What is the mechanism by which Leucovorin increases the cytotoxicity of 5-fluorouracil (5-FU)?
Thymidylate synthase is an enzyme necessary for DNA synthesis that is inhibited by a 5-FU metabolite, fluorodeoxyuridine monophosphate (5-FdUMP). A leucovorin metabolite, (6R)-5,10-methylene-THF, stabilizes the complex of 5-FdUMP and thymidylate synthase, leading to thymidylate depletion, thus serving as an inhibitor of thymidylate synthase, increasing the toxicity of 5-FU.
Danenberg PV, et al. Folates as adjuvants to anticancer agents: chemical rationale and mechanism of action. Crit Rev Oncol Hematol. 2016;106:118–131. [PubMed: 27637357], Machover D, et al. Treatment of advanced colorectal and gastric adenocarcinomas with 5-FU combined with high-dose folinic acid: a pilot study. Cancer Treat Rep. 1982;66:1803–1807. [PubMed: 6982099]
Contributed by: Oyeyimika Oyekanmi, DO : The Medical Toxicology Fellowship, Virginia Commonwealth University, Richmond, VA