화학공학소재연구정보센터
Biochemical and Biophysical Research Communications, Vol.280, No.4, 1155-1160, 2001
Cytotoxic mechanism of XK469: Resistance of topoisomerase II beta knockout cells and inhibition of topoisomerase I
Topoisomerase II beta knockout mouse cells (beta-/-) were found to have only slight resistance to m-AMSA, a dual topoisomerase II alpha -II beta 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 II beta poison during three day drug 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 that XK469 is a weak topoisomerase I catalytic inhibitor. The high IC50 for topoisomerase I inhibition (2 mM) suggests that topoisomerase I is not a significant target for XK469 cytotoxicity.