VA Class:AN200

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Streptozocin

Chemical Name:

• 2-Deoxy-2-[[(methylnitrosoamino)carbonyl]amino]-d-glucose

Molecular Formula:

• C₈H₁₅N₃O₇

Streptozocin is an antineoplastic antibiotic produced by Streptomyces achromogenes. 1,2,3,4,5,6,7

Pancreatic Islet Cell Carcinoma

Streptozocin is used for the treatment of metastatic islet cell carcinoma of the pancreas.4,136 The drug has been effective in patients with functional4,13,33,34,35,36,37,38,40,41,42,43,48,49,50,51,52,71,72,73,84,85,86,87,88,89,99,100,101,102 or nonfunctional4,33,37,39 and beta13,33,34,35,36,37,38,40,41,42,43,48,49,50,51,52,71,72 or non-beta37,73,84,85,86,87,88,89,99,100,101,102,103,104,105 cell islet tumors; however, because of streptozocin's nephrotoxic4,33 and emetogenic122 potential, and because pancreatic islet cell carcinoma may be an indolent tumor,37,61,122 therapy with the drug should be limited to patients with symptomatic or progressive disease.4,33,122

In the treatment of metastatic islet cell carcinoma of the pancreas, streptozocin is currently the most active single agent.3,26,33,34,35,36,37,38,40 Streptozocin is used in combination with other antineoplastic agents (e.g., doxorubicin, fluorouracil) for the treatment of islet cell cancer.136 Combination chemotherapy with streptozocin and fluorouracil appears to be superior to streptozocin alone,36,37,81,85,100 producing higher overall and complete response rates;37 the effect on survival remains to be clearly established.37 Other streptozocin-containing combination chemotherapy regimens are currently being investigated, and comparative efficacy is continually being evaluated.3,37

Streptozocin has been used alone13,33,34,35,36,37,38,40,41,42,43,71,72 or in combination with fluorouracil36,37,39,136 for the treatment of nonfunctional tumors of the islet cells4,33,37,39 and for the treatment of functional tumors of the islet cells4,13,33,34,35,36,37,38,40,41,42,43,48,49,50,51,52,71,72,79,80,81,82,83,84,85,86,87,88,89,99,100,101,102,103,104,105 that produce a variety of polypeptide hormones including insulin,13,33,34,35,36,37,38,40,41,42,43,48,49,50,51,52,71,72 glucagon,42,99,105 gastrin,42,72,79,80,81,82,83 somatostatin,104 corticotropin,71 chorionic gonadotropin,101 vasoactive intestinal peptide,84,85,86,87,88,89,91 serotonin,13 calcitonin,55 a parathormone-like substance,55,103 and unidentified hormones associated with watery diarrhea.36,89 Streptozocin alone or streptozocin-containing combination chemotherapy has produced objective evidence of biochemical response and/or measurable tumor regression in about 35-60% of patients with functional tumors producing one or more of these hormones13,33,34,35,36,37,38,40,41,42,43,48,49,50,51,52,55,71,72,79,80,81,82,83,84,85,86,87,88,89,91,99,101,103,104,105 or with nonfunctional tumors.33,37,39 Although the response rate in patients receiving streptozocin and fluorouracil therapy in one study appeared to be slightly higher in those with functional tumors than in those with nonfunctional tumors,37 streptozocin generally does not appear to be associated with preferential activity against any of the functional islet cell tumor types3,37 and appears to be equally effective in functional or nonfunctional islet cell tumors.33,37

In most patients with functional tumors who respond to streptozocin, signs and symptoms of the disease decrease to minimal levels or disappear.3,13,33,34,35,36,37,38,40,41,42,43,48,49,50,51,52,55,71,72,79,80,81,82,83,84,85,86,87,88,89,91,99,101,103,104,105 Objective response to streptozocin therapy in patients with either functional or nonfunctional islet cell tumors can be evidenced by measurable reductions in tumor size and/or organomegaly (e.g., pancreatic and/or extrapancreatic masses).4,33,34,35,36,37,38,40,41,42,43,48,49,50,51,52,63,71,72,79,80,81,82,83,84,85,86,87,88,89,99,100,101,102,103,104,105 Determination of biochemical response to streptozocin therapy in patients with functional islet cell tumors can also be achieved by monitoring appropriate serum polypeptide hormone concentrations (e.g., insulin, gastrin).4,33,34,35,36,37,38,40,41,42,43,48,49,50,51,52,63,71,72,79,80,81,82,83,84,85,86,87,88,89,99,100,101,102,103,104,105 Patients with hypoglycemia caused by increased serum insulin concentration associated with insulin-secreting tumors (insulinomas) often improve dramatically as a result of streptozocin therapy (alone or in combination).3,33 The insulin response to streptozocin therapy (i.e., normalization of serum insulin concentration) in patients with functional islet cell tumors is usually rapid, occurring in most patients by the second or third week of treatment with the drug and at a total cumulative dose of approximately 2 g/m².4,33

