Synthesis and Biological Activity of 2′,2′-Difluorodeoxycytidine (Gemcitabine)

GEMZAR® (gemcitabine·HCl) is a difluorinated analog of deoxy cytidine. It was initially synthesized as a novel anti-viral compound with broad spectrum in vitro activity against both RNA and DNA viruses. However, the compound proved to have a narrow therapeutic index when it was administered daily during the in vivo evaluation of antiviral activity. Using a staggered schedule of administration, GEMZAR is found to be a potent antitumor agent in murine and human xenograft solid tumor models. Studies have shown that gemcitabine diphosphate is a ribonucleotide reductase inhibitor, whereas the triphosphate is a potent and unique terminator of DNA synthesis. In phase I studies a variety of dose schedules were investigated. Based on phase I studies including pharmacokinetic data, phase II studies were initiated. Activity was observed in a variety of solid tumors. The results are specially encouraging for non-small cell lung and pancreatic cancer. GEMZAR is currently undergoing registration review of the Phase III clinical trials for treatment of non-small cell lung and pancreatic cancer.