title: A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo.
abstract: 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.
authors.affiliation: Exploratory Research Laboratories I, Daiichi Pharmaceutical Co., Ltd., Tokyo.
authors.forename: I
authors.initials: I
authors.lastname: Mitsui
authors.forename: E
authors.initials: E
authors.lastname: Kumazawa
authors.forename: Y
authors.initials: Y
authors.lastname: Hirota
authors.forename: M
authors.initials: M
authors.lastname: Aonuma
authors.forename: M
authors.initials: M
authors.lastname: Sugimori
authors.forename: S
authors.initials: S
authors.lastname: Ohsuki
authors.forename: K
authors.initials: K
authors.lastname: Uoto
authors.forename: A
authors.initials: A
authors.lastname: Ejima
authors.forename: H
authors.initials: H
authors.lastname: Terasawa
authors.forename: K
authors.initials: K
authors.lastname: Sato
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D012995:Solubility; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D014867:Water; C095887:exatecan; D002166:Camptothecin