Leucovorin enhancement of the effects of the fluoropyrimidines on thymidylate synthase.
Exposure of tumor cells to reduced folates before or with the fluoropyrimidines, 5-fluorouracil or 5-fluoro-2'deoxyuridine, results in a substantial increase in the activity of these drugs. Available evidence suggests that the mechanism of this synergism is a kinetic stabilization of complex formed between thymidylate synthase and fluorodeoxyuridylate that also involves a mole of the cofactor for the thymidylate synthase reaction, 5,10-methylenetetrahydrofolate. This effect results in an extended time of depletion of thymidine nucleotides with a resultant increased level of cell death. The biochemical aspects of this interaction are discussed and related to the therapeutics of this combination.
Morgan
R G
RG
Department of Pediatrics, University of Southern California, Los Angeles.
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004357:Drug Synergism; D005467:Floxuridine / Q000008:administration & dosage; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology*; D009369:Neoplasms / Q000201:enzymology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D005467:Floxuridine; D005468:Fluorodeoxyuridylate; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil