Improving fluorouracil chemotherapy with novel orally administered fluoropyrimidines.

During the 40 years since the initial synthesis of fluorouracil, there have been many attempts to improve fluoropyrimidine chemotherapy. These have included the utilisation of different schedules of fluorouracil administration, modulation of the metabolism of fluorouracil with other drugs to increase its therapeutic benefit, and the synthesis of prodrugs of fluorouracil that are potentially more effective and less toxic. Of particular interest at present is the clinical evaluation of several new fluoropyrimidine drugs that can be orally administered. These include capecitabine, tegafur/uracil (UFT), eniluracil (GW-776C85; 5-ethynyluracil), S-1, and emitefur (BOF-A2). The pharmacological principles that have influenced the development of these new drugs are initially presented. This is followed by a review of our current knowledge of the clinical pharmacology of each of these new agents, focusing on antitumour activity and toxicity from studies conducted in the US. Studies of capecitabine, tegafur/uracil, and early studies with eniluracil indicate that these drugs have at least similar activity to protracted fluorouracil infusion but with additional quality-of-life and economic benefits.