Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years

Figure 1 5-fluorouracil is converted to three major active metabolites. (1) fluorodeoxyuridine monophosphate (FdUMP); (2) fluorodeoxyuridine triphosphate (FdUTP); and (3) fluorouridine triphosphate (FUTP). The main mechanism of 5-fluorouracil (5-FU) activation is conversion to fluorouridine monophosphate (FUMP) either directly by orotate phosphoribosyl transferase (OPRT), or indirectly via fluorouridine (FUR) through the sequential action of uridine phosphorylase and uridine kinase. FUMP is then phosphorylated to fluorouridine diphosphate (FUDP), which can be either further phosphorylated to the active metabolite fluorouridine triphosphate (FUTP), or converted to fluorodeoxyuridine diphosphate (FdUDP) by ribonucleotide reductase. In turn, FdUDP can either be phosphorylated or dephosphorylated to generate the active metabolites FdUTP and FdUMP, respectively. An alternative activation pathway involves the thymidine phosphorylase catalyzed conversion of 5-FU to 5-fluoro-2’-deoxyuridine (5-FUDR), which is then phosphorylated by thymidine kinase to the thymidylate synthase inhibitor, FdUMP. Dihydropyrimidine dehydrogenase (DPD)-mediated conversion of 5-FU to dihydrofluorouracil (DHFU) is the rate-limiting step of 5-FU catabolism in normal and tumour cells[401].