Figure 4.

Gemcitabine mechanism of action. Gemcitabine enters cells via several nucleotide transporters, primarily Human Equilibrative Nucleoside Transporter 1 (hENT1). In the cytoplasm, Gemcitabine is modified extensively by a series of enzymatic reactions. Gemcitabine is phosphorylated by Deoxycytidine Kinase (dCK) to form dFdC monophosphate (dFdCMP), the rate-limiting step in Gemcitabine metabolism. Subsequently, dFdCMP can be deaminated by Deoxycytidylate Deaminase to form dFdUMP, a potent inhibitor of Thymidylate Synthase. Alternatively, dFdCMP can be phosphorylated by Nucleoside Monophosphate Kinase to become dFdC diphosphate (dFdCDP), inhibiting Ribonucleotide Reductase. dFdCDP can be further phosphorylated by Nucleoside Monophosphate Kinase A to form dFdCTP, which inhibits DNA polymerases. As an alternative to these activating modifications, Gemcitabine can be deaminated by Deoxycytidylate Deaminase to form dFdU, an inactive metabolite with no known anti-neoplastic effects.