Figures & data
Figure 1. Self-potentiation of gemcitabine. hNTs (hENT and hCNT) transports dFdC into the cell. dFdC is intracellularly phosphorylated by dCK to its monophosphate dFdCMP Citation[1] and subsequently into its active dFdCDP and dFdCTP metabolites by ribonucleotide mono- and diphosphate kinases, respectively. DNA polymerase (8) catalyzes the incorporation of dFdCTP into DNA, competing with dCTP. dFdCDP inhibits RNR (5), which inhibits the conversion of dinucleotides to deoxynucleotides, including CDP to dCDP and inhibits synthesis of dCTP. The feedback inhibition of dCK by dCTP is reduced, leading to an increase in the phosphorylation of dFdCTP. This will elevate the intracellular dFdCTP/dCTP ratio and enhance incorporation of dFdCTP into DNA.CDA deaminates dFdC to dFdU (2), which can occur in and outside the cell. dFdCMP can be dephosphorylated to dFdC by 5′-NT (4) and be deaminated to dFdUMP by dCMPD (3). dFdCTP can inhibit dCMPD, which stimulates its own formation. dFdCMP can also inhibit CTP synthetase (6) leading to a reduction in CTP, which has a dual effect, less competition of CTP with dFdCTP for incorporation into RNA (9), while the decrease in CTP will also decrease CDP, leading to an additional decrease in the reduction to dCDP. Finally, the deaminated product dFddUMP can inhibit thymidylate synthase (7), which will decrease dTTP pools but increase dUTP pools, leading to additional DNA damage. dFdUMP can also be formed from intra- and extracellularly produced dFdU, which can be taken up by hNTs, and subsequently phosphorylated to dFdUMP. This phosphorylation may be catalyzed by dCK, since dCK-deficient cells are also resistant to dFdU. However, dFdU is also a substrate for the mitochondrial thymidine kinase 2.
![Figure 1. Self-potentiation of gemcitabine. hNTs (hENT and hCNT) transports dFdC into the cell. dFdC is intracellularly phosphorylated by dCK to its monophosphate dFdCMP Citation[1] and subsequently into its active dFdCDP and dFdCTP metabolites by ribonucleotide mono- and diphosphate kinases, respectively. DNA polymerase (8) catalyzes the incorporation of dFdCTP into DNA, competing with dCTP. dFdCDP inhibits RNR (5), which inhibits the conversion of dinucleotides to deoxynucleotides, including CDP to dCDP and inhibits synthesis of dCTP. The feedback inhibition of dCK by dCTP is reduced, leading to an increase in the phosphorylation of dFdCTP. This will elevate the intracellular dFdCTP/dCTP ratio and enhance incorporation of dFdCTP into DNA.CDA deaminates dFdC to dFdU (2), which can occur in and outside the cell. dFdCMP can be dephosphorylated to dFdC by 5′-NT (4) and be deaminated to dFdUMP by dCMPD (3). dFdCTP can inhibit dCMPD, which stimulates its own formation. dFdCMP can also inhibit CTP synthetase (6) leading to a reduction in CTP, which has a dual effect, less competition of CTP with dFdCTP for incorporation into RNA (9), while the decrease in CTP will also decrease CDP, leading to an additional decrease in the reduction to dCDP. Finally, the deaminated product dFddUMP can inhibit thymidylate synthase (7), which will decrease dTTP pools but increase dUTP pools, leading to additional DNA damage. dFdUMP can also be formed from intra- and extracellularly produced dFdU, which can be taken up by hNTs, and subsequently phosphorylated to dFdUMP. This phosphorylation may be catalyzed by dCK, since dCK-deficient cells are also resistant to dFdU. However, dFdU is also a substrate for the mitochondrial thymidine kinase 2.](/cms/asset/9717180f-6bb1-4135-9536-c7ad7a0df82f/ieid_a_666236_f0001_b.jpg)
Table 1. Outcome in patients with platinum-sensitive ovarian cancer recurrence.