Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice

Abstract

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.

CPT-11 converting carboxylesterase and topoisomerase I activities in tumour and normal colon and liver tissues

“…The conversion of CPT-11 into SN-38 has been studied in a wide variety of tissues, cell lines and purified enzyme preparations in vitro (Jansen et al, 1997;Kawato et al, 1991;Ogasawara et al, 1995;Rivory et al, 1996;Satoh et al, 1994;Slatter et al, 1997;Tsuji et al, 1991;van Ark-Otte et al, 1998). The sensitivity of proliferating tissues or cell lines to cytotoxic effects of CPT-11 may be related to their carboxylesterase levels (Kawato et al, 1991;Ogasawara et al, 1995). A decreased conversion of CPT-11 to SN-38 has been reported in vitro in resistant ovarian and non-small-cell lung cancer cell lines (Niimi et al, 1992;Ogasawara et al, 1995).…”

A novel mouse model of rectal cancer established by orthotopic implantation of colon cancer cells

“…25,26) CPT derivatives such as irinotecan (CPT-11), 9-aminocamptothecin, 9-nitrocamptothecin and 9-nitro-20(S)-camptothecin (Rubitecan) have been developed, and the antitumor effects of these compounds were evaluated in recent preclinical and clinical studies. 13,14,[27][28][29] The effects of CPT-11 by the oral route have only been examined in a phase I study, in which oral administration of a CPT-11 preparation for intravenous use resulted in favorable pharmacokinetics and antitumor effects. 30) In a preclinicaI study using a mouse model with heterotopic tumor implantation, oral administration of CPT-11 showed marked antitumor effects.…”

“…Mice (25-26 mice/experiment) were randomly divided into two groups 2 days after intraluminal implantation of colon 26 cells. Administration of CPT-11 was performed according to the method described elsewhere 13,14) with slight modifications. Briefly, CPT-11 dissolved in saline was administered per os (p.o.)…”

DE‐310, a novel macromolecular carrier system for the camptothecin analog DX‐8951f: Potent antitumor activities in various murine tumor models

“…For example, CPT-11 was found to exhibit higher antitumor activity with less toxicity than camptothecin (CPT) and showed promising activity in clinical evaluation. [1][2][3][4][5][6][7][8] However, it causes side effects such as severe watery diarrhea and there are marked inter-patient variations in both its effects and toxicity. 7,9,10) To obtain a more effective analogue with a lower toxicity, DX-8951f was designed.…”

“…Fig. 1A), a CM-Dex-PA adduct of the antineoplastic agent, 2,3,9,12,4′:6,7]The carboxymethylated polyalcohol is covalently bonded to the DX-8951 moiety via a tetrapeptidyl spacer (Gly-Gly-Phe-Gly, GGFG). DX-8951f (Fig.…”