PRECLINICAL ANTITUMOR EFFICACY OF S-L - A NEW ORAL FORMULATION OF 5-FLUOROURACIL ON HUMAN TUMOR XENOGRAFTS

S-1 is a new oral formulation of 5-fluorouracil (5-FU) consisted of 1 M tegafur, 0.4 M 5-chloro-2,4- dihydroxypyridine that inhibits a degra dation of 5-FU. and 1M potassium oxonate that regulates the phosphoryl ation of 5-FU in the gastrointestinal tract, and has shown excellent a ntitumor efficacy against various murine tumors in rodents, compared t o the oral tegafur-based antitumor drug, UFT (1M tegafur plus 4M uraci l). which is used clinically in Japan. To assess the possibility of cl inically using S-1, we investigated the antitumor effect of S-1 on var ious human solid tumor xenografts in athymic rats and mice, In the nud e rat system, S-1 was significantly effective against all 12 tumor xen ografts tested when its minimum toxic dose (15 mg/kg) was administered for 14 days. Three tumors, stomach (H-81), colon (KM12C) and breast ( H-31) markedly regressed in response to treatment with S-1 but not wit h UFT. The antitumor potency of S-1 was weak against human tumors xeno grafted into nude mice anti likely similar to that of UFT. The reason of the discrepancy in the efficacy of S-1 between rats and mice was fo und to be that the 5-FU levels in the blood and tumor tissue of rats a lter oral administration of S-1 persisted much longer than in mice, an d this prolonged maintenance of plasma 5-FU levels was significantly r elated to the potent antitumor activity of S-1. In conclusion the resu lts of this study suggested that based on its biological and pharmacok inetic characteristics, oral S-1 should be active against various huma n cancers.