Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine
carbamate, which was designed to be sequentially converted to
5-fluorouracil (5-FU) by three
enzymes located in the liver and in
tumors. N4-alkoxycarbonyl-5'-deoxy-5-fluorocytidine derivatives including
capecitabine pass intact through the intestinal tract and are sequentially converted to
5-FU by a cascade of the three
enzymes. The first step is the conversion to
5'-deoxy-5-fluorocytidine (5'-DFCR) by
carboxylesterase located in the liver, then to
5'-deoxy-5-fluorouridine (5'-DFUR) by
cytidine deaminase highly expressed in the liver and various solid
tumors, and finally to
5-FU by
thymidine phosphorylase (dThdPase) preferentially located in
tumor tissues. Among large numbers of the derivatives,
capecitabine was selected based on its susceptibility to hepatic
carboxylesterase, oral bioavailability in monkeys and efficacy in a human
cancer xenograft.
Capecitabine given orally yielded substantially higher concentrations of
5-FU within
tumors than in plasma or normal tissue (muscle). The
tumor 5-FU levels were also much higher than those achieved by intraperitoneal administration of
5-FU at equi-toxic doses. This
tumor selective delivery of
5-FU ensured greater efficacy and a more favourable safety profile than with other fluoropyrimidines. In 24 human
cancer xenograft models studied,
capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than
5-FU, UFT or its intermediate metabolite
5'-DFUR. The susceptibility of the xenografts to
capecitabine correlated with
tumor dThdPase levels. Moreover, the conversion of
5'-DFUR to
5-FU by dThdPase in
tumor was insufficient in a xenograft model refractory to
capecitabine. In addition, the efficacy of
capecitabine was enhanced by dThdPase up-regulators, such as by
taxanes and
cyclophosphamide and by X-ray irradiation. The efficacy of
capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators.
Capecitabine has additional characteristics not found with
5-FU, such as potent antimetastatic and anticachectic actions in mouse
tumor models. With these profiles,
capecitabine may have substantial potential in
cancer treatment.