Biochemical rationale for the 5-fluorouracil leucovorin combination and update of clinical experience

Although 5-fluorouracil has been the drug of choice for the treatment of patients with advanced adenocarcinoma of the colon, the reported response rate dose not exceed 20% with a median survival time less than 9 months. Mechanisms of sensitivity to this agent include: 1) inhibition of thymidylate synthase by FdUMP, the active metabolite of 5-fluorouracil; 2) incorporation of FUTP into cellular RNA; and 3) incorporation of FdUTP into cellular DNA. Recent laboratory preclinical results suggest that the major site of action of 5-fluorouracil when combined with 5-formyltetrahydrofolate (folinic acid, leucovorin) is thymidylate synthase resulting in pronounced and prolonged inhibition of DNA synthesis. This effect is primarily due to the stabilization of FdUMP binding to thymidylate synthase by the reduced folate cofactor, N5, N10-methylenetetrahydrofolate. In this paper, the rationale for the modulation of 5-fluorouracil by leucovorin, the clinical pharmacology and the clinical experience of this combination will be reviewed.