Fluorouracil

Fluorouracil (5-fluorouracil, 5-fluorouracil, Efudex, Adrucil) is a halogenated pyrimidine analogue that must be activated metabolically. The active metabolite that inhibits DNA synthesis is the deoxyribonucleotide 5-fluoro-2'deoxyuridine-S'-phosphate (FdUMP). 5-Fluorouracil is selectively toxic to proliferating rather than non-proliferating cells and is active in both the G1-and S-phases. The target enzyme inhibited by 5-fluo-rouracilfluorouracil is thymidylate synthetase, which catalyzes the following reaction:

thymidylate synthetase

Uridylate->-thymidylate

methylenetetrahydrofolate—>-dihydrofolate

The carbon-donating cofactor for this reaction is N5,N10 methylenetetrahydrofolate, which is converted to dihydrofolate. The reduced folate cofactor occupies an allosteric site on thymidylate synthetase, which allows for the covalent binding of 5-FdUMP to the active site of the enzyme.

Another action proposed for 5-fluorouracil may involve the incorporation of the nucleotide 5-fluorouri-dine triphosphate (5-FUTP) into RNA. The cytotoxic role of these "fraudulent" 5-fluorouracil-containing RNAs is not well understood.

Several possible mechanisms of resistance to 5-fluo-rouracil have been identified, including increased synthesis of the target enzyme, altered affinity of thymidy-late synthetase for FdUMP, depletion of enzymes (especially uridine kinase) that activate 5-fluorouracil to nucleotides, an increase in the pool of the normal metabolite deoxyuridylic acid (dUMP), and an increase in the rate of catabolism of 5-fluorouracil.

The drug has been administered orally, but absorption by this route is erratic. The plasma half-life of 5-fluorouracil after intravenous injection is 10 to 20 minutes. It readily enters CSF. Less than 20% of the parent compound is excreted into the urine, the rest being largely metabolized in the liver.

5-Fluorouracil is used in several combination regimens in the treatment of breast cancer. It also has palliative activity in gastrointestinal adenocarcinomas, including those originating in the stomach, pancreas, liver, colon, and rectum. Other tumors in which some antitumor effects have been reported include carcinomas of the ovary, cervix, oropharynx, bladder, and prostate. Topical 5-fluorouracil cream has been useful in the treatment of premalignant keratoses of the skin and superficial basal cell carcinomas, but it should not be used in invasive skin cancer.

Floxuridine (FUDR) is the nucleoside of 5-fluo-rouracil that is readily converted into 5-fluorouracil in vivo. It has similar pharmacological effects but is preferred to 5-fluorouracil for hepatic arterial infusions because it is more extensively metabolized in the liver than 5-fluorouracil, with less systemic toxicity.

The toxicities of 5-fluorouracil vary with the schedule and mode of administration. Nausea is usually mild if it occurs at all. Myelosuppression is most severe after intravenous bolus administration, with leukopenia and thrombocytopenia appearing 7 to 14 days after an injection. Daily injection or continuous infusion is most likely to produce oral mucositis, pharyngitis, diarrhea, and alopecia. Skin rashes and nail discoloration have been reported, as have photosensitivity and increased skin pigmentation on sun exposure. Neurological toxic-ity is manifested as acute cerebellar ataxia that may occur within a few days of beginning treatment.

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