal mice from lethal virus challenge. Science . 1972; 176:1326-7. [PubMed 4338344]
976. Scott GM. Interferon: pharmacokinetics and toxicity. Philos Trans R Soc Lond B . 1982; 299:91-107.
977. Diez RA, Perdereau B, Peter M et al. Scintigraphic study of radiolabelled interferon-α in osteosarcoma patients. Clin Pharmacokinet . 1990; 18:82-9. [PubMed 2311332]
978. Bocci V, Pessina GP, Paulesu L et al. The lymphatic route. VI. Distribution of recombinant interferon-alfa 2 in rabbit and pig plasma and lymph. J Biol Response Mod . 1988; 7:390-400. [PubMed 3171601]
979. Billiau A, Heremans H, Ververken D et al. Tissue distribution of human interferons after exogenous administration in rabbits and monkeys. Arch Virol . 1981; 68:19-25. [PubMed 6166278]
980. Paulson G, Karp JP. Movement of sodium-22, radioiodinated protein and tritiated water from the cisterna magna into the cerbrovascular circulation. J Neurosurgery . 1967; 27:138-41.
981. Blasberg RG, Patlak C, Fenstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther . 1975; 195:73-83. [PubMed 810575]
982. Pestka S. The purification and manufacture of human interferons. Sci Am . 1983; 249:37-43. [PubMed 6194559]
983. Arvin AM, Schmidt NJ, Cnatell K et al. Alpha interferon administration to infants with congenital rubella. Antimicrob Agents Chemother . 1982; 21:259-61. [PubMed 6176183]
984. Bocci V, Russi-Sorce M, Cirri G et al. Role of liver in the inactivation of interferon. Proc Soc Exp Biol Med . 1968; 129:62-5. [PubMed 4176732]
985. Havell EA, Berman B, Ogburn CA et al. Two antigenically distinct species of human interferon. Proc Natl Acad Sci USA . 1975; 72:2185-7. [PubMed 49055]
986. Kadish AS, Tansey FA, Yu GS et al. Interferon as a mediator of human lymphocyte suppression. J Exp Med . 1980; 151:637-50. [PubMed 6444662]
987. Abdulhay G, DiSaia PJ, Blessing JA et al. Human lymphoblastoid interferon in the treatment of advanced epithelial ovarian malignancies: a Gynecologic oncology group study. Am J Obstet Gynecol . 1985; 152:418-23. [PubMed 4040329]
988. Levy WP, Rubinstein M, Shively J et al. Amino acid sequence of a human leukocyte interferon. Proc Natl Acad Sci USA . 1981; 78:6186-90. [PubMed 6171813]
989. Arnheiter H, Ohno M, Smith M et al. Orientation of a human leukocyte interferon molecule on ints cell surface receptor: carboxyl terminus remains accessible to a monoclonal antibody made against a synthetic interferon fragment. Proc Natl Acad Sci USA . 1983; 80:2539-43. [PubMed 6302694]
990. Arnheiter H, Thomas RM, Leist T et al. Physicochemical and antigenic properties of synthetic fragments of human leukocyte interferon. Nature . 1981; 294:278-80. [PubMed 6170893]
991. Franke AE, Shepard HM, Houck CM et al. Carboxyterminal region of hybrid leukocyte interferons affects antiviral specificity. DNA . 1982; 223-30.
992. Stewart WE II, Sulkin SE. Interferon production in hamsters experimentally infected with rabies virus. Proc Soc Exp Biol Med . 1966; 123:650-4. [PubMed 5958999]
993. Hilfenhaus J, Damm H, Hofstaetter T et al. Pharmacokinetics of human interferon-beta in monkeys. J Interferon Res . 1981; 1:427-36. [PubMed 6180075]
994. Cathala F, Baron S. Interferon in rabbit brain, cerebrospinal fluid, and serum following administration of polyinosinic-polycytidylic acid. J Immunol . 1970; 104:1355-8. [PubMed 4315896]
996. Kovach JS, Svingen PA. Enhancement of the antiproliferative activity of human interferon by polyamine depletion. Cancer Treat Rep . 1985; 69:97-103. [PubMed 3917854]
998. Pollard RB. Interferons and interferon inducers: development of clinical usefulness and therapeutic promise. Drugs . 1982; 23:37-55. [PubMed 6173188]
999. Panem S. Application of recombinant DNA technology to expression of human interferon genes. In: Came PE, Carter WA, eds. Handbook of experimental pharmacology. Vol. 71. Interferons and their applications. New York: Springer-Verlag; 1971:137-51.
1000. Stewart WE II. The interferon system. Vol 2. New York: Springer-Verlag; 1981:135-45.
1001. de Clercq E. Interferon inducers. Antibiot Chemother . 1980; 27:251-87. [PubMed 6996608]
1002. Grossberg SE. Interferons: an overview of their biological and biochemical properties. In: Stewart WE II, ed. Mechanism of interferon action. Boca Raton, FL: CRC Press; 1984:1-32.
1003. Golomb HM, Fefer A, Golde DW et al. Sequential evaluation of alpha-2b-interferon treatment in 128 patients with hairy cell leukemia. Semin Oncol . 1987; 14(2 Suppl 2):13-7. [PubMed 3589701]
1004. Rai K, Mick R, Ozer H et al. Alpha interferon therapy in untreated active hairy cell leukemia: a cancer and leukemia group B (CALGB) Study. Proc Am Soc Clin Oncol . 1987; 6:A624.
1005. Gastl G, Denz H, Abbrederis C et al. Treatment with low dose human recombinant interferon-alpha-2-ARG induces complete remission in patients with hairy cell leukemia. Onkologie . 1985; 8:143-4. [PubMed 3895095]
1006. Bardawil RG, Ratain MJ, Golomb HM et al. Changes in peripheral blood and bone marrow specimens during and after α2b-interferon therapy for hairy cell leukemia. Leukemia . 1987; 1:340-3. [PubMed 3669760]
1007. Golomb HM, Ratain MJ, Vardiman JW. Sequential treatment of hairy cell leukemia: a new role for interferon. In: DeVita VT Jr, Hellman S, Rosenberg SA. eds. Important advances in oncology 1986. Philadelphia: JB Lippincott Co. 1985:311-21.
1009. Aiba M, Raffa PP, Katayama I. Significance of leukocyte alkaline phosphatase in hairy cell leukemia. Am J Clin Pathol . 1980; 74:297-300. [PubMed 7416080]
1010. Ingimarsson S, Bergstrom K, Brostrom LA et al. Effect of long-term treatment with human leukocyte interferon on various laboratory parameters. Acta Med Scand . 1980; 208:155-9. [PubMed 6159778]
1012. Scott GM, Ward RJ, Wright DJ et al. Effects of cloned interferon α2 in normal volunteers: febrile reactions and changes in circulating corticosteroids and trace metals. Antimicrob Agents Chemother . 1983; 23:589-92. [PubMed 6859837]
1013. Cantell K, Ehnholm C, Mattila K et al. Interferon and high density lipoproteins. N Engl J Med . 1980; 302:1032- 3. [PubMed 6154239]
1014. Ehnholm C, Aho K, Huttunen JK et al. Effect of interferon on plasma lipoproteins and on the activity of postheparin plasma lipases. Arteriosclerosis . 1982; 2:68-73. [PubMed 6174110]
1015. Hofmann V, Scheel A, Schwarzmeier J et al. Wirksamkeit von Interferon-α2 (E. coli) bei der Haarzell-Leukamie. (German; with English abstract.) Schweiz Med Wochenschr . 1985; 115:235-8.
1016. Mandelli F, Tribalto M, Avvisati G et al. Recombinant alpha 2B interferon (intron A) as post-induction therapy for responding multiple myeloma patients: M84 protocol. Cancer Treat Rev . 1988; 15(Suppl A):43-8. [PubMed 3277709]
1017. Oken MM, Kyle RA, Kay NE et al. A phase II trial of interferon alpha 2 (RIFN(alpha2)) in the treatment of resistant multiple myeloma (MM). Proc Am Soc Clin Oncol . 1985; 4:215.
1018. Oken MM, Kyle RA, Greipp PR et al. Complete remission (CR) induction with VBMCP + interferon (RIFN ALPHA 2) in multiple myeloma: a 3 year follow-up. Proc Am Soc Clin Oncol . 1989; 8:A1062.
1019. Kyle RA. Multiple myeloma: an update on diagnosis and treatment. Acta Oncol . 1990; 29:1-8. [PubMed 2178649]
1020. Ohno R, Kimura K. Treatment of multiple myeloma with recombinant interferon alfa-2a. Cancer . 1986; 57:1685-8. [PubMed 3948139]
1021. Alexanian R, Migliore PJ. Normal immunoglobulins in multiple myeloma: effect of melphan chemotherapy. J Lab Clin Med . 1970; 75:225-33. [PubMed 5414404]
1022. Barlogie B, Alexanian R, Dixon D et al. Prognostic implications of tumor cell DNA and RNA content in multiple myeloma. Blood . 1985; 66:338-41. [PubMed 2410065]
1023. Talpaz M. McCredie KB, Mavligit GM et al. Leukocyte interferon-induced myeloid cytoreduction in chronic myelogenous leukemia. Blood . 1983; 62:689-92. [PubMed 6192858]
1024. Talpaz M, Kantarjian HM, McCredie KB et al. Clinical investigation of human alpha interferon in chronic myelogenous leukemia. Blood . 1987; 69:1280-8. [PubMed 3471281]
1025. Talpaz M, Mavligit G, Keating M et al. Human leukocyte interferon to control thrombocytosis in chronic myelogenous leukemia. Ann Intern Med . 1983; 99:789-92. [PubMed 6580836]
1026. Talpaz M, Trujillo JM, Hittelman WN et al. Suppression of clonal evolution in two chronic myelogenous leukaemia patients treated with leucocyte interferon. Br J Haematol . 1985; 60:619-24. [PubMed 3861194]
1027. Talpaz M. Clinical studies of alpha-interferons in chronic myelogenous leukemia. Cancer Treatment Rev . 1988; 15(Suppl A):49-53.
1028. Morra E, Alimena G, Liberati AM et al. Recombinant alpha 2 interferon (R-IFN ALPHA 2) in the treatment of chronic myelogenous leukemia (CML). Proc Am Soc Clin Oncol . 1987; 6:A571.
1029. Ozer H, Dear K, Testa J et al. Prolonged administration of subcutaneous alpha-interferon induces major clinical and complete cytogenetic remissions in untreated Philadelphia chromosome positive (PH+) chronic myelogenous leukemia (CML). Proc Am Soc Clin Oncol . 1990; 9:A783.
1031. Beran M, Kantarjian H, Talpaz M et al. Intensive combination chemotherapy and human leukocyte alpha interferon (HL-ALPHA-IF) results in patients with Philadelphia-positive (PH+) benign phase of chronic myelogenous leukemia (CML). Proceedings of the 3rd European Conference on Clinical Oncology and Cancer Nursing, Stockholm, Sweden; June 16-20, 1985:126. Abstract.
1032. Hill NO, Pardue A, Kahn A et al. Clinical trials of human leukocyte interferon in malignancy. Tex Rep Biol Med . 1982; 41(Part 2):634-40.
1033. Hill NO, Pardue A, Kahn A et al. Human leucocyte interferon and leukemia trials in leukaemia and cancer. Drugs Exp Clin Res . 1982; 8:677-82.
1034. Claxton D, Kantarjian H, Kurzrock R et al. Alpha interferon dose-dependent suppression of secondary clones in a patient with Philadelphia-positive chronic myelogenous leukemia. Acta Haematol (Basel) . 1990; 83:149-51.
1038. Koeffler HP, Golde DW. Chronic myelogenous leukemia—new concepts. N Engl J Med . 1981; 304:1269- 74. [PubMed 7012625]
1039. Kantarjian H, Keating M, Talpaz M et al. Characteristics and outcome of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis. Proc Am Soc Clin Oncol . 1988; 7:A748.
