Effects of quinolone derivatives on eukaryotic topoisomerase II. A novel mechanism for enhancement of enzyme-mediated DNA cleavage

Abstract

The effects of two novel quinolone derivatives, CP-67,804 and CP-115,953 (the 1-ethyl and 1-cyclopropyl derivatives of 6,8-difluoro-7-(4-hydroxyphenyl)-4-quinolone-3-carboxylic acid, respectively), on the enzymatic activities of Drosophila melanogaster topoisomerase II were examined. Both drugs enhanced the enzyme's pre- and post-strand passage DNA cleavage activities. CP-67,804 was nearly as potent an enhancer as etoposide, while CP-115,953 was approximately 2 times more potent than this topoisomerase II-targeted antineoplastic drug. In contrast to etoposide, which stabilizes enzyme-DNA cleavage complexes primarily by inhibiting topoisomerase II-mediated DNA religation, neither quinolone impaired the enzyme's ability to religate cleaved DNA. To further assess the characteristics of these unusual quinolone derivatives, the cytotoxic effects of CP-67,804 and CP-115,953 toward wild-type Chinese hamster ovary cells and VpmR-5 cells (an epipodophyllotoxin-resistant Chinese hamster ovary line) were examined. Both quinolones were cytotoxic to the wild-type cells. CP-115,953 was the more potent agent and displayed a level of cytotoxicity similar to that of etoposide. Finally, the VpmR-5 line showed cross-resistance to CP-67,804 (approximately 3.7-fold) and CP-115,953 (approximately 1.3-fold). Although quinolone cross-resistance was less pronounced than observed for etoposide (approximately 12-fold), it indicates that topoisomerase II is a physiological target for CP-67,804 and CP-115,953 in mammalian cells. These findings strongly suggest that these quinolone derivatives represent a novel class of topoisomerase II-targeted drugs which have potential as antineoplastic agents.