fig2

Figure 2. Metabolism and action of gemcitabine [difluoro 2’-deoxycytidine (dFdC)]. dFdC is transported into the cell through nucleoside transporters (hNTs), then stepwise phosphorylated by deoxycytidine kinase (DCK), nucleoside monophosphate kinase (NMPK), and nucleoside diphosphate kinase (NDPK), to form active triphosphate metabolite (dFdCTP). This molecule then inhibits DNA and RNA synthesis. Diphosphate metabolite (dFdCDP) inhibits ribonucleotide reductase (RR), an enzyme that catalyses the conversion of ribonucleotide (CDP) to deoxyribonucleotide (dCDP). The majority of dFdC is inactivated mainly by cytidine deaminase (CDA) mediated conversion to difluorodeoxyuridine (dFdU) and then excreted through the ABC transporter. Deamination of dFdCMP to dFdUMP by deoxycytidylate deaminase (dCMP deaminase) and subsequent dephosphorylation forms dFdU; this is another inactivation pathway of dFdC. dFdUMP inhibits thymidylate synthase (TS), resulting in the depletion of the dTMP pool. dFdCTP inhibits dCMP deaminase