1040. Yoffe G, Blick M, Kantarjian H et al. Molecular analysis of interferon-induced suppression of Philadelphia chromosome in patients with chronic myeloid leukemia. Blood . 1987; 69:961-3. [PubMed 2880616]
1041. The United States Pharmacopeial Convention, Inc. Interferon alfa-2b. Pharmacopeial Forum . 1990:1230-45.
1042. Wadler S, Schwartz EL. Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Res . 1990; 50:3473-86. [PubMed 1692761]
1043. Mandelli F, Avvisati G, Amadori S et al. Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med . 1990; 322:1430-34. [PubMed 2184356]
1044. Mellstedt H, Bjorkholm M, Johansson B et al. Interferon therapy in myelomatosis. Lancet . 1979; 1:245- 7. [PubMed 84901]
1045. Thomas ED, Clift RA, Fefer A et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med . 1986; 104:155-63. [PubMed 3511810]
1046. Wagstaff J, Loynds P, Scarffe JH. Phase II study of rDNA human alpha-2 interferon in multiple myeloma. Cancer Treat Rep . 1985; 69:495-8. [PubMed 4005872]
1047. Case DC Jr, Sonneborn HL, Paul SD et al. Phase II study of rDNA alpha-2 interferon (Intron A) in patients with multiple myeloma utilizing an escalating induction phase. Cancer Treat Rep . 1986; 70:1251-4. [PubMed 3768870]
1048. Mellstedt H, Osterberg A, Bjorkholm M et al. Induction treatment with alpha-interferon in multiple myeloma: an interim report from MGCS. Eur J Haematol Suppl . 1989; 51:124-8. [PubMed 2697585]
1049. Oken MM, Kyle RA, Greipp PR et al. Alternating cycles of VBMCP with interferon (RIFN ALPHA-2) in the treatment of multiple myeloma. Proc Am Soc Clin Oncol . 1988; 7:A868.
1050. Oken MM, Kyle RA, Greipp PR et al. Chemotherapy plus interferon (RIFN ALPHA2) in the treatment of multiple myeloma. Proc Am Soc Clin Oncol . 1990; 9:A116.
1051. Krown SE, Gold JWM, Niedzwiecki D et al. Interferon- α with zidovudine: safety, tolerance, and clinical and virologic effects in patients with Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1990; 112:812-21. [PubMed 1971504]
1052. Costanzi JJ, Cao J, Spiegel RJ et al. The efficacy of chemotherapy following interferon for relapsing multiple myeloma. In: Dianzani F, ed. The interferon system. New York: Raven Press; 1985:265-72.
1054. Perrillo RP, Schiff ER, Davis GL et al. A randomized, control trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med . 1990; 323:295-301. [PubMed 2195346]
1069. Lai CL, Lok ASF, Lin HJ et al. Placebo-controlled trial of recombinant α2-interferon in Chinese HBsAg- carrier children. Lancet . 1987; 2:877-80. [PubMed 2889081]
1081. Hoofnagle JH, Mullen KD, Jones DB et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. N Engl J Med . 1986; 315:1575-8. [PubMed 3097544]
1082. Thomson BJ, Doran M, Lever AML et al. Alpha-interferon therapy for non-A, non-B hepatitis transmitted by gammaglobulin replacement therapy. Lancet . 1987; 1:539-41. [PubMed 2434816]
1085. Lee CA, Kernoff PB, Karayiannis P et al. Interferon therapy for chronic non-A, non-B and chronic delta hepatitis. Br J Haematol . 1989; 72:235-8. [PubMed 2503026]
1086. Goldman JM, Gale RP, Horowitz MM et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: increased risk for relapse associated with T-cell depletion. Ann Intern Med . 1988; 108:806-14. [PubMed 3285744]
1087. Hoofnagle JH. Chronic hepatitis B. N Engl J Med . 1990; 323:337-9. [PubMed 2366843]
1088. Harju VT, Alitalo R, Andersson LC. Divergent in vitro effects of recombinant interferons on human osteosarcoma cells. Bone . 1990; 11:247-51. [PubMed 2122912]
1089. Rosina F, Rizzetto M. Treatment of chronic type D (Delta) hepatitis with alpha interferon. Semin Liver Dis . 1989; 9:264-6. [PubMed 2690350]
1090. Dinarello CA, Cannon JG, Wolff SM. New concepts on the pathogenesis of fever. Rev Infect Dis . 1988; 10:168-89. [PubMed 2451266]
1094. Quesada JR, Swanson DA, Gutterman JU. Phase II study of interferon alpha in metastatic renal-cell carcinoma: a progress report. J Clin Oncol . 1985; 3:1086-92. [PubMed 4020410]
1095. Takita T, Tanaka J, Murase T et al. Remarkable responses of metastatic renal cell cancer in multiple organs treated with alpha-interferon. J Urol . 1986; 136:1061-2. [PubMed 3773069]
1097. Marumo K, Murai M, Hayakawa M et al. Human lymphoblastoid interferon therapy for advanced renal cell carcinoma. Urology . 1984; 24:567-71. [PubMed 6506397]
1098. Vugrin D, Hood L, Taylor W et al. Phase II study of human lymphoblastoid interferon in patients with advanced renal carcinoma. Cancer Treat Rep . 1985; 69:817-20. [PubMed 4016792]
1099. Quesada JR. Interferons in the treatment of metastatic renal cell carcinoma. Dev Med Virol . 1988; 4:149-56.
1100. Fossa SD, Gunderson R, Moe B. Recombinant interferon- alfa combined with prednisone in metastatic renal cell carcinoma: reduced toxicity without reduction of the response rate—a phase II study. Cancer . 1990; 65:2451-4. [PubMed 2337859]
1101. Quesada JR, Swanson DA, Trindade A et al. Renal cell carcinoma: antitumor effects of leukocyte interferon. Cancer Res . 1983; 43:940-5. [PubMed 6336662]
1102. Vesikari T, Nuutila A, Cantell K. Neurologic sequelae following interferon therapy of juvenile laryngeal papilloma. Acta Paediatr Scand . 1988; 77:619-22. [PubMed 2455956]
1103. Gresser I, Maury C, Tovey M et al. Progressive glomerulonephritis in mice treated with interferon preparations at birth. Nature . 1976; 263:420-2. [PubMed 972680]
1104. Creagan ET, Schaid DJ, Ahmann DL et al. Recombinant interferons in the management of advanced malignant melanoma: updated review of five prospective clinical trials and long-term responders. Am J Clin Oncol . 1988; 11:652-9. [PubMed 3142248]
1105. Legha SS. Interferons in the treatment of malignant melanoma: a review of recent trials. Cancer . 1986; 57:1675-7. [PubMed 3512072]
1106. Creagan ET, Ahmann DL, Frytak S et al. Recombinant leukocyte A interferon (rIFN-αA) in the treatment of disseminated malignant melanoma: analysis of complete and long- term responding patients. Cancer . 1986; 58:2576-8. [PubMed 3779607]
1107. Creagan ET, Ahmann DL, Green SJ et al. Phase II study of low-dose recombinant leukocyte A interferon in disseminated malignant melanoma. J Clin Oncol . 1984; 2:1002-5. [PubMed 6470751]
1108. von Wussow P, Block B, Hartmann F et al. Intralesional interferon-alpha therapy in advanced malignant melanoma. Cancer . 1988; 61:1071-4. [PubMed 3342367]
1109. Papa G, Vegna ML, Defazio D et al. Recombinant interferon alfa-2A in untreated cutaneous T-cell lymphomas. J Interferon Res . 1989; 9(Suppl 2):S112.
1110. Covelli A, Papa G, Vegna ML et al. Recombinant alpha- 2A interferon (IFN) as initial therapy in mycosis fungoides (MF): results of a 3-year follow-up. Proc Am Soc Clin Oncol . 1989; 8:A978.
1111. Edelson RL. Treatment of cutaneous T cell lymphoma. In: van Vloten WA, Willemze R, Lange Vejlsgaard G et al, eds. Current Problems in Dermatology. Basel: Karger; 1990:226-37.
1116. Vonderheid EC, Thompson R, Smiles KA et al. Recombinant interferon alfa-2B in plaque-phase mycosis fungoides: intralesional and low-dose intramuscular therapy. Arch Dermatol . 1987; 123:757-63. [PubMed 3579357]
1117. Thestrup-Pedersen K, Hammer R, Kaltoft K et al. Treatment of mycosis fungoides with recombinant interferon- α2a2 alone and in combination with etretinate. Br J Dermatol . 1988; 118:811-8. [PubMed 3042011]
1118. Gilewski TA, Richards JM. Biologic response modifiers in Non-Hodgkin's lymphomas. Semin Oncol . 1990; 17:74-87. [PubMed 1689508]
1119. Bunn PA Jr, Foon KA, Ihde DC et al. Treatment of cutaneous T-cell lymphomas with biologic response modifiers: recombinant leukocyte A interferon and T101 monoclonal antibody. Dev Oncol . 1985; 32:579-90.
1120. Olsen EA, Rosen ST, Vollmer RT et al. Interferon alfa- 2a in the treatment of cutaneous T cell lymphoma. J Am Acad Dermatol . 1989; 20:395-407. [PubMed 2783939]
1121. DeVita VT Jr, Jaffe ES, Mauch P et al. Lymphocytic lymphomas. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer—principles and practice of oncology. Philadelphia: Lippincott; 1989;1741-1798.
1122. Rosenberg SA. The low-grade Non-Hodgkin's lymphomas: challenges and opportunities. J Clin Oncol . 1985; 3:299- 310. [PubMed 3882893]
1123. Portlock CS. Management of the low-grade Non-Hodgkin's lymphomas. Semin Oncol . 1990; 17:51-9. [PubMed 2406918]
1124. Hawkins MJ, O'Connell MJ, Schiller JH et al. Phase I evaluation of recombinant A interferon alpha (RIFN-(Alpha)A) in combination with COPA chemotherapy (I-COPA). Proc Am Soc Clin Oncol . 1985; 4:229.
1126. Foon KA. Biological response modifiers: the new immunotherapy. Cancer Res . 1989; 49:1621-39. [PubMed 2466558]
1129. Ikic D, Nola P, Maricic Z et al. Application of human leukocyte interferon in patients with urinary bladder papillomatosis, breast cancer, and melanoma. Lancet . 1981; 1:1022-4. [PubMed 6164883]
1130. Ferrari P, Castagnetti G, Pollastri CA et al. Chemoimmunotherapy for prophylaxis of recurrence in superficial bladder cancer: interferon-α2b versus interferon-α2b with epirubicin. Anticancer Drugs . 1992; 3 Suppl 1:25-7. [PubMed 1611113]
1131. Scorticatti CH, de la Pena NC, Bellora OG et al. Systemic IFN-alfa treatment of multiple bladder papilloma grade I or grade II patients: pilot study. J Interferon Res . 1982; 2:339-43. [PubMed 7130757]
1132. Di Stasi SM, Virgili G, Vespasiani G et al. Intralesional alpha interferon therapy in papillary superficial transitional cell carcinoma of the bladder: a pilot study. Br J Urol . 1993; 71:422-6. [PubMed 8499986]
1134. Reviewers' comments (personal observations) on bladder cancer.
1135. Niloff JM, Knapp RC, Jones G et al. Recombinant leukocyte alpha interferon in advanced ovarian carcinoma. Cancer Treat Rep . 1985; 69:895-6. [PubMed 4016797]
1136. Einhorn N, Cantell K, Einhorn S et al. Human leukocyte interferon therapy for advanced ovarian carcinoma. Am J Clin Oncol . 1982; 5:167-72. [PubMed 6178284]
1137. Freedman RS, Gutterman JU, Wharton JT et al. Leukocyte interferon (IFNα) in patients with epithelial ovarian carcinoma. J Biol Response Mod . 1983; 2:133-8. [PubMed 6644331]
1139. Healy GB, Gelber RD, Trowbridge AL et al. Treatment of recurrent respiratory papillomatosis with human leukocyte interferon. New Engl J Med . 1988; 319:401-7. [PubMed 3398891]
1140. Sessions RB, Goepfert H, Donovan DT et al. Further observations on the treatment of recurrent respiratory papillomatosis with interferon: a comparison of sources. Ann Otol Rhinol Laryngol . 1983; 92:456-61. [PubMed 6194728]
1141. Kerley SW, Buchon-Zalles C, Moran J et al. Chronic cavitary respiratory papillomatosis. Arch Pathol Lab Med . 1989; 113:1166-9. [PubMed 2552955]
1142. Fefer A, Thomas ED. Bone marrow transplantation for the treatment of chronic myelogenous leukemia. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Important Advances in Oncology 1990. Philadelphia: JB Lippencott; 1990:143-58.
1143. Gilewski TA, Golomb HM. Design of combination biotherapy studies: future goals and challenges. Semin Oncol . 1990; 17(Suppl 1):3-10. [PubMed 1689077]
1144. Berman E, Heller G, Kempin S et al. Incidence of response and long-term follow-up in patients with hairy cell leukemia treated with recombinant interferon alfa-2a. Blood . 1990; 75:839-45. [PubMed 2302457]
1145. Ratain MJ, Vardiman JW, Barker CM et al. Prognostic variables in hairy cell leukemia after splenectomy as initial therapy. Cancer . 1988; 62:2420-4. [PubMed 3179961]
1148. Horning S. Toward defining an optimal therapy for hairy cell leukemia. J Natl Cancer Inst . 1989; 81:1120- 1. [PubMed 2473213]
1152. Glaspy JA, Jacobs AD, Golde DW. Evolving therapy of hairy cell leukemia. Cancer . 1987; 59:652-7. [PubMed 10822465]
1153. Thompson JA, Fefer A. Evolving therapy of hairy cell leukemia. Cancer . 1987; 652-7. (IDIS 225547)
1154. Anon. Treatment of hairy cell leukaemia. Lancet . 1990; 336:149-50. [PubMed 1973476]
1156. Pralle H, Bartel A, Boedewadt-Radzun S et al. [Alpha interferon in the therapy of hairy cell leukemia. Results of 3 prospective multicenter studies in West Germany]. Onkologie . 1988; 11:44-7. [PubMed 3283625]
1157. Crowther D. The role of interferons in the treatment of patients with tumors of the immune system. J Interferon Res . 1986; 6(Suppl 1):42.
