ANTICANCER ACTIVITY AND TOXICITY OF S-1, AN ORAL COMBINATION OF TEGAFUR AND 2 BIOCHEMICAL MODULATORS, COMPARED WITH CONTINUOUS IV INFUSION OF 5-FLUOROURACIL

S-1 is an oral combined form of 1 M tegafur [a prodrug of 5-fluorourac il (5-FU)], 0.4 M 5-chloro-2,4-dihydroxypyridine (a reversible inhibit or of dihydropyrimidine dehydrogenase) and 1 M potassium oxonate (an i nhibitor of orotate phosphoribosyltransferase). S-1 has been shown to exert a potent antitumor effect with low gastrointestinal toxicity in experimental tumor models, We have therefore compared the antitumor ef fect of oral S-1 with that of continuous infusion of 5-FU in rats bear ing transplants of human and murine tumors. Almost complete inhibition of the tumor growth was obtained on 7 day schedules in Yoshida sarcom a-bearing rats by consecutive administration of 30 mg/kg/day of oral S -1 and 40 mg/kg/day infusion of 5-FU. However, a significant differenc e between the incidence of toxicities of S-1 and 5-FU, including body weight loss and diarrhea, was noted. The rats given the 5-FU infusion had marked weight loss and severe diarrhea, while those given oral S-1 had neither. Although about 50% inhibition of the tumor growth was at tained with 15 mg/kg/day of oral S-1 and 30 mg/kg/day infusion of 5-FU in nude rats with xenografted human colon cancer (KM12C), the rate of body weight loss in the 5-FU-treated group was distinctly higher than in the S-1-treated group. The ratio of the 5-fluoronucleotide concent rations in gastrointestinal tissue to that in the tumor was lower in t he S-1-treated rats than in the 5-FU-treated rats. In conclusion, the results suggest that oral S-1 might be more effective in the treatment of cancer patients than continuous infusion of 5-FU, from the standpo int of antitumor potency and toxicity. [(C) 1998 Lippincott Williams & Wilkins.].