MICRONUCLEUS INDUCTION BY CAMPTOTHECIN AND AMSACRINE IN BONE-MARROW OF MALE AND FEMALE CD-1 MICE

Camptothecin (CPT) and amsacrine (m-AMSA), specific inhibitors of topoisomerase I and II, were tested for micronucleus inducing potential in bone marrow of male and female CD-1 mice. CPT was given as intraperitoneal (i.p.) injections at 0 h in doses of 1, 2 and 4 mg/kg, and at 0 + 24 h in doses of 0.5, 1 and 2 mg/kg. Bone marrow samples were taken 30 and 48 h post 0 h dosing in both the single and split dose studies. The same i.p. regimens were used to evaluate m-AMSA at doses of 1.5, 3 and 6 in the single, and 0.75, 1.5 and 3 mg/kg in the split dose study. Both compounds were tested in two consecutive experiments using identical study designs to confirm findings or trends. The CPT experiment showed that more micronuclei (MN) were induced at 30 h than at 48 h following both 0 h and 0 + 24 h treatment, and that dose interaction occurred as two divided doses of CPT induced as much or more micronuclei than the same total single dose in both sexes. No overall sex differences were found in the 0 h dose study at 30 or 48 h. However, females had significantly more MN than males at 30 h following 0 + 24 h dosing, indicating an inducible female G2 mitotic effect in proliferating bone marrow blast cells. For m-AMSA, more MN were again induced at 30 h following both 0 h and 0 + 24 h exposure although dose interaction was dependent on compound concentration, as two equally divided 3 mg/kg doses induced more MN than a single 6 mg/kg dose, while at lower doses of m-AMSA the opposite held true. Across all doses, however, the single and split regimens proved roughly equipotent in terms of mediating micronucleus effects. No consistent sex differences were induced by m-AMSA although overall more MN were detected in female mice in both the 0 h and 0 + 24 h studies.