title: Liposomal encapsulation increases the activity of the topoisomerase I inhibitor topotecan.
abstract: Topotecan, a topoisomerase I poison and water-soluble derivative of camptothecin, has shown promise in treating solid tumors; however, the drug is unstable under physiological conditions and converts to an inactive form within 30 minutes. Encapsulating topotecan in liposomes (LIP-TPT) minimizes inactivation. The efficacy of LIP-TPT was examined with a novel in vivo bioassay called ICE for In vivo Complexes of Enzyme. This bioassay uses antibodies to probe DNA for the presence of topoisomerase I covalent complexes and thereby allows direct quantification of topoisomerase I driven DNA adducts in living cells. We report that LIP-TPT was three- to fourfold more effective than free TPT in stabilizing covalent topoisomerase I-DNA intermediates inside tumor cells. These findings reveal that liposomal wrapping permitted effective delivery of camptothecin derivatives to active enzyme in the nucleus of the cell.
authors.affiliation: Department of Molecular Genetics, Ohio State University, Columbus 43210, USA.
authors.forename: D
authors.initials: D
authors.lastname: Subramanian
authors.forename: M T
authors.initials: MT
authors.lastname: Muller
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001681:Biological Assay; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts; D004265:DNA Helicases / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004587:Electrophoresis, Agar Gel; D006367:HeLa Cells / Q000737:chemistry; D006801:Humans; D008081:Liposomes; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D008081:Liposomes; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D004247:DNA; D004265:DNA Helicases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin