Gemcitabine

Mechanism of action 

Gemcitabine is a potent and specific deoxycytidine analog. After uptake into malignant cells, gemcitabine is phosphorylated by deoxycytidine kinase to form gemcitabine monophosphate, which is then converted to the active compounds, gemcitabine diphosphate  and gemcitabine triphosphate . These active metabolites are nucleosides that mediate antitumour effects. gemcitabine triphosphate  competes with deoxycytidine triphosphate  for incorporation into DNA, thereby competitively inhibiting DNA chain elongation. The non-terminal position of gemcitabine triphosphate  in the DNA chain prevents detection of gemcitabine triphosphate in the chain and repair by proof-reading 3′5′-exonuclease: this process is referred to as "masked DNA chain termination." Incorporation of gemcitabine triphosphate into the DNA chain ultimately leads to chain termination, DNA fragmentation, and apoptotic cell death of malignant cells.

Gemcitabine has self-potentiating pharmacological actions that can increase the probability of successful incorporation of gemcitabine triphosphate into the DNA chain: gemcitabine diphosphate   inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxycytidine triphosphate  for DNA synthesis. Since gemcitabine diphosphate   reduces the levels of deoxycytidine triphosphate, there is less competition for gemcitabine triphosphate for incorporation into DNA. Gemcitabine can also reduce metabolism and elimination of active metabolites from the target ce1l, prolonging high intracellular concentrations of the active metabolites. Such self-potentiating effects are not present with cytarabine