Gemcitabine mechanisms

Gemcitabine is a deoxycytidine analog that is converted into the active diphosphate and triphosphate nucleotide form. Gemcitabine diphosphate appears to inhibit ribonucleotide reductase and thereby diminish the pool of deoxyribonucleoside triphosphates required for DNA synthesis. Gemcitabine triphosphate can be incorporated into DNA, where it causes chain termination. Gemcitabine is a substrate for deoxycytidine kinase, which phosphorylates the drug to 2’,2’-difluorodeoxycytidine triphosphate. The latter compound inhibits DNA synthesis by being incorporated into sites in the growing strand that ordinarily would contain cytosine. Evidence suggests that DNA repair does not readily occur. Levels of the natural nucleotide, dCTP, are lowered, because gemcitabine competes with the normal nucleoside substrate for deoxycytidine kinase. Gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for the generation of the deoxynucleoside triphosphates required for DNA synthesis.