Modulation of fluorouracil antitumor activity by folic acid in a murine model system.
The biochemical basis for modulation of fluorouracil (FU) activity by leucovorin is elevation of the metabolite methylenetetrahydrofolate, which stabilizes the inhibitory ternary complex formed between thymidylate synthase and the active metabolite of FU, 5-fluorodeoxyuridylate. Folic acid, because it can also potentially be metabolized to methylenetetrahydrofolate, was evaluated for its ability to potentiate FU antitumor activity in a dietary folic acid restricted murine model. The plasma pharmacokinetics and tissue distribution of folic acid and all stable metabolites thereof were determined in the model to establish administration schedules. FU was administered to mice implanted subcutaneously with a mammary adenocarcinoma 4 hr after folic acid administration, when the metabolites, methylenetetrahydrofolate and tetrahydrofolate, were elevated maximally in both plasma and tumor tissue. While FU alone suppressed growth 25%, folic acid in combination with FU increased growth suppression to over 70%. These results indicate that folic acid is a potent modulator of FU activity and could be considered as an alternative to leucovorin in the clinical setting.
Raghunathan
K
K
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425, USA.
Priest
D G
DG
D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004032:Diet; D004195:Disease Models, Animal; D004357:Drug Synergism; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005492:Folic Acid / Q000494:pharmacology*; D005494:Folic Acid Deficiency; D002955:Leucovorin / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism
D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D005492:Folic Acid; D002955:Leucovorin; D005472:Fluorouracil