The purpose of this study was to establish a nude rat orthotopic (organ-specific) human
colorectal cancer model as an in vivo secondary screen for general evaluation of new
anticancer agents against
colorectal cancer and to evaluate practically the antitumor activity of 1 M tegafur-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 growth 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 administered p.o. for 14 consecutive days from 7 days after
tumor cell implantation. S-1 showed a higher
tumor growth inhibition than UFT did [S-1, 57% (significantly different from the
tumor weight of the untreated 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 for 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 the administration of an equitoxic dose of both drugs, S-1 gave the higher levels than UFT in various pharmacokinetic parameters as follows: area under the curve 0-24 h of
5-fluorouracil in plasma (3.5-fold), area under the curve 0-24 h of
5-fluorouracil incorporated into
RNA in the
tumor (1.3-fold), and
thymidylate synthase inhibition rate (percentage) in the
tumor (about 20%). Collectively, these findings suggested that this orthotopic human
colorectal tumor model in nude rats is useful 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.