1159. Aapro MS, Alberts DS, Salmon SE. Interactions of human leukocyte interferon with vinca alcaloids and other chemotherapeutic agents against human tumors in clonogenic assay. Cancer Chemother Pharmacol . 1983; 10:161-6. [PubMed 6861260]
1160. Roos G, Leanderson T, Lundgren E. Interferon-induced changes in human hematopoietic cell lines and fresh leukemia cells. Cancer Res . 1984; 44:2358-62. [PubMed 6722775]
1161. Horoszewicz JS, Leong SS, Carter WA. Noncycling tumor cells are sensitive targets for the antiproliferative activity of human interferon. Science . 1979; 206:1091-3. [PubMed 493995]
1162. Balkwill F, Watling D, Taylor-Papadimitriou J. Inhibition by lymphoblastoid interferon of growth of cells derived from the human breast. Int J Cancer . 1978; 22:258-65. [PubMed 700890]
1163. Creasey AA, Bartholomew JC, Merigan TC. Role of G0-G1 arrest in the inhibition of tumor cell growth by interferon. Proc Natl Acad Sci USA . 1980; 77:1471-5. [PubMed 6154934]
1164. Lin SL, Kikuchi T, Pledger WJ et al. Interferon inhibits the establishment of competence in G0/S- phase transition. Science . 1986; 233:356-9. [PubMed 3726533]
1165. Einhorn S, Blomgren H, Strander H. Effect of an intramuscular injection of human leukocyte interferon on blood leukocyte counts and proportions of lymphocytes forming E, EA, and EAC rosettes. Int Arch Allergy Appl Immunol . 1980; 63:139-44. [PubMed 6158481]
1166. Minato N, Reid L, Cantor H et al. Mode of regulation of natural killer cell activity by interferon. J Exp Med . 1980; 152:124-37. [PubMed 6156979]
1171. Gewert DR, Clemens MJ. Inhibition by interferon of thymidine uptake and deoxyribonucleic acid synthesis in human lymphoblastoid cells. Biochem Soc Trans . 1980; 8:353-4. [PubMed 6156869]
1172. Gewert DR, Moore G, Clemens MJ. Inhibition of cell division by interferons: the relationship between changes in utilization of thymidine for DNA synthesis and control of proliferation in Daudi cells. Biochem J . 1983; 214:983- 90. [PubMed 6194788]
1173. Degre M, Hovig T. Functional and ultrastructural studies of the effects of human interferon on cell membranes of in vitro cultured cells. Acta Pathol Microbiol Immunol Scand B . 1976; 84B:347-58.
1174. Mihich E. Biological response modifiers: their potential and limitations in cancer therapeutics. Cancer Invest . 1985; 3:71-83. [PubMed 2578860]
1175. Mihich E. Future perspectives for biological response modifiers: a viewpoint. Semin Oncol . 1986: 13:234-54.
1176. Oldham RK. Biologicals and biological response modifiers: fourth modality of cancer treatment. Cancer Treat Rep . 1984; 68:221-32. [PubMed 6198081]
1177. Huez G, Silhol M, Lebleu B. Microinjected interferon does not promote an antiviral response in HeLa cells. Biochem Biophys Res Commun . 1983; 110:155-60. [PubMed 6301439]
1178. Arnheiter H, Zoon KC. Microinjection of anti- interferon antibodies into cells does not inhibit the induction of antiviral state by interferon. J Virol . 1984; 52:284- 7. [PubMed 6090705]
1179. Zoon KC, Arnheiter H, Zur Nedden D et al. Human interferon alpha enters cells by receptor-mediated endocytosis. Virology . 1983; 130:195-203. [PubMed 6314645]
1180. Branca AA, Faltynek CR, D'Alessandro SB et al. Interaction of interferon with cellular receptors: internalization and degradation of cell-bound interferon. J Biol Chem . 1982; 257:13291-6. [PubMed 6292184]
1182. Rochette-Egly C, Tovey MG. Cyclic GMP levels in interferon treated cells. Antiviral Res . 1985; 5:127-35. [PubMed 2411219]
1183. Rochette-Egly C, Tovey MG. Interferon enhances guanylate cyclase activity in human lymphoma cells. Biochem Biophys Res Commun . 1982; 107:150-6. [PubMed 6181782]
1184. Tovey MG, Rochette-Egly C. The effect of interferon on cyclic nucleotides. Ann NY Acad Sci . 1980; 350:266-78. [PubMed 6165281]
1185. Sarkar FH, Gupta SL. Interferon receptor interaction: internalization of interferon alpha 2 and modulation of its receptor on human cells. Eur J Biochem . 1984; 140:461-7. [PubMed 6327298]
1186. Yap WH, Teo TS, Tan YH. An early event in the interferon-induced transmembrane process. Science . 1986; 234:355-8. [PubMed 2429366]
1187. Dianzani F, Levy HB, Berg S et al. Kinetics of the rapid action of interferon. Proc Soc Exp Biol Med . 1976; 152:593-7. [PubMed 967891]
1188. Dianzani F, Baron S. Activation by interferon of the events leading to the antiviral state. Tex Rep Biol Med . 1977; 35:297-306. [PubMed 358457]
1189. Aguet M, Belardelli F, Blanchard B et al. High- affinity binding of125I-labeled mouse interferon to a specific cell surface receptor: IV. Mouse gamma interferon and cholera toxin do not compete for the common receptor site of alpha/beta interferon. Virology . 1982; 117:541-4. [PubMed 6175095]
1190. Branca AA, Baglioni C. Evidence that types I and II interferons have different receptors. Nature . 1981; 294:768-70. [PubMed 6172715]
1191. Dianzani F, Baron S. Unexpectedly rapid action of human interferon in physiologic conditions. Nature . 1975; 257:682-4. [PubMed 1186843]
1192. Gillespie D, Carter WA. Species specificity of interferon Texas Rep Biol Med . 1981-82; 41:37-42.
1193. Ankel H, Chany C, Galliot B et al. Antiviral effect of interferon covalently bound to sepharose. Proc Natl Acad Sci USA . 1973; 70:2360-3. [PubMed 4365374]
1194. Sarkar FH, Gupta SL. On the inhibition of interferon action by inhibitors of fatty acid cyclooxygenase. Virology . 1982; 123:448-51. [PubMed 6184880]
1195. Ohtsuki K, Dianzani F, Baron S. Decreased initiation factor activity in mouse L cells treated with interferon. Nature . 1977; 269:536-8. [PubMed 909608]
1196. Raziuddin A, Sarkar FH, Dutkowski R et al. Receptors for human alpha and beta interferon but not for gamma interferon are specified by human chromosome 21. Proc Natl Acad Sci USA . 1984; 81:5504-8. [PubMed 6206498]
1197. Anderson P, Yip YK, Vilcek J. Specific binding of125I-human interferon-gamma to high affinity receptors on human fibroblasts. J Biol Chem . 1982; 257:11301-4. [PubMed 6288678]
1198. Sarkar FH, Gupta SL. Receptors for human gamma interferon: binding and crosslinking of125I-labeled recombinant gamma interferon to receptors on WISH cells. Proc Natl Acad Sci USA . 1984; 81:5160-4. [PubMed 6089181]
1199. Schwarz LA, Fleischmann WR Jr. Potentiation of interferon action. Tex Rep Biol Med . 1981; 41:298-306. [PubMed 6184817]
1200. Fleischmann WR. Potentiation and inhibition of interferon action: antiviral and antitumor studies. Med Pediatr Oncol . 1981; 9:89-92. [PubMed 6162087]
1201. Fleischmann WR Jr, Georgiades JA, Osborne LC et al. Potentiation of interferon activity by mixed preparations of fibroblast and immune interferon. Infect Immun . 1979; 26:248-53. [PubMed 227796]
1202. Fleischmann WR Jr, Kleyn KM, Baron S. Potentiation of antitumor effect of virus-induced interferon by mouse immune interferon preparations. J Natl Cancer Inst . 1980; 65:963-6. [PubMed 6159498]
1203. Fleischmann WR Jr. Potentiation of the direct anticellular activity of mouse interferons: mutual synergism and interferon concentration dependence. Cancer Res . 1982; 42:869-75. [PubMed 6174218]
1204. Czarniecki CW, Fennie CW, Powers DR et al. Synergistic antiviral and antiproliferative activites of Escherichia coli- derived human alpha, beta, and gamma interferons. J Virol . 1984; 49:490-6. [PubMed 6319748]
1205. Schwarz LA, Fleischmann WR. Interferon potentiation occurs at a pretranscriptive stage. Infect Immun . 1983; 39:159-63. [PubMed 6185431]
1206. Dianzani F, Zucca M, Scupham A et al. Immune and virus-induced interferons may activate cells by different derepressional mechanisms. Nature . 1980; 283:400-2. [PubMed 7352017]
1207. Giacomini P, Fisher PB, Duigou GJ et al. Regulation of class II MHC gene expression by interferons: insights into the mechanism of action of interferon. Anticancer Res . 1988; 8:1153-61. [PubMed 2464333]
1208. Faltynek CR, McCandless S, Chebath J et al. Different mechanisms for activation of gene transcription by interferons alpha and gamma. Virology . 1985; 144:173-80. [PubMed 3933177]
1209. Schneck J, Rager-Zisman B, Rosen OM et al. Genetic analysis of the role of cAMP in mediating effects of interferon. Proc Natl Acad Sci USA . 1982; 79:1879-83. [PubMed 6177003]
1210. Brouty-Boye D, Zetter BR. Inhibition of cell motility by interferon. Science . 1980; 208:516-8. [PubMed 6154315]
1211. Gresser I, Bourali C, Levy JP et al. Increased survival in mice inoculated with tumor cells and treated with interferon preparations. Proc Natl Acad Sci USA . 1969; 63:51-7. [PubMed 5257966]
1214. Itoh K, Inoue M, Kataoka S et al. Differential effect of interferon expression of IgG- and IgM-Fc receptors on human lymphocytes. J Immunol . 1980; 124:2589-95. [PubMed 6154733]
1216. Chandrabose K, Cuatrecasas P, Pottathil R. Changes in fatty acyl chains of phospholipids induced by interferon in mouse sarcoma S-180 cells. Biochem Biophys Res Commun . 1981; 98:661-8. [PubMed 6164365]
1217. Grollman EF, Lee G, Ramos S et al. Relationships of the structure and function of the interferon receptor to hormone receptors and establishment of the antiviral state. Cancer Res . 1978; 38:4172-85. [PubMed 212189]
1218. Samid D, Chang EH, Friedman RM. Development of transformed phenotype induced by a human ras oncogene is inhibited by interferon. Biochem Biophys Res Commun . 1985; 126:509-16. [PubMed 3970704]
1219. Samid D, Schaff Z, Chang EH et al. Interferon-induced modulation of human ras oncogene expression. Prog Clin Biol Res . 1985; 192:265-8. [PubMed 2417251]
1220. Samid D, Chang EH, Friedman RM et al. Biological and morphological characteristics of phenotypic revertants appearing in interferon-treated mouse cells transformed by a human oncogene. J Exp Pathol . 1985; 2:211-22. [PubMed 2431116]
1221. Yap WH, Teo TS, McCoy E et al. Rapid and transient rise in diacylglycerol concentration in Daudi cells exposed to interferon. Proc Natl Acad Sci USA . 1986; 83:7765-9. [PubMed 2945205]
1222. Fish EN, Banerjee K, Stebbing N. Human leukocyte interferon subtypes have different antiproliferative and antiviral activities on human cells. Biochem Biophys Res Commun . 1983; 112:537-46. [PubMed 6303322]
1224. Chapekar MS, Glazer RI. Effects of fibroblast and recombinant leukocyte interferons and double-stranded RNA on PPP(2'-5')AN synthesis and cell proliferation in human colon carcinoma cells in vitro. Cancer Res . 1983; 43:2683-7. [PubMed 6189584]
1225. Talpaz M, McCredie K, Kantarjian H et al. Chronic myelogenous leukaemia: hematological remissions with alpha interferon. Br J Haematol . 1986; 64:87-95. [PubMed 3463363]
1226. Einhorn S, Blomgren H, Troye M. Proportion of lymphocytes forming E, EA, and EAC rosettes following treatment with human interferon preparations in vitro. Cell Immunol . 1980; 56:374-80. [PubMed 6162574]
1227. Hamburg SI, Fleit HB, Unkeless JC. Mononuclear phagocytes: responders to and producers of interferon. Ann NY Acad Sci . 1980; 350:72-90. [PubMed 6165307]
1228. Bourgeade MF, Chany C. Effect of sodium butyrate on the antiviral and anticellular action of interferon in normal and MSV-transformed cells. Int J Cancer . 1979; 24:314-9. [PubMed 226485]
1229. Bourgeade MF, Cerutti I, Chany C. Enhancement of interferon antitumor action by sodium butyrate. Cancer Res . 1979; 39:4720-3. [PubMed 498098]
1230. Knight E Jr, Korant BD. A cell surface alteration in mouse L cells induced by interferon. Biochem Biophys Res Commun . 1977; 74:707-13. [PubMed 836320]
1231. Pfeffer LM, Wang E, Tamm I. Interferon effects on microfilament organization, cellular fibronectin distribution, and cell motility in human fibroblasts. J Cell Biol . 1980; 85:9-17. [PubMed 6154057]
1232. Wang E, Pfeffer LM, Tamm I. Interferon increases the abundance of submembranous microfilaments in HeLa-S3 cells in suspension culture. Proc Natl Acad Sci USA . 1981; 78:6281-5. [PubMed 6171815]
1233. Pfeffer LM, Wang E, Tamm I. Interferon inhibits the redistribution of cell surface components. J Exp Med . 1980; 152:469-74. [PubMed 6156989]
1234. Schroder EW, Chou IN, Jaken S et al. Interferon inhibits the release of plasminogen activator from SV3T3 cells. Nature . 1978; 276:828-9. [PubMed 214713]
1235. Calvet MC, Gresser I. Interferon enhances the excitability of cultured neurones. Nature . 1979; 278:558-60. [PubMed 4317,20]
1236. Chandrabose KA, Cuatrecasas P, Pottahil R. Interferon- mediated changes in lipid metabolism. Tex Rep Biol Med . 1981-82; 41:499-508.
