GENOTOXICITY OF 17 GYRASE AND 4 MAMMALIAN TOPOISOMERASE-II POISONS INPROKARYOTIC AND EUKARYOTIC TEST SYSTEMS

The genotoxic potency of certain classes of topoisomerase II poisons i s correlated with their affinity to the topoisomerase protein rather t han with the presence of 'classical' structural alerts for DNA reactiv ity: bacterial topoisomerase II poisons (specifically named gyrase inh ibitors) are highly genotoxic in prokaryotic systems; mammalian topois omerase II poisons are potent mutagens/clastogens in eukaryotic system s. Studies with bacterial, lower eukaryotic and mammalian genotoxicity tests were performed to draw structure-activity conclusions and addre ss risk-benefit considerations for the class of quinolone gyrase inhib itors. All 17 gyrase inhibitors investigated in this study showed geno toxic activity in Salmonella typhimurium strain TA102 and the SOS test . The genotoxic and the toxic activities increased in a highly paralle l fashion from the parent compounds, nalidixic acid and oxolinic acid, to the new generation fluoroquinolones. Generally, the most potent fl uoroquinolones also show clear-cut positive effects in eukaryotic test systems, although at concentrations 100-1000-fold higher than those e ffective in bacteria and also 100-1000-fold higher than the minimal ge notoxic concentrations of antitumour topoisomerase II inhibitiors (ell ipticine, teniposide, mAMSA) used as reference compounds. However, sub tle structural modifications of the quinolones can strongly diminish t he preferential genotoxicity in the prokaryotic test systems.