[Antitumor activity of new derivatives of camptothecin].
With the purpose of obtaining more potent and less toxic camptothecin (CPT) analogs, we prepared many derivatives of CPT. Among them, 7-ethyl-CPT (SN 22) and 7-ethyl-10-hydroxy-CPT (SN 38) showed strong antitumor activity with less toxicity. They were, however, insoluble and when they were made soluble, their activity was markedly diminished, as a result of cleavage of the delta-lactone ring. We therefore attempted to make soluble derivatives without breaking the delta-lactone ring and obtained 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-CPT (CPT-11), which showed very strong antitumor activity by i.p., i.v. or p.o. administration against the ascites type of L1210 leukemia, P388 leukemia, sarcoma 180, Meth A fibrosarcoma, B16 melanoma, Ehrlich carcinoma and MH134 hepatoma and the solid type of sarcoma 180, Meth A fibrosarcoma, Lewis lung carcinoma, C3H/HeN mammary carcinoma, Ehrlich carcinoma and MH134 hepatoma. The antileukemic activity of CPT-11 against L1210 was much higher than that of adriamycin. The acute toxicity of CPT-11 was extremely low, particularly in the case of oral administration, the LD50 being 765.3 mg/kg, 22 times greater than that of CPT-Na.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D000077146:Irinotecan; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008813:Mice, Inbred ICR; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D000077146:Irinotecan; C051891:7-ethylcamptothecin; D004317:Doxorubicin; D002166:Camptothecin