Carcinoid Tumor and Syndrome

Streptozocin has been used alone and as a component of various combination chemotherapeutic regimens for the palliative treatment of metastatic carcinoid tumor†.3,13,36,39,43,59,92,93,94,106,136 When used alone, streptozocin has produced an objective response in a few patients with carcinoid tumor;36,43,59,106 however, as with other single agents, the responses to the drug were partial and of short duration.36,43,59,106 Because it has some activity, streptozocin has been used as a component of various chemotherapeutic regimens for the treatment of metastatic carcinoid tumor and carcinoid syndrome;3,63,94 however, the exact role of combination chemotherapy in the management of these conditions remains to be clearly established.3,94 Streptozocin has been used in combination with cyclophosphamide,94 with fluorouracil,94,136 and with cyclophosphamide, fluorouracil, and doxorubicin.3 In one prospective randomized study comparing streptozocin and cyclophosphamide with streptozocin and fluorouracil in patients with metastatic carcinoid tumor, objective evidence of biochemical response (e.g., decreased urinary excretion of 5-hydroxyindoleacetic acid [5-HIAA]) and/or measurable tumor regression occurred in 26% of patients receiving streptozocin in combination with cyclophosphamide and in 33% of patients receiving streptozocin in combination with fluorouracil.94 In this study, response rates were better in patients with tumors originating in the small intestine than in those with tumors originating in other sites (e.g., lung).94

Pancreatic Adenocarcinoma

Streptozocin has been used in the treatment of pancreatic adenocarcinoma†;3,36,40,43,59,62,69,70,74,75,76,77,78,110,111 however, with few exceptions,75 single-agent therapy with the drug in this disease has been only minimally effective.36,40,43,59 Although some streptozocin-containing combination chemotherapy regimens have been reported to produce slightly higher response rates than single-agent therapy,69,70,75,76,77,110,111 these results have not always been reproducible, and additional studies are needed to determine the role, if any, of such combination chemotherapy in the treatment of pancreatic adenocarcinoma.3,76,77,122

Reconstitution and Administration

Streptozocin is administered by direct IV injection3,4,32,35,37,40,43,70,73,74,77,79,83 or by IV infusion.3,4,13,35,38,40,42,60,81 Streptozocin has also been administered intra-arterially†;3,4,33,35,71,73,79,80,89,118 however, pending further accumulation of data, the manufacturer does not recommend intra-arterial administration of the drug because of the possibility of enhanced nephrotoxicity associated with this route of administration.4

The manufacturer recommends that protective gloves be used during handling of streptozocin powder for injection and preparation of streptozocin solutions, since topical contact with the drug may represent a carcinogenic hazard.4 (See Cautions: Mutagenicity and Carcinogenicity.) If streptozocin powder for injection or a solution of the drug comes in contact with the skin or mucosa, the affected area should be washed immediately and thoroughly with soap and water.4

Streptozocin powder for injection is reconstituted by adding 9.5 mL of 5% dextrose or 0.9% sodium chloride injection to a vial labeled as containing 1 g of the drug to provide a solution containing 100 mg/mL;4 if more dilute infusion solutions are desired, further dilution in 5% dextrose or 0.9% sodium chloride injection4 or in 5% dextrose and 0.9% sodium chloride injection121,132 is recommended.

IV Injection or Infusion

For IV administration, the desired dose of the reconstituted streptozocin solution may be given directly by rapid IV injection4,32,35,37,40,70,74,77 or may be further diluted and given as an IV infusion over a short or prolonged period;4 intermittent IV infusions over 15 minutes to 6 hours are commonly employed.13,35,38,40,42,43,73,78,81,83 Although continuous 5-day IV infusions of streptozocin have also been used, such prolonged continuous administration may be associated with increased CNS toxicity.60 (See Cautions: Other Adverse Effects.)

Intra-arterial Infusion

For intra-arterial† infusion, streptozocin has been administered via an appropriately placed catheter using a controlled-infusion device.35,71,73,79,80,118 The streptozocin dose has generally been diluted in 5% dextrose or 0.9% sodium chloride injection and infused over 1-2 hours.35,71,73,79,80,118 However, the manufacturer currently does not recommend this route of administration, since its nephrotoxic potential compared with that of other methods of administration has not been fully determined.4

Dosage

Because streptozocin is classified as an antineoplastic agent of high emetic risk, antiemetic therapy for the prevention of acute and delayed emesis is recommended.137 (See Cautions: GI Effects.)

