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CPT‐11, a semisynthetic derivative of camptothecin, exhibited strong antitumor activity against lymphoma, lung cancer, colorectal cancer, gastric cancer, ovarian cancer, and cervical cancer. CPT‐11 is a pro‐drug that is converted to an active metabolite, SN‐38, in vivo by enzymes such as carboxylesterase. We synthesized a water‐soluble and non‐pro‐drug analog of camptothecin, DX‐8951f. It showed both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The anti‐proliferative activity of DX‐8951f, as indicated by the mean GI50 value, was about 6 and 28 times greater than that of SN‐38 or SK&F 10486‐A (Topotecan), respectively. These three derivatives of camptothecin showed similar patterns of differential response among 32 cell lines, that is, their spectra of in vitro cytotoxicity were almost the same. The antitumor activity of three doses of DX‐8951f administered i.v. at 4‐day intervals against human gastric adenocarcinoma SC‐6 xenografts was greater than that of CPT‐11 or SK&F 10486‐A. Moreover, it overcame P‐glycoprotein‐mediated multi‐drug resistance. These data suggest that DX‐8951f has a high antitumor activity and is a potential therapeutic agent.

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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.

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