Antitumor Activity of 7-Ethyl-10-(4-(l-piperidino)-l-piperidino)carbonyloxy- camptothecin, a Novel Water-soluble Derivative of Camptothecin, against

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-(l-piperidino)-l-piperidinojcarbony]oxycamptothecin (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 LI 210 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 t 'IT-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 SISO, Meth A fibrosarcoma, Lewis lung carcinoma, Ehrlich carcinoma, MH134 hepatoma, mammary carcinoma of C3H/HeN mice, LI 210, and P388 leukemia. Probable cures of these tumors were induced frequently by CPT-11. The antitumor activity of CPT-11 against i.p.-implanted 1.1210 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. ( 'IT-11 is expected to be clinically useful.