Several
quinolones and antitumor compounds were tested as inhibitors of purified calf thymus
topoisomerase II in unknotting, catenation, radiolabeled DNA cleavage, and quantitative nonradiolabeled cleavage assays. The
antitumor agents VP-16 (demethylepipodophyllotoxin ethylio-beta-D-
glucoside) and
ellipticine demonstrated
drug-enhanced
topoisomerase II DNA cleavage (the concentration of
drug that induced 50% of the maximal DNA cleavage in the test system [CC50]) at levels of less than or equal to 5 micrograms/ml.
Nalidixic acid,
norfloxacin, and
oxolinic acid did not induce significant
topoisomerase II DNA cleavage, whereas
ciprofloxacin did induce some cleavage above background levels.
CP-67,015, a new 6,8-difluoro-7-pyridyl
4-quinolone which possesses potent antibacterial activity, inhibited
bacterial DNA gyrase at 0.125 micrograms/ml in a nonradioactive DNA cleavage assay. Unlike other
quinolones characterized to date,
CP-67,015 was shown to strongly enhance
topoisomerase II-induced radiolabeled DNA cleavage with a CC50 of 33 micrograms/ml and demonstrated cleavage in a nonradiolabeled DNA cleavage assay with a CC50 of 73 micrograms/ml. The
topoisomerase II-mediated cleavage of
DNA by
CP-67,015 is consistent with its reported clastogenic effect on
DNA in cell culture and its positive mutagenic response in mouse
lymphoma cells. In vitro
topoisomerase II catalytic and cleavage assays are useful for gaining preliminary information concerning the possible interaction(s) of some
quinolones with eucaryotic
topoisomerase II which may relate directly to their safety (mutagenicity, clastogenicity, or both) in human and veterinary medicinal usage.