FdUMP

FdUMP stands for 5-fluoro-2'-deoxyuridine-5'-monophosphate, an active intracellular metabolite of the anticancer drug 5-fluorouracil (5-FU). It is a nucleotide analog that acts as a potent inhibitor of thymidylate synthase (TS), the enzyme responsible for converting dUMP to dTMP in the synthesis of DNA.

Mechanism of action: FdUMP forms a stable ternary complex with thymidylate synthase and the folate cofactor 5,10-methylene-tetrahydrofolate. This complex blocks the production of deoxythymidine monophosphate (dTMP), leading to depletion of dTMP and disruption of DNA synthesis. The cytotoxic effect is especially pronounced in rapidly dividing cells, such as cancer cells, which rely heavily on DNA replication.

Formation and clinical relevance: FdUMP is generated intracellularly from 5-FU through a series of phosphorylation and reduction steps; thus it is the principal mediator of 5-FU’s antitumor activity. Leucovorin (folinic acid) is often coadministered to increase intracellular levels of 5,10-methylene-THF, which stabilizes the TS-FdUMP complex and enhances the inhibition of TS, thereby boosting therapeutic efficacy and toxicity.

Clinical use: 5-FU–based regimens, frequently with leucovorin, are used to treat colorectal and other solid tumors. FdUMP itself is not typically administered directly as a standalone drug; rather, it is a critical intracellular mediator of the pharmacologic action of 5-FU.