1237. Kelly K, Cochran B, Stiles C et al. Cell cycle control of c- myc expression. Dev Oncol . 1985; 28:67-75.
1238. Kelly K, Cochran BH, Stiles C et al. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet- derived growth factor. Cell . 1983; 35:603-10. [PubMed 6606489]
1239. Capon DJ, Chen EY, Levinson AD et al. Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature . 1983; 302:33-7. [PubMed 6298635]
1240. Delage R, Ritz J, Anderson KC. The evolving role of bone marrow transplantation in the treatment of chronic myelogenous leukemia. Hematol Oncol Clin North Am . 1990; 4:369-88. [PubMed 2182597]
1241. Gresser I, Maury C, Woodrow D et al. Interferon treatment markedly inhibits the development of tumor metastases in the liver and spleen and increases survival time of mice after intravenous inoculation of Friend erythroleukemia cells. Int J Cancer . 1988; 41:135-42. [PubMed 3422071]
1242. Ebsworth NM, Taylor-Papadimitriou J, Rozengurt E. Cyclic AMP does not mediate inhibition of DNA synthesis by interferon in mouse Swiss 3T3 cells. J Cell Physiol . 1984; 120:146-50. [PubMed 6204998]
1243. Taylor-Papadimitriou J, Balkwill F, Ebsworth N et al. Antiviral and antiproliferative effects of interferons in quiesecent fibroblasts are dissociable. Virology . 1985; 147:405-12. [PubMed 2416119]
1244. Taylor-Papadimitriou J, Ebsworth N, Rozengurt E. Possible mechanisms of interferon-induced growth inhibition. UT M . D. Anderson Symp Fundam Cancer Res. 1985; 37:283- 98.
1245. Hokland P, Hokland M, Olesen BK et al. Effect of recombinant alpha interferon on NK and ADCC function in lung cancer patients: results from a phase II trial. J Interferon Res . 1984; 4:561-9. [PubMed 6094685]
1246. Hersey P, Edwards A, Milton GW et al. No evidence for an association between natural killer cell activity and prognosis in melanoma patients. Nat Immun Cell Growth Regul . 1983- 84; 3:87-94.
1247. Maluish AE, Ortaldo JR, Conlon JC et al. Depression of natural killer cytotoxicity after in vivo administration of recombinant leukocyte interferon. J Immunol . 1983; 131:503-7. [PubMed 6863923]
1249. Zarling JM, Kung PC. Monoclonal antibodies which distinguish between human NK cells and cytotoxic T lymphocytes. Nature . 1980; 288:394-6. [PubMed 6968872]
1250. Kay HD, Horwitz DA. Evidence by reactivity with hybridoma antibodies for a probable myeloid origin of peripheral blood cells active in natural cytotoxicity and antibody-dependent cell-mediated cytotoxicity. J Clin Invest . 1980; 66:847- 51. [PubMed 6968324]
1251. Fast LD, Hansen JA, Newman W. Evidence for a T cell nature and heterogeneity within natural killer (NK) and antibody- dependent cellular cytotoxicity (ADCC) effectors: a comparison with cytotoxic T lymphocytes (CTL). J Immunol . 1981; 127:448-52. [PubMed 6788841]
1252. Sone S, Utsugi T, Nii A et al. Differential effects of recombinant interferons α,β, and γ on induction of human lymphokine (IL-2)-activated killer activity. J Natl Cancer Inst . 1988; 80:425-31. [PubMed 3130488]
1253. Welsh RM, Karre K, Hansson M et al. Interferon mediated protection of normal and tumor target cells against lysis by mouse natural killer cells. J Immunol . 1981; 126:219-25. [PubMed 6161162]
1254. Moore M, White WJ, Potter MR. Modulation of target cell susceptibility to human natural killer cells by interferon. Int J Cancer . 1980; 25:565-72. [PubMed 6154661]
1255. Schultz RM, Papamatheakis JD, Chirigos MA. Interferon: an inducer of macrophage activation by polyanions. Science . 1977; 197:674-6. [PubMed 877584]
1256. Virelizier JL, Arenzana-Seisdedos F. Immunological functions of macrophages and their regulation by interferons. Med Biol . 1985; 63:149-59. [PubMed 2419711]
1257. Pace JL, Russell SW, LeBlanc PA et al. Comparative effects of various classes of mouse interferons on macrophage activation for tumor cell killing. J Immunol . 1985; 134:977-81. [PubMed 2578167]
1258. LeBlanc PA. Macrophage activation for cytolysis of virally infected target cells. J Leukocyte Biol . 1989; 45:345-52. [PubMed 2467959]
1259. Hochkeppel HK, Alkan SS. Immunomodulatory actions of interferons. Dev Med Virol . 1988; 4:341-51.
1260. Chirigos MA, Schultz RM, Stylos WA. Interaction of interferon, macrophage and lymphocyte tumoricidal activity with prostaglandin effect. Ann NY Acad Sci . 1980; 350:91-101. [PubMed 6165308]
1261. Schultz RM. E-type prostaglandins and interferons: yin-yang modulation of macrophage tumoricidal activity. Med Hypotheses . 1980; 6:831-43. [PubMed 6160377]
1262. Schultz RM, Pavlidis NA, Stylos WA et al. Cytotoxic activity of interferon-treated macrophages studied by various inhibitors. Cancer Treat Rep . 1978; 62:1889-92. [PubMed 728906]
1263. Schultz RM, Pavlidis NA, Stylos WA et al. Regulation of macrophage tumoricidal function: a role for prostaglandins of the E series. Science . 1978; 202:320-1. [PubMed 694537]
1264. Douthart RJ, Kleinschmidt WJ, Murphy EB et al. Interferon induction and macrophage activation by a mycovirus double-stranded RNA/tobramycin complex following treatment with human serum. J Interferon Res . 1982; 2:493-9. [PubMed 6183374]
1266. Wreschner DH, McCauley JW, Skehel JJ et al. Interferon action—sequence specificity of the ppp(a2'p)nA-dependent ribonuclease. Nature . 1981; 289:414-7. [PubMed 6162102]
1267. Moore G, Gewert DR, Clemens MJ. Inhibition of cell proliferation by interferons: 2. Changes in processing and stability of newly synthesized DNA in human lymphoblastoid (Daudi) cells. Eur J Biochem . 1984; 139:627-35. [PubMed 6698030]
1268. Gewert DR, Moore G, Tilleray VJ et al. Inhibition of cell proliferation by interferons: 1. Effects on cell division and DNA synthesis in human lymphoblastoid (Daudi) cells. Eur J Biochem . 1984; 139:619-25. [PubMed 6698029]
1269. Lee SH, Epstein LB. Reversible inhibition by interferon of the maturation of human peripheral blood monocytes to macrophages. Cell Immunol . 1980; 50:177-90. [PubMed 6156767]
1274. Schering Corporation. Important safety information concerning use of alpha interferons. From manufacturer web site ([Web]).
1287. Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med . 1983; 309:129-33. [PubMed 6191217]
1326. Thomas ED. Marrow transplantation for chronic myelogenous leukemia. UCLA Symp Mol Cell Biol . 1989; 91:207-14.
1332. Weimar W, Mogensen KE, Cantell K. Highly purified leucocyte interferons for renal transplant recipients. Biomed Pharmacother . 1982; 36:94-7. [PubMed 6751424]
1333. Hirsch MS, Schooley RT, Cosimi AB et al. Effects of interferon-alpha on cytomegalovirus reactivation syndromes in renal-transplant recipients. N Engl J Med . 1983; 308:1489-93. [PubMed 6304513]
1334. White CW, Sondheimer HM, Crouch EC et al. Treatment of pulmonary hemangiomatosis with recombinant interferon alfa-2a. N Engl J Med . 1989; 320:1197-1200. [PubMed 2710192]
1335. Folkman J. Successful treatment of an angiogenic disease. N Engl J Med . 1989; 320:1211-2. [PubMed 2469017]
1336. White CW. Treatment of hemangiomatosis with recombinant interferon alfa. Semin Hematol . 1990; 27(3 Suppl 4):15-22. [PubMed 2197730]
1337. Appelbaum FR. Introduction and overview of interferon alfa in myeloproliferative and hemangiomatous diseases. Semin Hematol . 1990; 27(3 Suppl 4):1-5. [PubMed 2197729]
1338. Orchard PJ, Smith CM III, Woods WG et al. Treatment of haemangioendotheliomas with alfa interferon. Lancet . 1989; 2:565-7. [PubMed 2570269]
1339. Langer JA, Pestka S. Structure of interferons. Pharmacol Ther . 1985; 27:371-401. [PubMed 2413490]
1340. Lane HC, Deyton LR. Interferon alfa-induced cardiac dysfunction. N Engl J Med . 1990; 322:1469.
1341. Fischl M, Uttamchandani R, Gagnon S et al. Phase I study of interferon alpha-2b (INTRON), zidovudine and rGM-CSF in patients with AIDS-associated Kaposi's sarcoma. Int Conf AIDS. 1989 Jun 4-9. Abstract No. T.B.P.331.
1342. Rosenberg SA, Yang JC, Schwartzentruber DJ et al. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol . 1999; 17:968-75. [PubMed 10071291]
1343. Falkson CI, Ibrahim J, Kirkwood JM et al. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol . 1998; 16:1743-51. [PubMed 9586887]
1344. Johnston SR, Constenla DO, Moore J et al. Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma. Br J Cancer . 1998; 77:1280-6. [PubMed 9579834]
1345. Legha SS, Ring S, Bedikian A et al. Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha. Ann Oncol . 1996; 7:827-35. [PubMed 8922197]
1346. Legha SS, Ring S, Eton O et al. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol . 1998; 16:1752-9. [PubMed 9586888]
1347. Atkins MB, Flaherty LE, Sosman JA, principal investigators. Phase III study of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b versus cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (summary last modified 10/1999). Protocol ID: E-E3695. From CancerNet: PDQ Clinical Trials (database). Bethesda, MD: National Cancer Institute; accessed 1999 Nov 29.
1348. World Health Organization. WHO Expert Committee on Biological Standardization: thirty-fifth report. Part 2: description of preparation of proposed international standards for interferons. WHO Technical Report Series No. 725. Geneva, Swizterland: World Health Organization; 1985:41-9.
1355. Rodjer S, Vikrot O, Wahlin A et al. Effect of interferon alpha-2b in advanced multiple myeloma. J Intern Med . 1990; 227:45-8. [PubMed 2299297]
1356. Ambrus JL, Ambrus JL Jr, Chadha KC. Interferon inhibitors in lupus erythematosus. N Engl J Med . 1988; 319:582-3. [PubMed 2457158]
1357. Hooks JJ, Jordan GW, Cupps T et al. Multiple interferons in the circulation of patients with systemic lupus erythematosus and vasculitis. Arthritis Rheum . 1982; 25:396-400. [PubMed 6176247]
1358. Hooks JJ, Moutsopoulos HM, Geis SA et al. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med . 1979; 301:5-8. [PubMed 449915]
1359. Preble OT, Black RJ, Friedman RM et al. Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon. Science . 216:429-31.