Dosage of streptozocin must be based on the clinical, renal, hematologic, and hepatic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects.3,4,33 Clinicians should consult published protocols for the dosage of streptozocin and other chemotherapeutic agents and the method and sequence of administration. A repeat course of streptozocin should not be administered until the patient's renal, hematologic, and hepatic functions are within acceptable limits. 4,33 (See Cautions: Precautions and Contraindications.)

Pancreatic Islet Cell Carcinoma

For the treatment of metastatic islet cell carcinoma of the pancreas, streptozocin may be given in a consecutive-day or weekly dosing regimen.4 In the consecutive-day regimen, the recommended dosage of streptozocin is 500 mg/m² IV daily for 5 consecutive days every 6 weeks until optimum benefit or treatment-limiting toxicity occurs;4 the manufacturer does not recommend exceeding a dosage of 500 mg/m² daily in this regimen.4 In the weekly regimen, streptozocin is given as a single IV dose at weekly intervals.4 In the weekly regimen, the recommended initial dosage of streptozocin is 1 g/m² per week for the first 2 weeks;4 subsequently, the dose of streptozocin may be increased in patients who have not achieved a therapeutic response and who have not experienced clinically important drug-related toxicity with the previous dose.4 The manufacturer does not recommend exceeding a single dose of 1.5 g/m² in the weekly regimen, since higher doses may cause azotemia.4 When the weekly dosing regimen is used, the median time to onset of therapeutic response is about 17 days and the median time to achieve maximum therapeutic response is about 35 days;4,33 the median total cumulative dose to onset of therapeutic response is about 2 g/m² and the median total cumulative dose to achieve maximum therapeutic response is about 4 g/m².4,33 While the consecutive-day dosing regimen may produce a period of more severe nausea and vomiting in many patients, it may be more tolerable and acceptable to patients than the weekly regimen because of the longer interval between periods of treatment-induced nausea and vomiting.37

Other Malignant Neoplasms

For the treatment of other malignant neoplasms, the optimum dosage of streptozocin remains to be clearly established.3 Various dosage schedules and regimens of streptozocin, alone or in combination with other antineoplastic agents, have been used.3 Clinicians should consult published protocols for the dosage of streptozocin and other chemotherapeutic agents and the method and sequence of administration in the treatment of specific diseases.

Intra-arterial Dosage

When streptozocin has been administered intra-arterially† for the treatment of metastatic islet cell carcinoma of the pancreas, a dose of 1-4 g/m² at intervals ranging from 1-6 weeks for at least 1-4 courses of therapy33,35,71,73,79,80,89,118 has been used; however, the safety of this method of administering the drug has not been established.4,33

Dosage in Renal Impairment

Although the effects of renal impairment on the elimination of streptozocin have not been evaluated,45 some clinicians have suggested that patients with creatinine clearances of 10-50 mL/minute receive 75% of the usual dose and those with creatinine clearances less than 10 mL/minute receive 50% of the usual dose.120

Renal Effects

The most serious and dose-limiting adverse effect of streptozocin is nephrotoxicity,3,4,13,53,54,55,56,57,58 which reportedly occurs in approximately 25-75% of patients receiving the drug.3,13,33,43,59 Streptozocin-induced nephrotoxicity is cumulative and may be severe or fatal.3,4,13,33,43,53,54,55,56,57,58,59 Renal function must be carefully monitored in all patients receiving the drug.4 A reduction in dosage or discontinuance of streptozocin therapy is recommended if substantial renal toxicity occurs.4 (See Cautions: Precautions and Contraindications.)

Streptozocin-induced nephrotoxicity involves abnormalities of glomerular and renal tubular function3,4,13,33,43,53,54,55,56,57,58,59 and may be manifested by azotemia, anuria, proteinuria, hypophosphatemia, hyperchloremia, and proximal renal tubular acidosis which may be associated with a Fanconi-like syndrome evidenced by glycosuria, acetonuria, and aminoaciduria.3,4,8,13,32,33,40,43,53,54,55,56,57,58,59 Hypokalemia and hypocalcemia have also occurred.3 Hypophosphatemia8,13,53,56 and mild proteinuria4,13,33,40,59 appear to be the earliest signs of nephrotoxicity and may develop in some patients following administration of only a few doses of the drug;3,40,53 these findings may indicate an impending further deterioration of renal function.4 Although increases in BUN and serum creatinine concentrations may occur, these findings usually develop later following continued treatment with the drug.13 Although mild adverse renal effects (e.g., mild proteinuria) may be reversible following discontinuance of streptozocin,3,13 nephrotoxicity may be irreversible and fatalities associated with chronic renal failure may occur if therapy with the drug is continued after nephrotoxicity becomes manifested.3,13,33,39,56,57,58 The risk of nephrotoxicity may be increased when the drug is administered intra-arterially†.4,33

Histologic changes, including extensive tubular atrophy, interstitial inflammatory infiltration, interstitial fibrosis, and glomerular cellular nodules, have been observed in biopsy specimens from patients receiving streptozocin;55 acute tubular necrosis associated with renal tubular squamous metaplasia, principally in the proximal convoluted tubules and cortical collecting ducts, has also been observed.57 Although the exact mechanism is not known, renal toxicity may result from a direct effect of streptozocin and/or its metabolites on renal tubular epithelium.13,55 Adequate hydration has been recommended to decrease the risk of nephrotoxicity, possibly by decreasing renal and urinary concentrations of the drug and/or its metabolites;4,8,13 however, the role of hydration in decreasing streptozocin-induced nephrotoxicity has not been clearly established.13,122

The long-term effects of streptozocin on renal function are not fully known.58 Cumulative, delayed nephrotoxicity and chronic renal failure have reportedly occurred in at least one patient following discontinuance of streptozocin therapy.58

Nephrogenic diabetes insipidus has been reported in at least 2 streptozocin-treated patients;4,135 the condition improved without specific therapy in one patient4 and responded to indomethacin therapy in the other patient.4,135

GI Effects

Severe nausea and vomiting occur in most patients receiving streptozocin, and occasionally may require discontinuance of the drug.3,4,13,33,37,137 Because of its emetogenic potential, streptozocin is classified as an antineoplastic agent of high emetic risk (i.e., incidence of emesis exceeds 90% if no antiemetic agents are administered).137 Nausea and vomiting usually begin within 1-4 hours following administration of streptozocin and may persist for 24 hours or longer.3,13,33

There is some evidence that the incidence and/or severity of nausea and vomiting may be reduced with 5-day continuous IV infusions of streptozocin compared with rapid, intermittent IV administration.60 For the prevention of acute emesis, the American Society of Clinical Oncology (ASCO) currently recommends that a 3-drug antiemetic regimen consisting of a type 3 serotonin receptor antagonist, dexamethasone, and aprepitant be given before the administration of chemotherapy with high emetic risk, such as streptozocin.137 (See Aprepitant 56:22.92.) Currently available selective 5-HT₃ receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron, or tropisetron [not commercially available in the US]) are comparably effective in preventing acute nausea and vomiting.137 (See individual monographs for 5-HT₃ receptor antagonists in 56:22.20.)

For the prevention of delayed emesis, ASCO currently recommends a 2-drug regimen of dexamethasone and aprepitant following the administration of chemotherapy associated with high emetic risk, such as streptozocin.137 Aggressive antiemetic therapy for the prevention of acute and delayed emesis during early courses of emetogenic chemotherapy is the best way to prevent anticipatory nausea and vomiting; behavioral therapy also may be useful.137 Although evidence is lacking, many clinicians also find benzodiazepines useful in the management of anticipatory emesis.137

For further discussion of the mechanisms and management of emesis for antineoplastic agents of high emetic risk, see GI Effects: Emetogenic Effects, in Cautions in Cisplatin 10:00.

Diarrhea has occurred occasionally in patients receiving streptozocin.3,4,33 Duodenal ulcer has been reported rarely, but this effect has not been directly attributed to the drug.40

Hematologic Effects

The hematologic toxicity of streptozocin is usually mild to moderate and reversible.3,4,13,33 Mild to moderate myelosuppression, which may be manifested as leukopenia, thrombocytopenia, and anemia (decreased hematocrit and hemoglobin concentration), occurs in about 10-20% of patients receiving the drug;3,4,13,33 severe myelosuppression (substantial leukopenia and thrombocytopenia) leading to sepsis and death has occurred rarely.4,13,33 Myelosuppression may be cumulative and may be more severe in patients previously treated with other antineoplastic agents or radiation therapy.3,13,67,68 Leukocyte and platelet nadirs generally occur 1-2 weeks following treatment with the drug.13 Asymptomatic eosinophilia, which disappeared following discontinuance of streptozocin, has also been reported.13,43,60

Hepatic Effects

Minimal, transient increases in serum concentrations of AST (SGOT), ALT (SGPT), LDH, and/or alkaline phosphatase reportedly occur in about 25% of patients receiving streptozocin.4,13,32,33,37 Increases in serum bilirubin concentration33 and hypoalbuminemia4 have also been reported. Severe and fatal hepatic effects have occurred rarely.61

Metabolic Effects

Although streptozocin produces diabetes in some animals,4,16,18,19,20,28,31 the drug has not been shown to produce a clinically important diabetogenic effect in humans.3,4,8,28,32,33 Mild to moderate, reversible abnormalities of glucose tolerance have been noted in some patients.3,4,32,33,43 Insulin shock with severe hypoglycemia, requiring treatment with IV dextrose, has occurred rarely during streptozocin therapy in patients with insulinomas,4,8,33,61 usually within 24 hours after administration of the drug.33 Glycosuria, without hyperglycemia, has also occurred in some patients receiving streptozocin32,33,40,43 and probably results from the drug's effect on the proximal renal tubule.3,8 (See Cautions: Renal Effects.)

Local Effects

Streptozocin is irritating to tissues and severe tissue lesions and necrosis have been reported following extravasation of the drug.4,62 A burning sensation, extending from the site of injection up the arm, has been reported in some patients, especially following rapid IV injection of the drug.3,33,40 Manifestations of local inflammation (e.g., edema, erythema, burning, tenderness), usually resolving the same day or within a few days, also have been reported following extravasation of streptozocin.4

Other Adverse Effects

Confusion, lethargy, and depression have been reported in a limited number of patients receiving continuous IV infusion of streptozocin for 5 days.4,60 Adverse CNS effects have not been associated with other methods of administering the drug to date.3

Fever has occurred rarely in patients receiving streptozocin.3,134

Precautions and Contraindications

Streptozocin is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity.3,4,8,13,33 The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents and only when the potential benefits of streptozocin therapy are thought to outweigh the possible risks.4 Although hospitalization of the patient is not necessary, adequate diagnostic and supportive equipment and facilities should be readily available for management of therapy and potential complications.4

Renal function should be assessed in all patients prior to initiation of streptozocin therapy, and the manufacturer recommends that renal function be carefully monitored before and after each course of therapy.4 (See Cautions: Renal Effects.) The manufacturer also recommends that serial urinalyses and determinations of creatinine clearance, BUN, and serum creatinine and electrolyte concentrations be obtained prior to and at least weekly during administration of streptozocin therapy and then weekly for 4 weeks after discontinuance of the drug.4 Some clinicians suggest that assessment of renal function prior to each course of streptozocin therapy is sufficient in most patients.122 Serial urinalysis is particularly important for the early detection of proteinuria;4 if proteinuria is detected, quantitation should be performed, using a 24-hour urine collection.4 Mild proteinuria appears to be the earliest sign of streptozocin-induced nephrotoxicity4,13,33,40,59 and may indicate an impending further deterioration of renal function.4 Streptozocin-induced nephrotoxicity may be irreversible and fatalities associated with chronic renal failure may occur if therapy with the drug is continued after nephrotoxicity becomes manifested.3,13,33,39,56,57,58 Dosage reduction or discontinuance of streptozocin therapy is recommended if substantial renal toxicity occurs.4 Streptozocin should be used in patients with impaired renal function only when the drug's potential therapeutic benefits are thought to outweigh the known risk of serious streptozocin-induced nephrotoxicity.4

Patients also should be closely monitored for signs of hematologic and hepatic toxicity.4 Complete blood counts should be performed at least weekly in patients receiving streptozocin.4 The manufacturer recommends that liver function tests also be performed at least weekly;4 however, because severe hepatotoxic effects occur rarely during streptozocin therapy, some clinicians suggest that liver function can be monitored less frequently (e.g., prior to initiating each course of therapy).133 Dosage adjustment or discontinuance of the drug may be required, depending on the severity of toxicity noted.4

Streptozocin should not be used in combination with, or concomitantly with, other potentially nephrotoxic drugs.4

Patients receiving streptozocin should be informed that confusion, lethargy, and depression associated with therapy may increase risk of injury while driving or operating machinery.4

Pediatric Precautions

There are no data available on the use of streptozocin in children.63,132

Geriatric Precautions

Safety and efficacy of streptozocin in geriatric patients have not been specifically studied to date.4 Clinical studies of streptozocin did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.4 While other clinical experience has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.4 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients also should be considered.4

Mutagenicity and Carcinogenicity

Streptozocin is mutagenic in bacteria, plants, and mammalian cells.4 The drug is carcinogenic in mice and has been shown to induce renal, pancreatic, and stomach tumors in rats4,64 and hepatic and other tumors in hamsters.4 Following topical application in rats, benign tumors have developed at the site of application of streptozocin.4,132

