Cytotoxic mechanism of XK469: Resistance of topoisomerase II beta knockoutcells and inhibition of topoisomerase I

Topoisomerase II beta knockout mouse cells (beta-/-) were found to have onl y slight resistance to m-AMSA, a dual topoisomerase II alpha -II beta poiso n, as compared to wild-type cells (beta+/+) during 1 h or 3 day exposures t o the drug, In contrast, the beta-/- cells were greater than threefold resi stant to XK469, a selective topoisomerase II beta poison during three day d rug exposures (beta+/+ IC50 = 175 muM, beta-/- IC50 = 581 muM) 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 tha t XK469 is a weak topoisomerase I catalytic inhibitor. The high IC50 for to poisomerase I inhibition (2 mM) suggests that topoisomerase I is not a sign ificant target for XK469 cytotoxicity. (C) 2001 Academic Press.