Persistent induction of apoptosis and suppression of mitosis as the basis for curative therapy with S-1, an oral 5-fluorouracil prodrug in a colorectal tumor model

In an effort to improve the therapeutic selectivity of 5-fluorouracil (FUra ) against colorectal cancer, S-1, a combination agent including a prodrug o f FUra with two modulators, was recently developed by Taiho Pharmaceuticals Co. S-1 is a combination of tegafur (FT), 5-chloro-2,4-hydroxypyridine, an d potassium oxonate in the molar ratio of 1.0:0.4:1.0, with the latter two components as inhibitors of dihydropyrimidine dehydrogenase and phosphoribo sylpyrophosphate transferase, respectively. In this study, the therapeutic selectivity and efficacy of S-1 (oral) was compared with FT (oral) and FUra (i.v. infusion) in rats bearing advanced colorectal cancer by using clinic ally relevant schedules. The maximum tolerated doses (MTDs) of S-1, FT, and FUra were 31.5, 200, and 25 mg/kg/d for 7 days and 22.5, 150, and 12.5 mg/ kg/d for 28 days, respectively. The therapeutic index of S-1 was 4- to 5-fo ld higher than that of either FT or FUra, S-1 achieved 100% complete tumor regression (CR) at its MTD in both 7-day and 28-day schedules. Furthermore, the high incidences of stomatitis, alopecia, and diarrhea observed with FU ra and FT, were not observed with S-1, In an attempt to understand the basi s for the observed superior therapeutic selectivity with S-1, we studied ph armacokinetic analysis of FUra, drug-induced apoptosis, suppression of mito sis, and inhibition of thymidylate synthase (TS) after S-1, FUra, or FT adm inistration. The peak plasma FUra concentrations derived from FUra or S-1 ( FT) at comparable MTDs were similar, but the plasma level of FUra was highe r with S-l than with FUra, Induction of high and sustained apoptosis was ac hieved with S-l, Although the initial level of apoptosis induced by FUra wa s comparable to S-l, it was not sustained. The sustained level of apoptosis appears to correlate with tumor growth inhibition Mitotic figures were mor e greatly suppressed with S-l treatment than with FUra, Studies on TS inhib ition indicated that, although both S-l and FUra caused a 4- to 6-fold indu ction of total TS protein, single oral administration of S-l was superior t o 24-h infusion of FUra in suppressing free TS, The data are consistent wit h the observation that the therapeutic efficacy of S-l (100% cure) over FUr a is associated with high and sustained levels of drug-induced apoptosis, g reater suppression of mitosis, and inhibition of free TS in tumor tissues.