title: Cytotoxic mechanism of XK469: resistance of topoisomerase IIbeta knockout cells and inhibition of topoisomerase I.
abstract: Topoisomerase IIbeta knockout mouse cells (beta-/-) were found to have only slight resistance to m-AMSA, a dual topoisomerase IIalpha-IIbeta poison, as compared to wild-type cells (beta+/+) during 1 h or 3 day exposures to the drug. In contrast, the beta-/- cells were greater than threefold resistant to XK469, a selective topoisomerase IIbeta poison during three day drug exposures (beta+/+ IC(50) = 175 microM, beta-/- IC(50) = 581 microM). Short term (1 h) exposure to XK469 was not cytotoxic to either beta-/- or beta+/+ cells, suggesting that anticancer therapy with XK469 may be more efficacious if systemic levels can be prolonged. During studies on topoisomerase activity in nuclear extracts of the beta+/+ and beta-/- cells, we found evidence that XK469 is a weak topoisomerase I catalytic inhibitor. The high IC(50) for topoisomerase I inhibition (2 mM) suggests that topoisomerase I is not a significant target for XK469 cytotoxicity.
authors.affiliation: Department of Radiology, Ohio State University, Columbus, Ohio, 43210, USA. snapka.1@osu.edu
authors.forename: R M
authors.initials: RM
authors.lastname: Snapka
authors.forename: H
authors.initials: H
authors.lastname: Gao
authors.forename: D R
authors.initials: DR
authors.lastname: Grabowski
authors.forename: D
authors.initials: D
authors.lastname: Brill
authors.forename: K K
authors.initials: KK
authors.lastname: Chan
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: G C
authors.initials: GC
authors.lastname: Li
authors.forename: R
authors.initials: R
authors.lastname: Ganapathi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D018345:Mice, Knockout; D011810:Quinoxalines / Q000494:pharmacology*; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D011810:Quinoxalines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C118180:XK 469; D004247:DNA; D004250:DNA Topoisomerases, Type II