Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice.
The antitumor effects of the camptothecin (CPT) derivative CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin , were tested on human tumor xenografts in nude mice. CPT-11 showed antitumor activity higher than that of Adriamycin, 5-fluorouracil, or futraful, with little or no reduction of body weight being observed in the mice. The growth of colon adenocarcinoma Co-4 was significantly inhibited after a single i.v. injection of CPT-11 at 25, 50, or 100 mg/kg. The single i.v. injection was also significantly effective against mammary carcinoma MX-1 and gastric adenocarcinoma St-15. All of the mice bearing MX-1 tumors were cured by the administration of CPT-11 every 4 days for a total of three treatments at a total dose of 200 mg/kg given i.v. or of 400 mg/kg given p.o. Three i.v. or oral treatments were also effective against Co-4, St-15, gastric adenocarcinoma SC-6, and squamous-cell lung carcinoma QG-56. To achieve the same efficacy attained by i.v. injection, however, oral doses 2-4 times higher than the i.v. doses were required. When the total dose was fixed at 100 mg/kg, a triple i.v. injection was most effective, followed by a single i.v. injection and, finally daily p.o. administration for 10 days. Although SN-38 (7-ethyl-10-hydroxycamptothecin), a metabolite of CPT-11, showed much stronger cytotoxic activity in vitro than did CPT-11, its antitumor effects were similar, if not inferior, to those of CPT-11 in vivo at the same dose level. CPT-11 was converted into SN-38 by human tumors, but the sensitivity of these tumors to CPT-11 in vivo was independent of their ability to produce SN-38. These results suggest that CPT-11 may be clinically effective, depending on the schedule of administration, but that its effectiveness is not related to the ability of the tumor to produce SN-38.
Kawato
Y
Y
Exploratory Research Laboratories, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Furuta
T
T
Aonuma
M
M
Yasuoka
M
M
Yokokura
T
T
Matsumoto
K
K
D000230:Adenocarcinoma / Q000188:drug therapy*; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D002277:Carcinoma / Q000188:drug therapy*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007275:Injections, Intravenous; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin