The bacterial gyrase inhibitors,
ciprofloxacin and
PD 124816, were tested 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
chromosomal aberration (SCA) analysis, cells were incubated for 18 h, and treated with
Colcemid for 2 h before harvest. For micronucleus (MN) analysis, 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 significant 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 response. The induced MN were predominantly K --, indicating that aneugenicity was not playing a major role in their induction. A possible explanation for the chromosome effects is that cross-reactivity of the gyrase inhibitors with mammalian
topoisomerase II interferes with the separation of chromatids at anaphase leading to
chromosome breaks and MN.
Quinolones are known to inhibit resolution of the normally transient
topoisomerase II-
DNA cleavable complex, which may result in chromosome stickness. Thus, SCAs detected in metaphase cells may be attributed to
quinolone-induced inhibition of
topoisomerase II prior to mitosis while MN arise in binucleated cells as a result of this effect which interferes with chromatid separation during anaphase.