1360. Shi SN, Feng SF, Wen Y et al. Serum interferon in systemic lupus erythematosus. Br J Dermatol . 1987; 117:155-9. [PubMed 2443158]
1361. Pichert G, Jost LM, Zobeli L et al. Thyroiditis after treatment with interleukin-2 and interferon alfa-2a. Br J Cancer . 1990; 62:100-4. [PubMed 2390468]
1362. Conlon KC, Urba WJ, Smith JW et al. Exacerbation of symptoms of autoimmune disease in patients receiving alpha- interferon therapy. Cancer . 1990; 65:2237-42. [PubMed 2346907]
1363. Sonnenblick M, Rosenmann D, Rosin A. Reversible cardiomyopathy induced by interferon. Br Med J . 1990; 300:1174-5.
1364. von Wussow, Jakschies D, Freund M et al. Humoral response to recombinant interferon-alpha 2b in patients receiving recombinant interferon-alpha 2b therapy. J Interferon Res . 1989; 9(Suppl 1):S25-31. [PubMed 2809276]
1365. Dianzani F, Antonelli G, Amicucci P et al. Low incidence of neutralizing antibody formation to interferon-alpha 2b in human recipients. J Interferon Res . 1989; 9(Suppl 1):S33-6. [PubMed 2681442]
1366. Itri LM, Sherman MI, Palleroni AV et al. Incidence and clinical significance of neutralizing antibodies in patients receiving recombinant interferon-alpha 2a. J INterferon Res . 1989; 9(Suppl 1):S9-15. [PubMed 2681444]
1367. Speigel RJ, Jacobs SL, Treuhaft MW. Anti-interferon antibodies to interferon-alpha 2b: results of comparative assays and clinical perspective. J Interferon Res . 2. 1989; 9(Suppl 1):S17-24.
1368. Bekiscz JB, zur Nedden DL, Enterline JC et al. Antibodies to interferon-alpha 2 in patients treated with interferon-alpha 2 for hairy cell leukemia. I Interferon Res . 1989; 9(Suppl 1):S1-7.
1369. Ludwig CU, Ludwig-Hagemann R, Obrist R et al. Improved tolerance of interferon alpha-2a by continuous subcutaneous infusion. Onkologie . 1990; 13:117-22. [PubMed 2197582]
1370. Freund M, von Wussow P, Diedrich H et al. Rrcombinant human interferon (IFN) alpha-2b in chronic myelogenous leukaemia: dose dependency of response and frequency of neutralizing anti- interferon antibodies. Br J Haematol . 1989; 72:350-6. [PubMed 2765403]
1371. Porres JC, Carreno V, Ruiz M et al. Interferon antibodies in patients with chronic HBV infection treated with recombinant interferon. J Hepatol . 1989; 8:351-7. [PubMed 2732449]
1372. Overall ML, Marzuki S, Hertzog PJ. Comparison of different ELISAa for the detection of monoclonal antibodies to human interferon-alpha. Implications for antibody screening. J Immunol Methods . 1989; 119:27-33. [PubMed 2708826]
1373. Craxi A, Di Marco V, Volpes R et al. Anti-alpha interferon antibodies after alpha interferon treatment in patients with chronic viral hepatitis. Hepato- Gastroenterology . 1988; 35:304-5. [PubMed 3063647]
1374. Figlin RA, deKernion JB, Mukamel E et al. Recombinant interferon alfa-2a in metastatic renal cell carcinoma: assessment of antitumor activity and anti-interferon antibody formation. J Clin Oncol . 1988; 6:1604-10. [PubMed 3049952]
1375. Olsen E, Rosen S, Vollmer R et al. Interferon alfa-2a in the treatment of cutaneous T-cell lymphoma. Proc Am Soc Clin Oncol . 1987; 6:A746.
1376. O'Connell MJ, Colgan JP, Oken MM et al. Clinical trial of recombinant leukocyte A interferon as initial therapy for favorable histology non-Hodgkin's lymphomas and chronic lymphocytic leukemia. An Eastern Cooperative Oncology Group pilot study. J Clin Oncol . 1986; 4:128-36. [PubMed 3511183]
1377. Leavitt S, Kaplan E, Bonnem M et al. Interferon alpha- 2: high and low dose treatment for high and low grade non- Hodgkin's lymphoma. Dev Oncol . 1985; 57-73.
1382. Bunn PA Jr, Fuks Z. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer—principles and practice of oncology. Philadelphia: Lippincott; 1989:1799-1808.
1383. Louie AC, Gallagher JG, Sikora K et al. Follow-up observations on the effect of human leukocyte interferon in non- Hodgkin's lymphoma. Blood . 1981; 58:712-8. [PubMed 6168319]
1384. Leavitt RD, Kaplan S, Bonnem E et al. Interferon alpha-2: High and low dose treatment for high and low grade non- Hodgkin's lymphoma. Dev Oncol . 1985; 27:57-73.
1385. Simoni R, Cavalieri R, Coppola G et al. Recombinant leukocyte interferon alfa-2A in the treatment of mycosis fungoides. J Biol Regul Homeost Agents . 1987; 1:93-9. [PubMed 3504088]
1386. Safai B. Pathophysiology and epidemiology of epidemic Kaposi's sarcoma. Semin Oncol . 1987; 14(2 Suppl 3):7-12. [PubMed 3299718]
1387. Gridelli C, Palmieri G, Airoma G et al. Complete regression of laryngeal involvement by classic Kaposi's sarcoma with low-dose alpha-2b interferon. Tumori . 1990; 76:292- 3. [PubMed 2368177]
1397. Levin MJ, Judson FN, Eron L et al. Comparison of intramuscular recombinant alpha interferon (rIFN-2-A) with topical acyclovir for the treatment of first-episode herpes genitalis and prevention of recurrences. Antimicrob Agents Chemother . 1989; 33:649-52. [PubMed 2751279]
1398. Sacks SL, Varner TL, Davies KS et al. Randomized, double-blind, placebo-controlled, patient-initiated study of topical high- and low-dose interferon-alpha with nonooynol-9 in the treatment of recurrent genital herpes. J Infect Dis . 1990; 161:692-8. [PubMed 2156945]
1399. Birch CJ, Tachedijian G, Doherty RR et al. Altered sensitivity to antiviral drugs of herpes simplex virus isolates from a patient with the aquired immunodeficiency syndrome. J Infect Dis . 1990; 162:731-4. [PubMed 2167340]
1400. Pfeffer LM, ed. Mechanisms of interferon actions. Vol 2. CRC Press: Boca Raton; 1987:130-41.
1401. Pazin GJ, Armstrong JA, Lam MT et al. Prevention of reactivated herpes simplex infection by human leukocyte interferon after operation on the trigeminal root. New Eng J Med . 1979; 301:225-230. [PubMed 221812]
1403. Meyers JD. Day LM. Recombinant leukocyte A interferon for the treatment of serious viral infections after marrow transplant: a phase I study. J Infect Dis . 1983; 148:551-6. [PubMed 6311915]
1404. Speck B. Bone marrow transplantation in chronic myelogenous leukemia (CML). J Chemother Infect Dis Malignancies . 1989; (Suppl 1):A390.
1405. Meyers JD, McGuffin RW, Neiman PE et al. Toxicity and efficacy of human leukocyte interferon for treatment of cytomegalovirus pneumonia after marrow transplantation. J Infect Dis . 1980; 141:555-62. [PubMed 6154755]
1406. Herzog C, Berger R, Fernex M et al. What dose of intranasal interferon for the common cold? Lancet . 1986; 1:1089-90. Letter.
1407. Herzog C, Berger R, Fernex M et al. Intranasal interferon (rIFN-alpha A, Ro 22-8181) for contact prophylaxis against common cold: a randomized, double-blind and placebo- controlled field study. Antiviral Res . 1986; 6:171-6. [PubMed 3524441]
1408. Montos AS, Albrecht JK, Schwartz SA. Demonstration of dose-response relationship in seasonal prophylaxis of respiratory infections with alpha-2b interferon. Antimicrob Agents Chemother . 1988; 32:47-50. [PubMed 2831814]
1410. Monto AS, Schwartz SA, Albrecht JK. Ineffectiveness of postexposure prophylaxis of rhinovirus infection with low-dose intranasal alpha 2b interferon in families. Antimicrob Agents Chemother . 1989; 33:387-90. [PubMed 2543280]
1411. Monto AS, Shope TC, Schwartz SA et al. Intranasal interferon alpha-2b for seasonal prophylaxis of respiratory infection. J Infect Dis . 1986; 154:128-33. [PubMed 3011917]
1412. Turner RB, Felton A, Kosak K et al. Prevention of experimental coronavirus colds with intranasal alpha-2b interferon. J Infect Dis . 1986; 154:443-7. [PubMed 3016111]
1414. Scott G. Interfering with the real cold. BMJ . 1986; 292:1413-4. [PubMed 2424541]
1418. Iaffaioli RV, Fiorenza L, D'Avino M et al. Neurotoxic effects of long-term treatment with low-dose alpha 2b interferon. Curr Ther Res . 1990; 48:403-8.
1420. Kantarjian HM, Talpaz M, Kurzrock R et al. Intensive combination chemotherapy and interferons in the management of chronic myelogenous leukemia. Acta Haematol (Basel) . 1987; 78(Suppl 1):70-4.
1423. Trotta PP, Spiegel RJ. Interferon: current concepts of mechanisms of action. Cancer Treat Res . 1987; 36:141-59.
1424. Vontver LA, Reeves WC, Rattray M et al. Clinical course and diagnosis of genital herpes simplex virus infection and evaluation of topical surfactant therapy. Am J Obstet Gynecol . 1979; 133:548-54. [PubMed 375733]
1426. O'Brien WJ, Coe EC, Taylor JL. Nucleoside metabolism in herpes simplex virus-infected cells following treatment with interferon and acyclovir, a possible mechanism of synergistc antiviral activity. Antimicrob Agents Chemother . 1990; 34:1178-82. [PubMed 2393279]
1427. Taylor JL, Casey MS, O'Brien WJ. Synergistic antiherpes virus activity of acyclovir and interferon in human corneal stromal cells. Invest Ophthalmol Vis Sci . 1989; 30:365-70. [PubMed 2466806]
1428. Hammer SM, Kaplan JC, Lowe BR et al. Alpha interferon and acyclovir treatment of herpes simplex virus in lymphoid cell lines. Antimicrob Agents Chemother . 1982; 21:634-40. [PubMed 6177287]
1429. Levin MJ, Leary PL. Inhibition of human herpesviruses by combination of acyclovir and human leukocyte interferon. Infect Immun . 1981; 32:995-9. [PubMed 6166569]
1433. de Koning EWJ, van Bijsterveld P, Cantell K. Combination therapy for dendritic keratitis with acyclovir and α-interferon. Arch Ophthalmol . 1983; 101:1866-8. [PubMed 6360110]
1434. Chirigos MA, Pearson JW. Cure of murine leukemia with drug and interferon treatment. J Natl Cancer Inst . 1973; 51:1367-8. [PubMed 4745868]
1435. Smyth JF, Balkwill FR, Fergusson RJ. Interferons combined with other anti-cancer agents—studies in experimental systems. In: Smyth JF, ed. European School of Oncology Monographs. New York: Springer; 1987;39-42.
1436. Wolf LM, Leitzel KE, Pegg AE et al. The in vitro interaction of alpha-difluoromethyl ornithine (DFMO) and several interferons on human cell lines. J Biol Response Mod . 1985; 4:391-5. [PubMed 3928826]
1437. Kyriakidis DA, Kortsaris A. Effects of human interferon and alpha-difluoromethylornithine on T47D cells. J Interferon Res . 1986; 6:527-33. [PubMed 2433364]
1438. Bregman MD, Meyskens FL Jr. Alpha- difluoromethylornithine and either dexamethasone, interferon, putrescine, retinoic acid, and sodium butyrate cooperatively modulate the growth of melanoma. First International Conference on Skin Melanoma. 1985: abstract 220.
1439. Bregman MD, Meyskens FL Jr. Difluoromethylornithine (DFMO) enhances inhibition of melanoma cell growth in soft agar by dexamethasone(DEX), clone A interferon(IFN), and trans retinoic acid(RA): a new approach to biological modification. Proc Annu Meet Am Soc Clin Oncol . 1985; 26:326.
