S-1 review from preclinical pharmacology

S-1, developed by the scientific theory of both potentiating the antitumor efficacy of 5-fluorouracil (5-FU) and reducing the gastrointestinal (GI) toxicity induced by 5-FU, is a new oral formulation consisting of 1 M tegafur, 0.4 M gimeracil, and 1 M potassium oteracil. By combining gimeracil, a potent inhibitor of 5-FU degradation, and potassium oteracil, which protects against 5-FU-induced GI toxicity to tegafur, S-1, as a dihydropyrimidine dehydrogenase (DPD)-inhibitory fluoropyrimidine (DIF), showed higher antitumor activity, with low intestinal toxicity, compared to continuous infusion of 5-FU (the most effective dosing schedule for 5-FU) and compared to clinically useful oral fluoropyrimidines in various murine and human tumors. In regard to combinations of S-1 with other anticancer drugs, S-1 plus CDDP markedly prolonged survival time in mice suffering gastrointestinal (GI) tumors compared to S-1 in combination with mitomycin-C and/or adriamycin. Furthermore, in combination with irinotecan and taxanes (docetaxel), S-1 exercised synergistic antitumor efficacy not only against 5-FU-sensitive GI cancers with low expression levels of thymidylate synthase (TS) but also against 5-FU-resistant GI tumors with originally elevated levels of TS expression. As one of the reasonable mechanisms of anticancer synergism exerted by an S-1 combination, irinotecan and docetaxel were found to downregulate the expression of TS in gastric cancers. Throughout our pharmacological studies of S-1, alone and in combination with other anticancer drugs, we found that S-1 could be expected to contribute greatly to the treatment of patients with gastric cancer.