Enhancement of the antitumor effects of 5-fluorouracil by folinic acid

Abstract

Although 5-fluorouracil (FUra) is one of the most effective cytotoxic agents in the treatment of various solid tumors (carcinomas of the gastro-intestinal tract, breast, head and neck), remissions occur in only 20-30% of cases and usually are of short duration. Recently, preclinical studies have shown that the antitumor activity of FUra can be potentiated by modulating the metabolism of this drug by using other substances, in particular 5-formyltetrahydrofolate (folinate, LV). Reduced folates (LV and 5-methyltetrahydrofolate) at concentrations greater than or equal to 1 microM can, by raising the intracellular levels of 5,10-methylenetetrahydrofolate, increase and prolong the inhibition of the target enzyme, thymidylate synthase, with formation of a stable ternary complex formed by the enzyme, the folate coenzyme and the fluoropyrimidine inhibitor (5-fluorodeoxyuridylate). After phase II clinical trials reported encouraging results with the combination LV-FUra in the treatment of patients with various solid tumors, randomized controlled studies in patients with colorectal carcinoma have documented an increase in the response rate of the combination compared to treatment with FUra alone. The integration of the LV-FUra combination into multidrug regimens is now under investigation for the treatment of carcinomas of the breast, stomach, and head and neck.