Cell cycle-specific with activity in the S-phase.
Inactive in its parent form and requires activation to cytotoxic metabolite forms.
Inhibition of the target enzyme thymidylate synthase (TS) by the 5-FU metabolite, FdUMP.
Incorporation of the 5-FU metabolite FUTP into RNA, resulting in alterations in RNA processing and/or mRNA translation.
Incorporation of the 5-FU metabolite FdUTP into DNA, resulting in inhibition of DNA synthesis and function.
Inhibition of TS leads to accumulation of dUMP, which then gets misincorporated into DNA in the form of dUTP, resulting in inhibition of DNA synthesis and function.
Increased expression of thymidylate synthase (TS).
Decreased levels of reduced folate substrate 5, 10-methylenetetrahydrofolate for TS reaction.
Decreased incorporation of 5-FU into RNA.
Decreased incorporation of 5-FU into DNA.
Increased activity of DNA repair enzymes, uracil glycosylase and dUTPase.
Increased salvage of physiologic nucleosides, including thymidine.
Increased expression of dihydropyrimidine dehydrogenase (DPD).
Decreased expression of mismatch repair enzymes (hMLH1, hMSH2).
Alterations in TS, with decreased binding affinity of enzyme for FdUMP.
After IV administration, 5-FU is widely distributed to tissues, with highest concentration in GI mucosa, bone marrow, and liver. Penetrates into third-space fluid collections such as ascites and pleural effusions. Crosses the blood-brain barrier and distributes into CSF and brain tissue. Binding to plasma proteins has not been well characterized.
Colorectal cancer—Adjuvant setting and advanced disease.
Breast cancer—Adjuvant setting and advanced disease.
GI malignancies, including anal, esophageal, gastric, and pancreatic cancer.
Head and neck cancer.
Hepatoma.
Ovarian cancer.
Topical use in basal cell cancer of skin and actinic keratoses.
Bolus monthly schedule: 425-450 mg/m2 IV on days 1-5 every 28 days.
Bolus weekly schedule: 500-600 mg/m2 IV every week for 6 weeks every 8 weeks.
24-hour infusion: 2,400-2,600 mg/m2 IV every week.
96-hour infusion: 800-1,000 mg/m2/day IV.
120-hour infusion: 1,000 mg/m2/day IV on days 1-5 every 21-28 days.
Protracted continuous infusion: 200-400 mg/m2/day IV.
Leucovorin—Leucovorin enhances the antitumor activity and toxicity of 5-FU. Stabilizes the TS-FdUMP-reduced folate ternary complex, resulting in maximal inhibition of TS.
Methotrexate, trimetrexate—Antifolate analogs increase the formation of 5-FU nucleotide metabolites when given 24 hours before 5-FU.
Thymidine—Rescues against the TS- and DNA-mediated toxic effects of 5-FU.
Vistonuridine (uridine triacetate)—Rescues against the toxic effects of 5-FU.
No dose adjustments are necessary in patients with mild to moderate liver or renal dysfunction. However, patients should be closely monitored, as they may be at increased risk for toxicity.
Contraindicated in patients with bone marrow depression, poor nutritional status, infection, active ischemic heart disease, or history of myocardial infarction within previous 6 months.
Patients should be monitored closely for mucositis and/or diarrhea, as there is increased potential for dehydration, fluid imbalance, and infection. Elderly patients are at especially high risk for GI toxicity.
Patients who experience unexpected, severe grades 3 or 4 myelosuppression, GI toxicity, and/or neurologic toxicity with initiation of therapy may have an underlying deficiency in DPD. Therapy must be discontinued immediately. Further testing to identify the presence of this pharmacogenetic syndrome (autosomal recessive) should be considered.
Vistonuridine, at a dose of 10 g PO every 6 hours for 20 doses, may be used in patients who have been overdosed with 5-FU or in those who experience severe toxicity.
Vitamin B6 (pyridoxine 50 mg PO bid), celecoxib (200 mg PO bid), and nicotine patch may be used to prevent and/or reduce the incidence and severity of hand-foot syndrome.
Use of ice chips in mouth 10-15 minutes pre- and 10-15 minutes post-IV bolus injections of 5-FU may reduce the incidence and severity of mucositis.
Pregnancy category D. Breastfeeding should be avoided.
Myelosuppression. Dose-limiting for the bolus schedules and less frequently observed with infusional therapy. Neutropenia and thrombocytopenia more common than anemia.
Mucositis and/or diarrhea. May be severe and dose-limiting for infusional schedules. Nausea and vomiting are mild and rare.
Hand-foot syndrome (palmar-plantar erythrodysesthesia). Characterized by tingling, numbness, pain, erythema, dryness, rash, swelling, increased pigmentation, nail changes, pruritus of the hands and feet, and/or desquamation. Most often observed with infusional therapy and can be dose-limiting.
Neurologic toxicity manifested by somnolence, confusion, altered mental status, seizures, cerebellar ataxia, and rarely encephalopathy.
Cardiac symptoms of chest pain, ECG changes, and serum enzyme elevation. Rare event but increased risk in patients with prior history of ischemic heart disease.
Blepharitis, tear-duct stenosis, acute and chronic conjunctivitis.
Dry skin, photosensitivity, and pigmentation of the infused vein are common.
Metallic taste in mouth during IV bolus injection.