Streptozocin is potentially carcinogenic in humans.4,54,55,57,65 The mutagenic and carcinogenic potentials of the drug should be considered when determining whether streptozocin therapy is indicated.4 Atypia of cells lining the alveoli, pancreatic acinar cells, hepatocytes, hepatobiliary ductules, and regenerating proximal renal tubular cells has reportedly developed in patients who received streptozocin for the treatment of pancreatic neoplasms.54,55 Multiple spindle cell tumors in the renal cortex have also been reported in one patient receiving the drug.55 Although there are no reports to date of squamous cell carcinoma in animals or humans receiving streptozocin, renal tubular squamous metaplasia reportedly developed in one patient following treatment with streptozocin for metastatic islet cell carcinoma of the pancreas.57 Acute leukemia also reportedly developed in one patient approximately 1 year after discontinuance of prolonged streptozocin therapy for the treatment of metastatic islet cell carcinoma of the pancreas.65

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in humans, streptozocin has been shown to be teratogenic in rats and has an abortifacient effect in rabbits.4 Streptozocin should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.4

Fertility

The effect of streptozocin on fertility in humans is not known.132 Reproduction studies in male and female rats have shown the drug to impair fertility.4

Lactation

It is not known if streptozocin is distributed into milk.4 Because of the potential for serious adverse reactions to streptozocin in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.4

Nephrotoxic Drugs

Because streptozocin may produce cumulative nephrotoxicity which may be severe or fatal, the drug should not be used in combination with or concomitantly with other potentially nephrotoxic drugs.4

Phenytoin

Limited data suggest that the cytotoxic effects of streptozocin on the beta cells of the pancreas may be decreased by concomitant administration of phenytoin.3,4,66 Although further documentation is needed, it has been recommended that concomitant administration of phenytoin be avoided in patients receiving streptozocin for the treatment of islet cell carcinoma of the pancreas.66

Antineoplastic Agents

Since streptozocin appears to prolong the elimination half-life of doxorubicin, dosage of doxorubicin should be decreased in patients receiving streptozocin concurrently.4,61,67

Concomitant administration of streptozocin and a myelosuppressive nitrosourea antineoplastic agent (e.g., carmustine) may synergistically increase the hematologic toxicity of the drugs;3,68 the mechanism of this apparent synergistic effect is not known.3,68 Other drugs that decrease hematopoiesis may also increase the risk of hematologic toxicity when used concomitantly with streptozocin.132

Pharmacology

Antineoplastic Effect

Streptozocin is an antineoplastic antibiotic.1,2,3,4,5,6,7,8,14,15,16,17 The drug is active against gram-positive and gram-negative bacteria,1,2,7,8 but its cytotoxicity precludes its use as an anti-infective agent.3,15,16,17,18,19,20 The precise mechanism(s) of antineoplastic action of streptozocin is not fully known,4,5 but the drug is generally considered to be an alkylating agent.3,9,10 In vivo, streptozocin undergoes spontaneous decomposition to produce reactive methylcarbonium ions that alkylate DNA and cause interstrand cross-linking.3,9,23,24,25 Unlike other currently available nitrosoureas that possess bifunctional alkylating activity, streptozocin lacks a chloroethyl group and is therefore considered a monofunctional alkylating agent.26 The alkylating activity of streptozocin is weak compared with that of other nitrosoureas.3,12

Streptozocin has been shown to inhibit DNA synthesis in bacterial and mammalian cells.3,4,9,10,12,15,21,22 In bacteria, the drug causes degradation of DNA via a specific interaction with cytosine moieties.4 Although the exact mechanism has not been conclusively determined, streptozocin inhibits precursor incorporation into DNA of mammalian cells.4,15,27 Cell proliferation is inhibited at a substantially lower concentration than that required to inhibit precursor incorporation into DNA or to inhibit several of the enzymes involved in DNA synthesis (e.g., deoxycytidine kinase, thymidine kinase, DNA polymerase, thymidylate synthetase).4,15 Streptozocin blocks progression of cells into mitosis, particularly from phase G₂ to M of the cell cycle;15 however, since the cytotoxic activity of the drug affects cells in all phases of the cell cycle, streptozocin is cycle-phase nonspecific.4,8,15 The drug does not appear to markedly inhibit RNA or protein synthesis.15,17,22

Like other nitrosoureas, streptozocin has the ability to carbamoylate various proteins and nucleic acids (principally lysine) following in vivo decomposition and subsequent formation of an organic isocyanate;12 in vitro, carbamoylation delays the repair of DNA damaged by nitrosourea-induced alkylation.15,26 The in vitro carbamoylating activity of streptozocin is markedly less than that of other currently available nitrosoureas because of the presence of the d-glucopyranose moiety in streptozocin.27 However, because the antineoplastic activity of streptozocin does not correlate with the degree of carbamoylating activity, carbamoylation appears to have little, if any, role in mediating the cytotoxic activity of the drug.3,12 In addition, although it has been suggested that the reduced myelosuppressive activity of streptozocin may result from its decreased carbamoylating activity, experimental evidence indicates that its reduced myelosuppressive activity is independent of its in vitro carbamoylating activity.12

Unlike other nitrosoureas that do not contain a sugar moiety, streptozocin appears to have marked specificity for beta and exocrine cells of the pancreas,8,18,26,28 and studies in animals indicate that the presence of the d-glucopyranose moiety is responsible for the enhanced uptake of streptozocin by pancreatic islet cells.31

Diabetogenic Effect

Streptozocin has a potent diabetogenic effect in several animal species including mice, dogs, and monkeys;4,16,18,19,20,28,31 however, the diabetogenic action exhibits species variability and the drug has not been shown to produce a clinically important diabetogenic effect in humans.3,4,8,28,32 (See Cautions: Metabolic Effects.) Streptozocin-induced diabetes in animals is irreversible and generally resembles type II (noninsulin-dependent) diabetes mellitus in humans;4 however, manifestations of ketoacidosis have been observed in animals receiving the drug.3

The diabetogenic activity of streptozocin in animals appears to be mediated via a reduction in nicotinamide adenine dinucleotide (NAD) concentration within beta cells of the pancreas.4,29,30 The decrease in NAD concentration is associated with histopathologic alteration of beta cells of the pancreatic islets of Langerhans4 and apparently results from decreased uptake of precursors by the beta cells and reduced intracellular synthesis of NAD.30 Streptozocin-induced diabetes in animals can be prevented by concomitant administration of niacinamide (nicotinamide);29,30 concomitant administration of niacinamide does not interfere with the antineoplastic effect of streptozocin.29,30

Pharmacokinetics

Absorption

Streptozocin is not active orally and must be administered IV.4 Preliminary studies showed streptozocin to be poorly absorbed following oral administration.7,126

Following IV infusion over 4 minutes of a single 200- or 400-mg/m² dose in one patient, serum streptozocin concentrations 1 minute after completion of the infusion were 32 or 39 mcg/mL, respectively, and had decreased to 1 or 6 mcg/mL, respectively, 1 hour after completion of the infusion;38 following IV infusion over 40 minutes of a 1.6-g/m² dose in this patient, serum streptozocin concentration 1 minute after completion of the infusion was 41 mcg/mL and had decreased to 12 mcg/mL 1 hour after completion.38

Distribution

Distribution of streptozocin into human body tissues and fluids has not been fully characterized.4 The protein binding of the drug has not been determined.126 In a limited number of adults with normal renal function in one study, the apparent volume of distribution of streptozocin following a single 1.5-g/m² IV dose reportedly averaged 43.8 L.46 Following intraperitoneal or IV administration of streptozocin in animals, the drug and its metabolites are rapidly distributed mainly into the liver, kidneys, intestine, and pancreas, with lower concentrations being distributed into skeletal muscle, spleen, lungs, heart, and thymus.44,124,125 Concentrations of the drug or its metabolites in the liver, kidneys, intestine, and pancreas are consistently higher than those in plasma.44,124,125 Streptozocin does not appear to cross the blood-brain barrier in animals44,126 or humans;45 however, in humans, metabolites of streptozocin readily distribute into CSF.45 In one study in patients receiving¹⁴C- and³H-labeled streptozocin, CSF concentrations of¹⁴C-labeled metabolites (containing the nitrosourea moiety) were equivalent to those in plasma 2 hours after IV administration and were detectable in CSF for at least 24 hours after administration; however,³H-labeled metabolites (containing the d-glucopyranose moiety) could not be detected in CSF during the first 2 hours.45 Although the nitrosourea metabolites of streptozocin appear to distribute into CSF more rapidly than those of other nitrosourea-derivative antineoplastic agents (e.g., carmustine, lomustine), further study is needed to determine if these metabolites have clinically useful antineoplastic activity in the treatment of CNS tumors.45

It is not known whether streptozocin crosses the placenta in humans, but the drug readily crosses the placenta in monkeys.4 It is not known if streptozocin is distributed into milk.4

Elimination

Plasma concentrations of streptozocin decline rapidly in a biphasic manner.8,45,46 Following IV administration of a single 1.5-g/m² dose in a limited number of patients with advanced malignancies and normal renal and hepatic function, the mean plasma half-life of streptozocin in the initial phase (t_½α) has been reported to be about 5 minutes and the mean plasma half-life in the terminal phase (t_½β) has been reported to be about 35-40 minutes.45,46 Following rapid IV injection of a 1.5-g/m² dose, the rate of clearance of streptozocin from plasma reportedly averaged 478 mcg/minute (range: 173-718 mcg/minute) in adults with normal renal and hepatic function.46

