Effects of a low dose leucovorin with 5-fluorouracil derivative on colorectal tumors induced with 1,2-dimethylhydrazine in rats

Thymidylate synthase, which is a key enzyme involved in the de novo pathway for pyrimidine nucleotide synthesis, is inhibited by 5-fluorodeoxyuridine monophosphate, forming an inactive ternary complex with intracellular folat e. We investigated the effect of a 5-fluorouracil derivative (UFT) with or without low dose leucovorin on the number of 5-fluorodeoxyuridine monophosp hate binding sites, thymidine kinase activity and intracellular folate conc entration in 1,2-dimethylhydrazine-induced rat colorectal carcinomas. A 10 - day administration of UFT with or without leucovorin enhanced the thymidi ne kinase activity and the number of 5-fluorodeoxyuridine monophosphate bin ding sites, with an increase of thymidylate synthase mRNA expression. Thymi dylate synthase inhibition was slightly increased as the intracellular fola te concentration increased. These results indicate that thymidylate synthas e inhibition increases when the intracellular folate is exogenously supplem ented and maintained at an adequate concentration.