1440. Heston WD, Fleischmann J, Tackett RE et al. Effects of alph-difluorodimethyl ornithine and recombinant interferon-alpha 2 on the growth of a human renal cell adenocarcinoma xenograft in nude mice. Cancer Res . 1984; 44:3220-5. [PubMed 6430546]
1441. Edmonson JH, Kovach JS, Buckner JC et al. Phase I study of difluoromethylornithine in combination with recombinant alpha 2a-interferon. Cancer Res . 1988; 48:6584-6. [PubMed 3141046]
1442. Croghan MK, Booth A, Meyskens FL Jr. A phase I trial of recombinant interferon-alpha and alpha-difluoromethylornithine in metastatic melanoma. J Biol Response Mod . 1988; 7:409-15. [PubMed 3139843]
1443. Bajetta E, Di Leo A, Zampino MG et al. Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma. J Clin Oncol . 1994; 12:806-11. [PubMed 8151323]
1444. Thomson DB, Adena M, McLeod GR et al. Interferon-alpha 2a does not improve response or survival when combined with dacarbazine in metastatic malignant melanoma: results of a multi-institutional Australian randomized trial. Melanoma Res . 1993; 3:133-8. [PubMed 8518552]
1445. Falkson CI, Falkson G, Falkson HC. Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma. J Clin Oncol . 1991; 9:1403-8. [PubMed 2072144]
1446. Oncologic Drugs Advisory Committee Meeting. 55th meeting. Bethesda, MD: Food and Drug Administration; 1997 Dec 19.
1447. Atkins MB, Lotze MT, Dutcher JP et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol . 1999; 17:2105-16. [PubMed 10561265]
1448. Talpaz M, Plager C, Quesada J et al. Difluoromethylornithine and leukocyte interferon: a phase I study in cancer patients. Eur J Cancer Clin Oncol . 1986; 22:685-9. [PubMed 3091371]
1449. Buckner JC, Brown LO, Cascino TL et al. Recombinant alpha interferon (RIFN ALPHA) and BCNU in recurrent gliomas. Proc Am Soc Clin Oncol . 1988; 7:A317.
1450. Creagan ET, Kovach JS, Long HJ et al. Phase I study of recombinant leukocyte A human interferon combined with BCNU in selceted patients with advanced cancer. J Clin Oncol . 1986; 4:408-13. [PubMed 3950678]
1451. Reviewers' comments (personal observations) on melanoma.
1452. Scott GM, Stewart WE, Tyrrell DAJ et al. Skin reactions to interferon inoculations are reduced but not abolished by purification. J Interferon Res . 1980; 1:79- 86. [PubMed 6180048]
1453. Heller WM, ed. USAN 1991: USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1990:
1454. Dutcher JP, Salva KM, Wiernik PH. Successful treatment of hairy cell leukemia with 2'-deoxycorformycin after failure of interferons alpha or beta. Am J Clin Oncol . 1990; 13:290-3. [PubMed 2198792]
1455. Spiers ASD, Moore D, Cassileth P et al. Remissions in hairy-cell leukemia wth pentostatin (2'-deoxycorformycin). N Engl J Med . 1987; 316:825-30. [PubMed 2434850]
1456. Johnston JB, Eisenhauer E, Corbett WE et al. Efficacy of 2'-deoxycorformycin in hairy-cell leukemia: a study of the National Cancer Institute of Canada clinical trials. J Natl Cancer Inst . 1988; 80:765-9. [PubMed 3290498]
1457. Kraut EH, Bouroncle BA, Grever MR. Pentostatin in the treatment of advanced hairy cell leukemia. J Clin Oncol . 1989; 7:168-72. [PubMed 2783731]
1458. Durrleman S, Grem JL, Cheson BD. 2'- deoxycorformycin after failure of alpha-interferon in hairy cell leukemia. Eur J Haematol. 1989; 43:297-302.
1459. Piro LD, Carrera CJ, Carson DA et al. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med . 1990; 322:1117-21. [PubMed 1969613]
1460. Martin A, Nerenstone S, Urba WJ et al. Treatment of hairy cell leukemia with alternating cycles of pentostatin and recombinant leukocyte A interferon: results of a phase II study. J Clin Oncol. 1990; 8:721-30.
1461. Douglas RG Jr. Antimicrobial agents [[continued]]: antiviral agents. In: Gilman AG, Rall TW, Nies AS et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:1189-91,1193-1201.
1462. Umeda T, Nijima T. Phase II study of alpha interferon and renal cell carcinoma: summary of three clinical trials. Cancer . 1986; 58:1231-1235. [PubMed 3742449]
1463. Mogensen KE, Bandu MT, Vignaux F et al. Binding of [125I] labelled human alpha interferon to human lymphoid cells. Int J Cancer . 1981; 28:575-82. [PubMed 6171531]
1464. Pestka S, Langer JA, Zoon KC et al. Interferons and their actions. Annu Rev Biochem . 1987; 56:727-77. [PubMed 2441659]
1465. Turner RB, Durcan FJ, Albrecht JK et al. Safety and tolerance of ocular administration of recombinant alpha interferon. Antimicrob Agents Chemother . 1989; 33:396-7. [PubMed 2729934]
1466. Grob JJ, Collet AM, Munoz MH et al. Treatment of large basal-cell carcinomas with intralesional interferon-alpha-2a. Lancet . 1988; 1:878-9. [PubMed 2895379]
1467. Greenway HT, Cornell RC, Tanner DJ et al. Treatment of basal cell carcinoma with intralesional interferon. J Am Acad Dermatol . 1986; 15:437-43. [PubMed 3760271]
1468. Edwards L, Tucker SB, Perednia D et al. The effect of an intralesional sustained-release formulation of interferon alfa-2b on basal cell carcinomas. Arch Dermatol . 1990; 126:1029-1032. [PubMed 2383027]
1469. Greenway HT, Cornell RC. Interferon: coming of age. Arch Dermatol . 1990; 126:1080-2. [PubMed 2200348]
1470. Cornell RC, Greenway HT, Tucker SB et al. Intralesional interferon therapy for basal cell carcinoma. J Am Acad Dermatol . 1990.
1471. Shuttleworth D, Marks R. The response of precancerous lesions of the epidermis to intra-lesional α-2 interferon. Br J Dermatol . 1988; 119(Suppl 33):18-9.
1472. Ludwig H, Cortelezzi A, Fritz E et al. A prospective and randomized clinical trial of combined interferon polychemotherapy versus polychemotherapy in multiple myeloma (MM). Proc Am Soc Clin Oncol . 1987; 6:A586.
1473. Rice AP, Roberts WK, Kerr IM. 2-5A accumulates to high levels in interferon-treated, vaccinia virus-infected cells in the absence of any inhibition of virus replication. J Virol . 1984; 50:220-8. [PubMed 6422053]
1478. Royer HD, Reinherz EL. Current concepts: T lymphocytes. Ontogeny, function, and relevance to clinical disorders. N Engl J Med . 1987; 317:1136-42. [PubMed 3309657]
1479. American Medical Association Diagnostic and Therapeutic Technology Assessment (DATTA) panel. Alpha-interferon and chronic myelogenous leukemia. JAMA . 1990; 264:2137- 40. [PubMed 2214085]
1480. Whitaker-Dowling PA, Wilcox DK, Widnell CC et al. Interferon-mediated inhibition of virus penetration. Proc Natl Acad Sci USA . 1983; 80:1083-6. [PubMed 6189119]
1481. Billiau A, Edy VG, Sobis H et al. Influence of interferon on virus-particle synthesis in oncornavirus-carrier lines. II. Evidence for a direct effect on particle release. Int J Cancer . 1974; 14:335-40. [PubMed 4376516]
1482. Schering Plough Corporation. Interferon Backgrounder. Kenilworth, NJ; 1988 Jun.
1483. Kirkpatrick DV. Interferon: current clinical trials. Hosp Phys . 1984:16-27.
1484. Furuich Y, LaFiandra A, Shatkin AJ. 5'-terminal structure and mRNA stability. Nature . 1977; 266:235-9. [PubMed 557727]
1485. Muss HB, Homesley HD, Rudnick SA et al. A phase I trial of recombinant leukocyte α2 interferon in patients with advanced malignancy. Am J Clin Oncol . 1985; 8:97-107. [PubMed 3834792]
1487. Costanzi J, Cooper MR, Scarffe JH et al. Use in patients with resistant and relapsing multiple myeloma. A phase II study. Dev Oncol . 1985; 27:75-9.
1488. van de Griend RJ, van Krimpen BA, Bolhuis RLH. Beta- interferon and recombinant IL-2 both enhance the nonspecific cytolytic potential of T3- natural killer cell derived clones rather than that of T3+ clones. Paper presented 7th European Immunology Meeting. Jerusalem, Israel: 1985 Sep 8-13. Abstract.
1489. Gresser I. On the mechanisms of the antitumor effects of interferon. Tex Rep Biol Med . 1982; 41(Part 2):582-9.
1490. Gresser I. How does interferon inhibit tumor growth? Philos Trans R Soc London B . 1982; 299:69-76.
1519. Balch CM, Buzaid AC. Finally, a successful adjuvant therapy for high-risk melanoma. J Clin Oncol . 1996; 14:1-3. [PubMed 8558183]
1520. Cole BF, Gelber RD, Kirkwood JM et al. Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol . 1996; 14:2666-73. [PubMed 8874325]
1521. Creagan ET, Dalton RJ, Ahmann DL et al. Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol . 1995; 13:2776-83. [PubMed 7595738]
1522. Pehamberger H, Soyer HP, Steiner A et al. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. J Clin Oncol . 1998; 16:1425-9. [PubMed 9552047]
1523. Haluska FG. Adjuvant interferon for stage II melanoma. J Clin Oncol . 1998; 16:3205-6. [PubMed 9738597]
1524. Grob JJ, Dreno B, de la Salmoniere P et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet . 1998; 351:1905-10. [PubMed 9654256]
1525. Kirkwood JM. Adjuvant IFNα2 therapy of melanoma. Lancet . 1998; 351:1901-3. [PubMed 9654253]
1526. Ascierto PA, Palmieri G. Adjuvant therapy of cutaneous melanoma. Lancet . 1999; 353:328. [PubMed 9929057]
1527. Kirkwood JM, Ibrahim JG, Sondak VK et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol . 2000; 18:2444-58. [PubMed 10856105]
1529. Houghton A, Coit D, Bloomer W et al. NCCN melanoma practice guidelines. National Comprehensive Cancer Network. Oncology (Huntingt) . 1998; 12:153-77.
1530. Sparano JA, Fisher RI, Sunderland M et al. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol . 1993; 11:1969-77. [PubMed 8410122]
1531. Dorval T, Negrier S, Chevreau C et al. Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: a Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study. Cancer . 1999; 85:1060-6. [PubMed 10091789]
1532. Marincola FM, White DE, Wise AP et al. Combination therapy with interferon alfa-2a and interleukin-2 for the treatment of metastatic cancer. J Clin Oncol . 1995; 13:1110-22. [PubMed 7738617]
1533. Renault PF, Hoofnagle JH. Side effects of alpha interferon. Semin Liver Dis . 1989; 9:273-7. [PubMed 2690351]
1534. Silver RT, Benn P, Szatrowski TP et al. Infusional cytosine arabinoside (ARA-C) and recombinant interferon-α(rIFN- α) for the treatment of chronic myeloid leukemia. Proc Am Soc Clin Oncol . 1990; 9:209.
1535. Arlin Z, Feldman E, Ahmed T et al. Intensive chemotherapy with interferon for induction of true remission in chronic phase of chronic myelogenous leukemia (CML). Proc Am Soc Clin Oncol . 1990; 9:211.
1537. Foss F, Fischmann A, Schecter G et al. Phase II trial of human interferon-alfa-2A and pentostatin in advanced stage mycosis fungoides/Sezary syndrome. Proc Am Soc Clin Oncol . 1990; 9:259.
1539. Dow LW, Culbert SJ, Kennedy W et al. Response and toxicity to alpha-interferon in childhood Philadelphia chromosome positive (Ph+) chronic myelocytic leukemia (CML). Proc Annu Meet Am Soc Clin Oncol . 1988; 29:224.
1540. Meyers JD, Flournoy N, Sanders JE et al. Prophylactic use of human leukocyte interferon after allogeneic marrow transplantation. Ann Intern Med . 1987; 107:809-16. [PubMed 2825571]
1541. Newland AC, Jones L, Mir N et al. Alpha 2 interferon in chronic myeloid leukemia following relapse post-allogeneic transplant. Br J Haematol . 1987; 66:141-3. [PubMed 3297127]
1542. Ernstoff MS, Nair S, Bahnson RR et al. A phase IA trial of sequential administration recombinant DNA-produced interferons: combination recombinant interferon gamma and recombinant interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol . 1990; 8:1637-49. [PubMed 2120392]
1543. Yee GC, McGuire TR. Allogeneic bone marrow transplantation in the treatment of hematologic diseases. Clin Pharm . 1985; 4:149-60. [PubMed 3886273]
1544. Genentech. Actimmune (interferon gamma-1b) prescribing information. South San Francisco, CA; 1991 Jan 2.
1545. Nielsen B, Hokland P, Ellegaard J et al. Whole blood assay for NK activity in splenectomized and non-splenectomized hairy cell leukemia patients during IFN-α-2b treatment. Leuk Res . 1989; 13:451-6. [PubMed 2770329]
1546. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Drug Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA website. Accessed 2012 Nov 9. [Web]
1547. Ross C, Hansen MB, Schyberg T et al. Autoantibodies to crude human leucocyte interferon (IFN), native human IFN, recombinant human IFN-alpha 2b and human IFN-gamma in healthy blood donors. Clin Exp Immunol . 1990; 82:57-62. [PubMed 2119920]
1548. Doane LL, Ratain MJ, Golomb HM. Hairy cell leukemia: current management. Hematol Oncol Clin North Am . 1990; 4:489-502. [PubMed 2182604]
1549. Reviewers' comments (personal observations).
1550. Grups JW, Frohmuller HG, Ackermann R. Can recombinant human alpha-2 interferon prevent recurrence of high-grade superficial bladder tumors? Cancer Detect Prev . 1987;10:405-9.
1551. Batuman V, Chadha I. Effect of alpha interferon on glucose and alanine transport by rat renal brush border membrane vesicles. Life Sci . 1990; 47:1187-93. [PubMed 2243534]
1552. Glashan RW. A randomized controlled study of intravesical α-2b-interferon in carcinoma in situ of the bladder. J Urol . 1990; 144:658-61. [PubMed 2201795]
1553. Bergsagel DE, Haas RH, Messner HA. Interferon alfa-2b in the treatment of chronic granulocytic leukemia. Invest New Drugs . 1987; 5(Suppl):S9-17. [PubMed 3298136]
1554. Kantarjian HM, Talpaz M, Keating MJ et al. Combined modality therapy with intensive chemotherapy (DOAP) followed by interferon (IFN-A) maintenance in chronic myelogenous leukemia (CML). Proc Annu Meet Am Soc Clin Oncol . 1988; 29:A836.
1556. Lohmann CP, Kroher G, Bogenrieder T et al. Severe loss of vision during adjuvant interferon alfa-2b treatment for malignant melanoma. Lancet . 1999; 353:1326. [PubMed 10218534]
1557. Talpaz M, Kantarjian H, Kurzrock R et al. Update on therapeutic options for chronic myelogenous leukemia. Semin Hematol . 1990; 27(3 Suppl 4):31-6. [PubMed 2197731]
1558. Kurzrock R, Gutterman JU, Kantarjian H et al. Therapy of chronic myelogenous leukemia with interferon. Cancer Invest . 1989; 7:83-91. [PubMed 2472193]
1559. Niederle N, Kloke O. Interferon in the treatment of hairy cell leukemia and chronic myelogenous leukemia. In: Smyth JF, ed. European School of Oncology Monographs. New York: Springer; 1987:11-24.
1560. Scheithauer W, Theyer G, Zechner O et al. Experiences with continuous intraarterial administration of recombinant interferon alpha-2C (rIFN-alpha 2) for treatment of patients with advanced transitional cell bladder cancer. J Biol Regul Homeost Agents . 1988; 2:67-70. [PubMed 3188978]
1562. Scheithauer W, Cortelezzi A, Fritz E et al. Combined alpha-2c-interferon/VMCP polychemotherapy as induction therapy in multiple myeloma: a prospective randomized trial. J Biol Response Mod . 1989; 8:109-15. [PubMed 2659740]
1563. Ludwig H, Cortelezzi A, Fritz E et al. Combined interferon-polychemotherapy versus polychemotherapy in multiple myeloma: a phase III study. In: Cantell K, Schellekens H, eds. The biology of the interferon system. Boston: Martin Nijhoff Publishers; 1987:363-70.
1564. Kassianides C, Di Bisceglie AM, Hoofnagle JH et al. Alpha-interferon therapy in patients with decompensated chronic type B hepatitis. In: Zuckerman AJ, ed. Viral hepatitis and liver disease. New York: Alan R. Liss, Inc; 1988:840-3.
1565. Lisker-Melman M, Di Bisceglie AM, Usala SJ et al. Autoimmune thyroid disease associated with recombinant human alpha interferon therapy in patients with chronic viral hepatitis. (unpublished observations)
1567. Ghezzi P, Dinarello CA. Il-1 induces Il-1. III: Specific inhibition of IL-1 production by IFN-gamma. J Immunol . 1988; 140:4238-44. [PubMed 3131429]
1573. Krown SE, Paredes J, Bundow D et al. Combination therapy with interferon-alpha (IFN-alpha), zidovudine (AZT), and recombinant granulocyte-macrophage colony-stimulating factor (GM- CMF): a phase I trial in patients with AIDS-associated Kaposi's sarcoma. Int Conf AIDS. 1990; June 20-23; 6:214. Abstract No. S.B.513.
1574. Ludwig CU, Ludwig-Hagemann R, Obrist R et al. Improved tolerance of interferon alpha-2a by continuous subscutaneous infusion. Onkologie . 1990; 13:117-22. [PubMed 2197582]
1575. Li BL, Zhao XX, Liu XY et al. Alpha-interferon structure and natural killer cell stimulatory activity. Cancer Res . 1990; 50:5328-32. [PubMed 2201435]
1576. Redlich PN, Grossberg SE. Immunochemical characterization of antigenic domains on human interferon-beta: spatially distinct epitopes are associated with both antiviral and antiproliferative activities. Eur J Immunol . 1990; 20:1933-9. [PubMed 1698636]
1594. Talpaz M, Kantarjian H, Kurzrock R et al. Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia: Philadelphia chromosome-positive patients. Ann Intern Med . 1991; 114:532-8. [PubMed 2001086]
1595. Marcellin P, Colin JF, Boyer N et al. Fatal exacerbation of chronic hepatitis B induced by recombinant alpha-interferon. Lancet . 1991; 338:828. [PubMed 1681203]
1597. White CW, Wolf SJ, Korones DN et al. Treatment of childhood angiomatous diseases with recombinant interferon alfa-2a. J Pediatr . 1991; 118:59-66. [PubMed 1986099]
1598. Janssen HLA, Berk L, Vermeulen M et al. Seizures associated with low-dose α-interferon. Lancet . 1990; 336:1580. [PubMed 1979391]
1610. Kamisako T, Adachi Y, Chihara J et al. Interstitial pneumonitis and interferon-alfa. BMJ . 1993; 306:896. [PubMed 8490417]
1616. Papo T, Marcellin P, Bernuau J et al. Autoimmune chronic hepatitis exacerbated by alpha-interferon. Ann Intern Med . 1992; 116:51-3. [PubMed 1727095]
1619. Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet . 1992; 340:952-6. [PubMed 1357355]
1620. Jaiyesimi IA, Kantarjian HM, Estey EH. Advances in therapy for hairy cell leukemia. A review. Cancer . 1993; 72:5-16. [PubMed 7685243]
1621. Spielberger RT, Golomb HM. Hairy cell leukemia 1992. Leukemia . 1992; 6(Suppl 4):142-6. [PubMed 1279327]
1622. Tallman MS, Hakimian D, Variakojis D et al. A single cycle of 2-chlorodeoxyadenosine results in complete remission in the majority of patients with hairy cell leukemia. Blood . 1992; 80:2203-9. [PubMed 1358262]
1623. Golomb HM, Ratain MJ, Mick R et al. The treatment of hairy cell leukemia: an update. Leukemia . 1992; 6(Suppl 2):24-7. [PubMed 1349662]
1624. Baltz JK, Montello MJ. Cladribine for the treatment of hematologic malignancies. Clin Pharm . 1993; 12:805-13. [PubMed 7903917]
1625. Anon. Drugs of choice for cancer. Med Lett Treat Guid . 2003; 1:41-52.
1627. Saven A, Piro LD. Treatment of hairy cell leukemia. Blood . 1992; 79:1111-20. [PubMed 1371410]
1629. Anon. Pentostatin and 2-chlorodeoxyadenosine for hairy-cell leukemia. Med Lett Drugs Ther . 1992; 34:89-90. [PubMed 1355592]
1631. Levenson JL, Fallon HJ. Fluoxetine treatment of depression caused by interferon-α. Am J Gastroenterol . 1993; 88:760-1. [PubMed 8480744]
1632. Bryson HM, Sorkin EM. Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies. Drugs . 1993; 46:872-94. [PubMed 7507037]
1633. Graessle D, Bonacini M, Chen S. Alpha-interferon and reversible hypertriglyceridemia. Ann Intern Med . 1993; 118:316-7. [PubMed 8420459]
1634. Sunderkötter C, Luger T, Kolde G. Severe hypertriglyceridaemia and interferon-α. Lancet . 1993; 342:1111-2. [PubMed 8105328]
1635. Dorr RT. Interferon-α in malignant and viral disease. A review. Drugs . 1993; 45:177-211. [PubMed 7681371]
1636. Saven A, Piro LD, Carrera CJ et al. Hairy cell leukemia: new understanding of biology and treatment. In: Freireich EJ, Kantarjian H, eds. Leukemia—advances in research and treatment. Boston: Kluwer Academic Publishers; 1993:15-34.
1637. Saven A, Piro L. Newer purine analogues for the treatment of hairy-cell leukemia. N Engl J Med . 1994; 330:691-7. [PubMed 7906385]
1638. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med . 1994; 330:820-5. [PubMed 8114834]
1639. Wetzler M, Kantarjian H, Kurzrock R et al. Interferon-α therapy for chronic myelogenous leukemia. Am J Med . 1995; 99:402-11. [PubMed 7573097]
1640. Kantarjian HM, Smith TL, O'Brien S et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-α therapy. Ann Intern Med . 1995; 122:254-61. [PubMed 7825760]
1641. Hehlmann R, Heimpel H, Hasford J et al. Randomized comparison of interferon-α with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood . 1994; 84:4064-77. [PubMed 7994025]
1642. Kantarjian HM, Talpaz M. Interferon-α therapy in chronic myelogenous leukemia: questions related to the German randomized trial. Blood . 1995; 85:2998-9. [PubMed 7742562]
1643. Tura S, Baccarani M. α-Interferon in the treatment of chronic myeloid leukemia. Blood . 1995; 85:2999-3000. [PubMed 7742563]
1644. Hehlmann R, Heimpel H, Hasford J. Randomized comparison of interferon-α, hydroxyurea, and busulfan and in chronic myelogenous leukemia: response to Kantarjian and Talpaz and to Tura and Baccarani. Blood . 1995; 85:3000-2.
1647. Northfelt DW. Treatment of Kaposi's sarcoma: current guidelines and future perspectives. Drugs . 1994; 48:569-82. [PubMed 7528130]
1648. Krown SE. Interferon and other biologic agents for the treatment of Kaposi's sarcoma. Hematol Oncol Clin N Am . 1991; 5:311-22.
1650. Krown SE, Real FX, Lester T et al. Interferon-α (IFN-α2a± vinblastine in AIDS-related Kaposi's sarcoma: a prospective randomized trial. Proc ASCO . 1986; 5. Abstract No. 6.
1652. Kirkwood JM, Strawderman MH, Ernstoff MS et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol . 1996; 14:7-17. [PubMed 8558223]
1659. Guilhot F, Chastang C, Michallet M et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med . 1997; 337:223-9. [PubMed 9227927]
1660. Goldman JM. Optimizing treatment for chronic myeloid leukemia. N Engl J Med . 1997; 337:270-1. [PubMed 9227935]
1661. Patel T, Roychowdhury DF. Interferon alfa-2b and cytarabine in chronic myelogenous leukemia. N Engl J Med . 1997; 337:1634. [PubMed 9411231]
1662. Guilhot F, Guilhot J, Chastang C. Interferon alfa-2b and cytarabine in chronic myelogenous leukemia. N Engl J Med . 1997; 337:1634-5. [PubMed 9411231]
1663. Kurth KH. Diagnosis and treatment of superficial transitional cell carcinoma of the bladder: facts and perspectives. Eur Urol . 1997; 31(Suppl 1):10-9. [PubMed 9076481]
1664. Boccardo F, Cannata D, Rubagotti A et al. Prophylaxis of superficial bladder cancer with mitomycin or interferon alfa-2b: results of a multicentric Italian study. J Clin Oncol . 1994; 12:7-13. [PubMed 8270987]
1665. Sargent ER, Williams RD. Immunotherapeutic alternatives in superficial bladder cancer: interferon, interleukin-2, and keyhole-limpet hemocyanin. Urol Clin North Am . 1992; 19:581-9. [PubMed 1378983]
1666. Witjes JA. Current recommendations for the management of bladder cancer: drug therapy. Drugs . 1997; 53:404-14. [PubMed 9074842]
1667. Raghaven D, Huben R. Management of bladder cancer. Curr Prob Cancer . 1995; 19:1-64.
1668. Hrouda D, Muir GH, Dalgleish AG. The role of immunotherapy for urological tumours. Br J Urol . 1997; 79:307-16. [PubMed 9117,206]
1669. Nseyo UO, Lamm DL. Therapy of superficial bladder cancer. Semin Oncol . 1996; 23:598-604. [PubMed 8893870]
1694. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med . 1996; 335:865-75. [PubMed 8778606]
1695. NCCN practice guidelines for kidney cancer. National Comprehensive Cancer Network. Oncology (Huntingt) . 1998; 12:396-412.
