title: Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11.
abstract: It is known that 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), a semisynthesized derivative of camptothecin (CPT), has a potent antitumor activity in vivo, but 7-ethyl-10-hydroxycamptothecin (SN-38), a metabolite of CPT-11, shows much stronger cytotoxicity in vitro than CPT-11. In this study, we demonstrated that the relaxation of SV40 DNA plasmids by type I DNA topoisomerase prepared from P388 murine leukemia cells was inhibited by 50% by SN-38 at approximately 1 microM, although CPT-11 at 1 mM slightly inhibited the relaxation. SN-38 and CPT showed strong, time-dependent inhibitory activity against DNA synthesis of P388 cells. However, CPT-11 weakly inhibited DNA synthesis independently of time with coincident inhibition of the total thymidine uptake by the cells. By alkaline and neutral elution assays, it was demonstrated that SN-38 caused much more frequent DNA single-strand breaks in P388 cells than did CPT-11. The same content of SN-38 and a similar frequency of single-strand breaks were detected in the cells treated with SN-38 at 0.1 microM or with CPT-11 at 100 microM. Therefore, single-strand breaks by CPT-11 seem to be due to SN-38 produced from CPT-11 in cells. These results indicate that CPT-11 itself possesses a marginal antiproliferative effect but that SN-38 plays an essential role in the mechanism of action of CPT-11.
authors.affiliation: Exploratory Research Laboratories 1, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawato
authors.forename: M
authors.initials: M
authors.lastname: Aonuma
authors.forename: Y
authors.initials: Y
authors.lastname: Hirota
authors.forename: H
authors.initials: H
authors.lastname: Kuga
authors.forename: K
authors.initials: K
authors.lastname: Sato
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects*; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects*; D004277:DNA, Single-Stranded / Q000187:drug effects; D000077146:Irinotecan; D007700:Kinetics; D007941:Leukemia P388 / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D014529:Uridine / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004277:DNA, Single-Stranded; D012334:RNA, Neoplasm; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D013936:Thymidine; D014529:Uridine; D002166:Camptothecin