Although the exact metabolic fate of streptozocin has not been clearly established, the drug is extensively metabolized, probably in the liver and kidneys.3,4,44,45,46,47 Several metabolites have been detected, but their exact structures have not been elucidated.44,45,46,47,126 Following rapid IV injection of a single 1.5-g/m² dose of ¹⁴C- and ³H-labeled streptozocin in a limited number of patients with advanced malignancies and normal renal and hepatic function, the plasma half-life of radiolabeled streptozocin metabolites in the initial phase (t_½α) was approximately 5 minutes, the half-life in the second phase (t_½β) was approximately 3.5 hours, and the half-life in the terminal phase (t_½γ) was greater than 40 hours.45 The ¹⁴C-labeled metabolites containing the nitrosourea moiety had a substantially longer half-life than the ³H-labeled metabolites containing the d-glucopyranose moiety.45 Unchanged streptozocin could not be detected in plasma in these patients 3 hours following administration of radiolabeled drug, but metabolites could be detected in plasma for up to 24 hours.45

Streptozocin and its metabolites are excreted principally in urine.3,5,8,44,45,46,47 In adults with normal renal and hepatic function, approximately 60-70% of an IV dose of streptozocin is excreted in urine within 24 hours, principally as metabolites;45 approximately 10% of a dose is excreted unchanged.45 Streptozocin and/or its metabolites may also be eliminated in expired air;45,46 in one patient, approximately 5% of a radiolabeled IV dose of the drug was eliminated in expired air within 24 hours.45 Less than 1% of an administered dose of streptozocin is excreted in feces.45,46

Chemistry and Stability

Chemistry

Streptozocin is an antineoplastic antibiotic produced by Streptomyces achromogenes. 1,2,3,4,5,6,7 The commercially available drug is prepared synthetically.3,4,5 Streptozocin is a glucosamine-1-methylnitrosourea compound which is chemically similar to other nitrosourea antineoplastic agents (e.g., carmustine),4,8 but which differs structurally from other nitrosourea derivatives in the absence of a chloroethyl side chain and the presence of a d-glucopyranose moiety.3,8 Addition of the d-glucopyranose moiety to 1-methylnitrosourea is associated with reduced myelosuppressive activity compared with that of methylnitrosourea3,12 and that of chloroethylnitrosourea compounds which do not contain a sugar moiety (e.g., carmustine, lomustine).3,12,13 The presence of the sugar moiety in streptozocin is also associated with reduced alkylating activity compared with that of methylnitrosourea.3,12

Streptozocin occurs as an ivory-colored, crystalline powder4,7 and is very soluble in water and soluble in alcohol.4,7,14 The drug has a pK_a of 1.35.11 Commercially available streptozocin for injection occurs as a sterile, pale yellow, lyophilized powder4 and contains anhydrous citric acid as a buffer;3,4,5 sodium hydroxide is added during manufacture of the powder for injection to adjust pH.4,5 Streptozocin powder for injection is very soluble in water and in 0.9% sodium chloride and soluble in alcohol.3,4 Following reconstitution of the commercially available powder for injection with 5% dextrose or 0.9% sodium chloride injection as recommended (see Dosage and Administration: Reconstitution and Administration), solutions containing 100 mg of streptozocin per mL are pale-gold and have a pH of 3.5-4.5 and a citric acid concentration of 22 mg/mL.4

Stability

Commercially available streptozocin powder for injection should be protected from light and stored at 2-8°C, preferably in the manufacturer's carton.4 When stored as recommended, the powder for injection is stable for at least 3 years after the date of manufacture;121,123 when stored at room temperature, the powder for injection is stable for at least 1 year after the date of manufacture.121,123 Following reconstitution with 5% dextrose or 0.9% sodium chloride injection, streptozocin solutions containing 100 mg/mL are stable for 48 hours when stored at room temperature and for at least 96 hours when stored at 2-8°C.121,123 Reconstituted streptozocin solutions that have been further diluted to a final concentration of 2 mg/mL with 5% dextrose and 0.9% sodium chloride injection are stable for 48 hours at room temperature and for at least 96 hours at 2-8°C.121,123 However, since streptozocin powder for injection does not contain a preservative, the manufacturer cautions that vials of the drug are not intended for multiple-dose withdrawal and recommends that vials of reconstituted solution be discarded within 12 hours after reconstitution.4

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs.

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