Regulation of 5‐fluorodeoxyuridine monophosphate‐thymidylate synthase ternary complex levels by autophagy confers resistance to 5‐fluorouracil

Abstract

The properties of 5-fluorouracil (5-FU), including its chemical synthesis and widespread anticancer effects, in fundamental and clinical terms were first published in 1957. 1-3 5-FU is still widely used today, mainly for the treatment of gastrointestinal cancers, such as colorectal cancer (CRC). 4,5 5-FU is converted to the active metabolite 5-fluorodeoxyuridine monophosphate (FdUMP), which is a potent inhibitor of thymidylate synthase (TS). 3,[5][6][7][8] FdUMP forms a ternary complex with TS and 5, 10-methylenetetrahydrofolate (5, 10-CH 2 -THF). 4-9 TS catalyzes the conversion of dUMP to dTMP using the coenzyme 5, 10-CH 2 -THF as a methyl donor. 10 The ternary complex inhibits TS function, depletes intracellular dTTP, dNTP pools, and subsequently inhibits DNA synthesis. [3][4][5]8