1696. Bukowski RM. Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin-2. Cancer . 1997; 80:1198-220. [PubMed 9317170]
1697. Vogelzang NJ, Stadler WM. Kidney cancer. Lancet . 1998; 352:1691-6. [PubMed 9853456]
1698. Negrier S, Escudier B, Lasset C et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. N Engl J Med . 1998; 338:1272-8. [PubMed 9562581]
1699. Hernberg M, Pyrhonen S, Muhonen T. Regimens with or without interferon-alpha as treatment for metastatic melanoma and renal cell carcinoma: an overview of randomized trials. J Immunother . 1999; 22:145-54. [PubMed 10093039]
1700. Minasian LM, Motzer RJ, Gluck L et al. Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up. J Clin Oncol . 1993; 11:1368-75. [PubMed 8315435]
1701. Young RC. Metastatic renal-cell carcinoma: what causes occasional dramatic regressions? N Engl J Med . 1998; 338:1305-6. Editorial.
1702. Henriksson R, Nilsson S, Colleen S et al. Survival in renal cell carcinoma-a randomized evaluation of tamoxifen vs interleukin 2, alpha-interferon (leucocyte) and tamoxifen. Br J Cancer . 1998; 77:1311-7. [PubMed 9579838]
1703. Gleave ME, Elhilali M, Fradet Y et al. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group. N Engl J Med . 1998; 338:1265-71. [PubMed 9562580]
1704. Pizzocaro G, Piva L, Costa A et al. Adjuvant interferon (IFN) to radical nephrectomy in Robson's stages II and III renal cell cancer (RCC), a multicenter randomized study with some biological evaluations. Proc Annu Meet Am Soc Clin Oncol . 1997; 16:A1132.
1705. Trump DL, Elson P, Propert K et al. Randomized, controlled trial of adjuvant therapy with lymphoblastoid interferon (L-IFN) in resected, high-risk renal cell carcinoma (HR-RCC). Proc Annu Meet Am Soc Clin Oncol . 1996; 15:A648.
1706. Galligioni E, Quaia M, Merlo A et al. Adjuvant immunotherapy treatment of renal carcinoma patients with autologous tumor cells and bacillus Calmette-Guerin: five-year results of a prospective randomized study. Cancer . 1996; 77:2560-6. [PubMed 8640706]
1707. Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet . 1999; 353:14-7. [PubMed 10023944]
1708. Amato R. Modest effect of interferon alfa on metastatic renal-cell carcinoma. Lancet . 1999; 353:6-7. [PubMed 10023941]
1709. Pyrhonen S, Salminen E, Ruutu M et al. Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol . 1999; 17:2859-67. [PubMed 10561363]
1710. Kriegmair M, Oberneder R, Hofstetter A. Interferon alfa and vinblastine versus medroxyprogesterone acetate in the treatment of metastatic renal cell carcinoma. Urology . 1995; 45:758-62. [PubMed 7747370]
1711. Steineck G, Strander H, Carbin BE et al. Recombinant leukocyte interferon alpha-2a and medroxyprogesterone in advanced renal cell carcinoma. A randomized trial. Acta Oncol . 1990; 29:155-62. [PubMed 2185803]
1712. Palmer PA, Atzpodien J, Philip T et al. A comparison of 2 modes of administration of recombinant interleukin-2: continuous intravenous infusion alone versus subcutaneous administration plus interferon alpha in patients with advanced renal cell carcinoma. Cancer Biother . 1993; 8:123-36. [PubMed 7804353]
1713. Atzpodien J, Lopez Hanninen E, Kirchner H et al. Multiinstitutional home-therapy trial of recombinant human interleukin-2 and interferon alfa-2 in progressive metastatic renal cell carcinoma. J Clin Oncol . 1995; 13:497-501. [PubMed 7844611]
1714. Lopez Hanninen E, Kirchner H, Atzpodien J. Interleukin-2 based home therapy of metastatic renal cell carcinoma: risks and benefits in 215 consecutive single institution patients. J Urol . 1996; 155:19-25. [PubMed 7490829]
1715. Vogelzang NJ, Lipton A, Figlin RA. Subcutaneous interleukin-2 plus interferon alfa-2a in metastatic renal cancer: an outpatient multicenter trial. J Clin Oncol . 1993; 11:1809-16. [PubMed 8355047]
1716. Lissoni P, Barni S, Ardizzoia A et al. A randomized study of low-dose interleukin-2 subcutaneous immunotherapy versus interleukin-2 plus interferon-alpha as first line therapy for metastatic renal cell carcinoma. Tumori . 1993; 79:397-400. [PubMed 8171738]
1717. Boccardo F, Rubagotti A, Canobbio L et al. Interleukin-2, interferon-alpha and interleukin-2 plus interferon-alpha in renal cell carcinoma. A randomized phase II trial. Tumori . 1998; 84:534-9. [PubMed 9862512]
1718. Jayson GC, Middleton M, Lee SM et al. A randomized phase II trial of interleukin 2 and interleukin 2-interferon alpha in advanced renal cancer. Br J Cancer . 1998; 78:366-9. [PubMed 9703284]
1719. Atkins MB, Sparano J, Fisher RI et al. Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J Clin Oncol . 1993; 11:661-70. [PubMed 8478661]
17,20. Dillman RO, Church C, Oldham RK et al. Inpatient continuous-infusion interleukin-2 in 788 patients with cancer: the National Biotherapy Study Group experience. Cancer . 1993; 71:2358-70. [PubMed 8453558]
1721. Figlin RA, Belldegrun A, Moldawer N et al. Concomitant administration of recombinant human interleukin-2 and recombinant interferon alfa-2A: an active outpatient regimen in metastatic renal cell carcinoma. J Clin Oncol . 1992; 10:414-21. [PubMed 1482425]
1722. Oldham RK, Blumenschein G, Schwartzberg L et al. Combination biotherapy utilizing interleukin-2 and alpha interferon in patients with advanced cancer: a National Biotherapy Study Group trial. Mol Biother . 1992; 4:4-9. [PubMed 1627272]
1723. Ilson DH, Motzer RJ, Kradin RL et al. A phase II trial of interleukin-2 and interferon alfa-2a in patients with advanced renal cell carcinoma. J Clin Oncol . 1992; 10: 1124-30. [PubMed 1607918]
1724. Lipton A, Harvey H, Givant E et al. Interleukin-2 and interferon-α-2a outpatient therapy for metastatic renal cell carcinoma. J Immunother . 1993; 13:122-9.
1725. Bukowski RM, McLain D, Olencki T et al. Interleukin-2: use in solid tumors. Stem Cells . 1993; 11:26-32. [PubMed 8457777]
1726. Rosenberg SA, Lotze MT, Yang JC et al. Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol . 1989; 7:1863-74. [PubMed 2685181]
1727. Bergmann L, Fenchel K, Weidmann E et al. Daily alternating administration of high-dose alpha-2b-interferon and interleukin-2 bolus infusion in metastatic renal cell cancer. A phase II study. Cancer . 1993; 72:1733-42. [PubMed 8348502]
1728. Figlin RA. Renal cell carcinoma: management of advanced disease. J Urol . 1999; 161:381-7. [PubMed 9915408]
1729. Dutcher JP, Atkins M, Fisher R et al. Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. Cancer J Sci Am . 1997; 3(Suppl 1):S73-8.
1730. Motzer RJ, Murphy BA, Bacik J et al. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol . 2000; 18:2972-80. [PubMed 10944130]
1731. Fossa SD, Martinelli G, Otto U et al. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol . 1992; 3:301-5. [PubMed 1390305]
1732. Neidhart JA, Anderson SA, Harris JE et al. Vinblastine fails to improve response of renal cancer to interferon alfa-n1: high response rate in patients with pulmonary metastases. J Clin Oncol . 1991; 9:832-6. [PubMed 2016626]
1733. Fossa SD, Raabe N, Moe B. Recombinant interferon-alpha with or without vinblastine in metastatic renal carcinoma. Results of a randomised phase II study. Br J Urol . 1989; 64:468-71. [PubMed 2611615]
1734. Atzpodien J, Kirchner H, Lopez Hanninen E et al. Alpha-interferon, interleukin-2 and 5-fluorouracil as a promising biochemotherapy regimen for the management of advanced renal cell carcinoma. Proc Annu Meet Am Soc Clin Oncol . 1993; 12:A708.
1735. Sella A, Zukiwski A, Robinson E et al. Interleukin-2 (IL-2) with interferon-alfa (IFN-alpha) and 5-fluorouracil (5-FU) in patients (pts) with metastatic renal cell cancer (RCC). Proc Annu Meet Am Soc Clin Oncol . 1994; 13:A733.
1736. Ellerhorst JA, Sella A, Amato RJ et al. Phase II trial of 5-fluorouracil, interferon-alpha and continuous infusion interleukin-2 for patients with metastatic renal cell carcinoma. Cancer . 1997; 80:2128-32. [PubMed 9392335]
1737. Ravaud A, Audhuy B, Gomez F et al. Subcutaneous interleukin-2, interferon alfa-2a, and continuous infusion of fluorouracil in metastatic renal cell carcinoma: a multicenter phase II trial. Groupe Francais d'Immunotherapie. J Clin Oncol . 1998; 16:2728-32. [PubMed 9704724]
1738. Tourani JM, Pfister C, Berdah JF et al. Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: results of a sequential nonrandomized phase II study. Subcutaneous Administration Propeukin Program Cooperative Group. J Clin Oncol . 1998; 16:2505-13. [PubMed 9667271]
1739. Negrier S, Escudier B, Douillard JY et al. Randomized study of interleukin-2 (IL2) and interferon (IFN) with or without 5-FU (FUCY study) in metastatic renal cell carcinoma (MRCC). Proc Am Soc Clin Oncol . 1997; 16:A1161.
1740. Igarashi T, Marumo K, Onishi T et al. Interferon-alpha and 5-fluorouracil therapy in patients with metastatic renal cell cancer: an open multicenter trial. The Japanese Study Group Against Renal Cancer. Urology . 1999; 53:53-9. [PubMed 9886588]
1741. Elias L, Blumenstein BA, Kish J et al. A phase II trial of interferon-alpha and 5-fluorouracil in patients with advanced renal cell carcinoma. A Southwest Oncology Group study. Cancer . 1996; 78:1085-8. [PubMed 8780547]
1742. Haarstad H, Jacobsen AB, Schjolseth SA et al. Interferon-alpha, 5-FU and prednisone in metastatic renal cell carcinoma: a phase II study. Ann Oncol . 1994; 5:245-8. [PubMed 8186172]
1743. De Mulder PH, Oosterhof G, Bouffioux C et al. EORTC (30885) randomised phase III study with recombinant interferon alpha and recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma. The EORTC Genitourinary Group. Br J Cancer . 1995; 71:371-5. [PubMed 7841054]
1744. Sagaster P, Micksche M, Flamm J et al. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol . 1995; 6:999-1003. [PubMed 8750152]
1745. Creagan ET, Twito DI, Johansson SL et al. A randomized prospective assessment of recombinant leukocyte A human interferon with or without aspirin in advanced renal adenocarcinoma. J Clin Oncol . 1991; 9:2104-9. [PubMed 1960551]
1747. Prometheus. Proleukin® (aldesleukin) for injection prescribing information. San Diego, CA; 2012 Jul.
1748. Parker MG, Atkins MB, Ucci AA et al. Rapidly progressive glomerulonephritis after immunotherapy for cancer. J Am Soc Nephrol . 1995; 5:1740-4. [PubMed 7787140]
1749. Atzpodien J, Kirchner H, Franzke A et al. Results of a randomized clinical trial comparing SC interleukin-2, SC alpha-2a-interferon, and IV bolus 5-fluorouracil against oral tamoxifen in progressive metastatic renal cell carcinoma patients. Proc Annu Meet Am Soc Clin Oncol . 1997; 16:A1164.
1750. Halperin EC. Kidney cancer. Lancet . 1999; 353:594. [PubMed 10029013]
1751. Sawczuk IS, Graham Jr SD, Miesowicz F. Randomized, controlled trial of adjuvant therapy with ex vivo activated T cells (ALT) in T1-3a,b,c or T4N+,M0 renal cell carcinoma. Proc Am Soc Clin Oncol . 1997; 16:A1163.
1752. Reviewers' comments (personal observations) on aldesleukin.