Selective Toxicity: The Activities of 4-Quinolones against Eukaryotic DNA Topoisomerases

Abstract

A number of new 4-quinolone antibacterials have been recently introduced for clinical use that have greater potency than the older analogs nalidixic acid and oxolinic acid (Andriole 1988; Bergan 1988). Like nalidixic acid, 4-quinolones are believed to inhibit bacterial growth by binding to the A subunit of DNA gyrase, a type II topoisomerase (Geliert et al. 1977). Since a homologous enzyme exists in the nucleus of eukaryotic cells, studies have been performed to examine the effects of 4-quinolones on this topoisomerase. Quinolones such as ciprofloxacin, norfloxacin, fleroxacin, and ofloxacin have, in general, been found to be only weak inhibitors of the eukaryotic enzyme in in vitro assays that measure the catalytic relaxation, unknotting, and catenation activities of the enzyme (Hussy et al. 1986; Riou et al. 1986). An alternative approach to assessing the effects of test agents on topoisomerases, involves measuring the extent of drug-enhanced DNA cleavage obtained in vitro in the presence of the enzyme. While DNA cleavage assays have been used to measure the effects of anti-tumour agents such as VP-16, VM-26, and ellipticine on eukaryotic topoisomerase II, 4-quinolones have not been extensively examined by this method. We have used four different topoisomerase II assay methods, including a non-radiolabeled DNA cleavage assay, for measuring the effects of some quinolones on purified calf thymus topoisomerase II. An experimental quinolone, CP-67,015, was found to elicit significant levels of DNA cleavage products in the presence of enzyme.KeywordsNalidixic AcidOxolinic AcidCleavage AssayQuinolone AntibacterialThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.