ANTITUMOR-ACTIVITY OF 1 M TEGAFUR-0.4 M 5-CHLORO-2,4-DIHYDROXYPYRIDINE-1 M POTASSIUM OXONATE (S-1) AGAINST HUMAN COLON-CARCINOMA ORTHOTOPICALLY IMPLANTED INTO NUDE RATS

The purpose of this study was to establish a nude rat orthotopic (orga n-specific) human colorectal cancer model as an in vivo secondary scre en for general evaluation of new anticancer agents against colorectal cancer and to evaluate practically the antitumor activity of 1 M tegaf ur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1), a new p,o. fluoropyrimidine, in comparison to 1 M tegafur-4 M uracil [( UFT) effective on colorectal tumor in clinical], After implantation of KM12C, a human colorectal cancer cell line, into the subserosal layer of the colon as a single-cell suspension, extensive local tumor growt h and invasion to both the mucosal and the serosal sides were observed in all rats, Metastatic foci were also formed in both lymph nodes and lungs following local tumor growth in all of them, Using this method, an equitoxic dose of S-1 (15 mg/kg/day) and UFT (30 mg/kg/day) was ad ministered p,o, for 14 consecutive days from 7 days after tumor cell i mplantation, S-1 showed a higher tumor growth inhibition than UFT did [S-1, 57% (significantly different from the tumor weight of the untrea ted group at P < 0.05) and UFT, 18% (P > 0.05)], When both drugs were administered to nude rats bearing KM12C injected into the cecal wall f or 28 consecutive days at equitoxic doses, the mean survival in the S- 1 group was 16 days longer than that in the untreated group (P < 0.01) but that in the UFT group was only 8 days longer (P > 0.05), After th e administration of an equitoxic dose of both drugs, S-1 gave the high er levels than UFT in various pharmacokinetic parameters as follows: a rea under the curve 0-24 h of 5-fluorouracil in plasma (3.5-fold), are a under the curve 0-24 h of 5-fluorouracil incorporated into RNA in th e tumor (1.3-fold), and thymidylate synthase inhibition rate (percenta ge) in the tumor (about 20%). Collectively, these findings suggested t hat this orthotopic human colorectal tumor model in nude rats is usefu l to evaluate the clinical therapeutic efficacy of drugs or therapies for colorectal cancer, and that S-1 had a higher therapeutic effect on human colorectal tumor than UFT did.