Gemcitabine: preclinical pharmacology and mechanisms of action.

Gemcitabine is a nucleoside analog which exhibits metabolic characteristics that distinguish it from related compounds and may explain its activity in solid tumors. The active nucleotide forms are effectively accumulated to high concentrations in cells. This is due to both efficient phosphorylation and relatively slow elimination. The diphosphate is a potent inhibitor of ribonucleotide reductase, an action that reduces deoxynucleotide pools. Decreased cellular concentrations of deoxycytidine triphosphate permit more rapid phosphorylation of gemcitabine and decreases the metabolic clearance of gemcitabine nucleotides by deoxycytidine monophosphate deaminase. Most importantly, the ratio of the cellular concentrations of gemcitabine triphosphate to deoxycytidine triphosphate increases, favoring analog incorporation into DNA, which is strongly associated with loss of viability.