title: Novel 7-alkyl methylenedioxy-camptothecin derivatives exhibit increased cytotoxicity and induce persistent cleavable complexes both with purified mammalian topoisomerase I and in human colon carcinoma SW620 cells.
abstract: An alkylating camptothecin (CPT) derivative, 7-chloromethyl-10,11-methylenedioxy-camptothecin (7-CM-MDO-CPT) was recently shown to produce irreversible topoisomerase I (top1) cleavage complexes by binding to the +1 base of the scissile strand of a top1 cleavage site. We demonstrate that 7-CM-EDO-CPT (7-chloromethyl-10,11-ethylenedioxy-camptothecin) also induces irreversible top1-DNA complexes. 7-CM-MDO-CPT, 7-CM-EDO-CPT, and the nonalkylating derivative 7-ethyl-10,11-methylenedioxy-camptothecin (7-E-MDO-CPT) also induced reversible top1 cleavable complexes, which were markedly more stable to salt-induced reversal than those induced by 7-ethyl-10-hyroxy-CPT, the active metabolite of CPT-11. This greater stability of the top1 cleavable complexes was contributed by the 7-alkyl and the 10,11-methylene- (or ethylene-) dioxy substitutions. Studies in SW620 cells showed that 7-E-MDO-CPT, 7-CM-MDO-CPT, and 7-CM-EDO-CPT are more potent inducers of cleavable complexes and more cytotoxic than CPT. The reversal of the cleavable complexes induced by 7-E-MDO-CPT, 7-CM-MDO-CPT, and 7-CM-EDO-CPT was markedly slower after drug removal than that for CPT, which is consistent with the data with purified top1. By contrast to CPT, 7-E-MDO-CPT, 7-CM-MDO-CPT, and 7-CM-EDO-CPT were cytotoxic irrespective of the presence of 10 microM aphidicolin. These results suggest that 7-E-MDO-CPT, 7-CM-MDO-CPT, and 7-CM-EDO-CPT are more potent top1 poisons than CPT and produce long lasting top1 cleavable complexes and greater cytotoxicity than CPT in cells.
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
authors.forename: M
authors.initials: M
authors.lastname: Valenti
authors.forename: W
authors.initials: W
authors.lastname: Nieves-Neira
authors.forename: G
authors.initials: G
authors.lastname: Kohlhagen
authors.forename: K W
authors.initials: KW
authors.lastname: Kohn
authors.forename: M E
authors.initials: ME
authors.lastname: Wall
authors.forename: M C
authors.initials: MC
authors.lastname: Wani
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016590:Aphidicolin / Q000494:pharmacology; D001483:Base Sequence; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000473:pathology; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016590:Aphidicolin; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin