5-Fluorodeoxyuridine-5 monophosphate FUMP

Fig. 1. 5-FU metabolism. Abbreviations.- 5-FU (5-fluorouracil) FdUMP (fluorodeoxyuridine monophosphate) IS (thymidylate synthase) FUMP (fluorouridme monophosphate) DPD (dihydropyrimidine dehydrogenase) FUTP (fluorouridine triphosphate) FU H2 (dihydrofluorouracil) FBAL (fluoro-p-alanine).

FIGURE 51-5 Activation pathways for 5 fluorouracil (5-FU) and 5-floxuridine (FUR). FUDP, floxuridine diphosphate FUMP, floxuridine monophosphate FUTP, floxuridine triphosphate FUdR, fluorodeoxyuridine FdUDP fluorodeoxyuridine diphosphate FdUMP fluorodeoxyuridine monophosphate FdUTP fluorodeoxyuridine triphosphate PRPP 5-phosphoribosyl-1 -pyrophosphate. 

The key steps in Fluorouracil metabolism are shown in Scheme 1. Up to 80 % of 1 administered as injection is transformed to dihydrofluorouracil (DHFU, 13) by dihydropyrimidine dihydrogenase (mostly in liver tissues). However, this metabolite is not involved into antineoplastic activity instead, 13 itself and its further metabolites are responsible for most of the toxic effects of 1. The main mechanism of activation of Fluorouracil is conversion to fluorouridine monophosphate (FUMP, 14), either directly by orotate phosphoribosyltransferase, or via fluorouridine (FUR, 15) through the sequential action of uridine phosphorylase and uridine kinase. 14 is then phosphorylated to give fluorouridine diphosphate (FUDP, 16), which can be either phosphorylated again to the active metabolite fluorouridine triphosphate (ITJTP, 19), or reduced to fluorodeoxyuridine diphosphate (FdUDP, 18) by ribonucleotide reductase. In turn, 18 can either be dephosphorylated or phosphorylated to generate... 

Fig. 3. Metabolism of the fluoropyrimidines dTMP = deoxythymidine monophosphate, dUMP = deoxyuridine monophosphate, FdUDP = fluorodeoxyuridine diphosphate, FdUMP - fluoro-deoxyuridine monophosphate, FdUTP = fluorodeoxyuridine triphosphate, FU-DNA= fluorouracil-deoxyribonucleic acid, FUDP = fluorouracil diphosphate, FUMP = fluorouracil monophosphate, FU-RNA = fluorouracil-ribonucleic acid, FUTP = fluorouracil triphosphate.

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