IN-VITRO INDUCTION OF MICRONUCLEI AND CHROMOSOME-ABERRATIONS BY QUINOLONES - POSSIBLE MECHANISMS

The bacterial gyrase inhibitors, ciprofloxacin and PD 124816, were tes ted for clastogenic and aneugenic activity in V79 Chinese hamster lung cells in vitro. Cells were exposed for 3 h, washed free of drug, and subcultured for assessment of various endpoints. For structural chromo somal aberration (SCA) analysis, cells were incubated for 18 h, and tr eated with Colcemid(R) for 2 h before harvest. For micronucleus (MN) a nalysis, treated cells were incubated with cytochalasin B (CYB) for 16 h. Aneugenicity was assessed by utilizing antikinetochore antibody to detect kinetochore-containing (K+) MN. Both quinolones induced signif icant increases in SCAs and MN, indicating clastogenic activity. With both compounds, however, the MN response was apparent at lower doses, and remained much higher throughout the dose range than the SCA respon se. The induced MN were predominantly K-, indicating that aneugenicity was not playing a major role in their induction. A possible explanati on for the chromosome effects is that cross-reactivity of the gyrase i nhibitors with mammalian topoisomerase II interferes with the separati on of chromatids at anaphase leading to chromosome breaks and MN. Quin olones are known to inhibit resolution of the normally transient topoi somerase II-DNA cleavable complex, which may result in chromosome stic kness. Thus, SCAs detected in metaphase cells may be attributed to qui nolone-induced inhibition of topoisomerase II prior to mitosis while M N arise in binucleated cells as a result of this effect which interfer es with chromatid separation during anaphase.