Fluorouracil metabolic and resistance pathways (5-FU pathway)

The fluorouracil metabolic and resistance pathways encompass the biochemical network responsible for the activation, catabolism, and cellular response to the antimetabolite 5-fluorouracil (5-FU) [3, 13]. 5-FU is a pyrimidine analog that acts as a prodrug, requiring intracellular conversion by enzymes such as orotate phosphoribosyltransferase (UMPS) and thymidine phosphorylase (TP) into active metabolites, primarily fluorodeoxyuridine monophosphate (FdUMP) [4, 18]. FdUMP inhibits thymidylate synthase (TYMS), the rate-limiting enzyme in dTMP synthesis, thereby halting DNA replication and repair [12, 13]. Resistance to 5-FU is a major clinical challenge, often driven by the overexpression of TYMS, decreased activity of activating enzymes, or increased degradation by dihydropyrimidine dehydrogenase (DPD) [3, 9, 13]. These pathways are critical in the treatment of colorectal, breast, and aerodigestive cancers, where patient outcomes are heavily influenced by genetic variations in these metabolic components [13, 15]. Understanding these pathways allows for the identification of biomarkers like DPYD genotype to prevent severe toxicity [15]. Additionally, the pathway involves the incorporation of fluorinated nucleotides into RNA and DNA, further contributing to its cytotoxic profile [3, 12]. Therapeutic strategies often involve modulating these pathways, such as using leucovorin to stabilize the TYMS-FdUMP complex [13, 17].

Other names

5-FU metabolic pathwayFluoropyrimidine metabolism5-Fluorouracil resistance mechanismsPyrimidine metabolic pathway

5-FU is converted to active metabolites (FdUMP, FUTP, FdUTP) that exert cytotoxicity through three main mechanisms: (1) FdUMP binds to thymidylate synthase (TYMS) in a ternary complex with 5,10-methylenetetrahydrofolate, inhibiting dTMP synthesis and causing "thymineless" cell death; (2) FUTP is incorporated into RNA, disrupting processing and translation; and (3) FdUTP is incorporated into DNA, leading to strand breaks and apoptosis [3, 12, 13, 18].