Gemcitabine

1. Gemcitabine triphosphate (GemPPP) is incorporated by the DNA polymerase into the growing strand of newly synthesized DNA and stops further chain elongation thereby blocking DNA synthesis and cell growth.
2. This inhibitory effect is enhanced by Gemcitabine’s primary activity in inhibiting RRM1/2, which synthesizes the deoxynucleoside diphosphates (dNDP) from their ribonucleoside-diP precursors (e.g., CDP → dCDP). The dNDP are further phosphorylated to the triphosphates that are substrates for the DNA polymerase. With reduced levels of dCTP in the cell, more gemPPP is likely to be incorporated by the DNA polymerase.
3. ENT1 transports gemcitabine into the cell
4. DCK phosphorylates it to the monophosphate which is then further phosphorylated to the di- and tri-phosphates.
5. HuR stabilizes the DCK mRNA resulting in increased levels of DCK protein.

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Green squares, sensitivity markers. Red squares, resistance markers