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Chemotherapy Division [T. K., K. N., N. U., H. B., M. T.] and Pharmacology Division [T. T.], National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuoku, Tokyo 104; Yakult Central Institute, Kunitachi, Tokyo 186 [T. Y., S. S., M. M.]; and Showa University School of Pharmaceutical Sciences, Hatanodai, Shinagawaku, Tokyo 142 [T. M.], Japan
The search for new water-soluble analogues of camptothecin (CPT) with higher activity and less toxicity has led to the development of a novel compound, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), which showed significant antitumor activity against a broad spectrum of experimental tumor models by i.p., i.v., or oral administration. When its activity against L1210 was compared with that of CPT and known derivatives, CPT-11 was most effective, giving the highest maximum increase in life span (ILS) and showing good activity over a wide dose range. The antitumor activity of CPT-11 was shown against tumors not only in the ascites form but also in the solid form. Included among the more susceptible murine tumors are S180, Meth A fibrosarcoma, Lewis lung carcinoma, Ehrlich carcinoma, MH134 hepatoma, mammary carcinoma of C3H/HeN mice, L1210, and P388 leukemia. Probable cures of these tumors were induced frequently by CPT-11. The antitumor activity of CPT-11 against i.p.-implanted L1210 was superior to that of Adriamycin in maximum ILS, the number of cured mice, and the therapeutic ratio. CPT-11 at a dose of 100 mg/kg produced an ILS in excess of 300% with five of six mice surviving tumor free, and effected 100% tumor regression at 200 mg/kg, whereas the optimum dose of Adriamycin, 12.5–25 mg/kg, brought about 114–129% ILS with one of six mice surviving. The acute toxicity of CPT-11 was extremely low, particularly in the case of oral administration. CPT-11 is expected to be clinically useful.
1 Supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture and from the Ministry of Health and Welfare.
2 To whom requests for reprints should be addressed.
Received 3/31/87. Revised 7/21/87. Accepted 8/13/87.
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