To investigate the chromosomal effects of topoisomerase II-interactive drugs on mammalian primary oocytes, female Chinese hamsters were treated with etoposide (VP-16) at various intervals pre- and post-human chorionic gonadotropin (hCG) injections. Chromosome analysis of oocytes at metaphase II showed that treatment with VP-16 at 50 h pre-hCG had no effect, but the treatments between 24 h pre-hCG and 2 h post-hCG often caused structural chromosome berrations. Although treatment at 4 h post-hCG had no effect, subsequent treatments at 6 h and 8 h post-hCG produced a significant increase in structural chromosome aberrations. No effect was found following treatment at 10 h post-hCG. The incidence of aneuploidy following exposure to VP-16 was also dependent on the time of hCG injection. Taking the time course of meiotic progression in primary oocytes following hCG injection and pharmacokinetics of VP-16 into consideration, it is likely that meiotic stages from late dictyate to diakinesis are highly sensitive to VP-16, while stages at dictyate and from metaphase I to telophase I are relatively insensitive to the drug. Moreover, the effect of VP-16 on structural chromosome aberrations and aneuploidy was dose-dependent. Chromosome analysis at metaphase I detected a frequent occurrence of structural chromosome aberrations in treated oocytes. This suggests that structural aberrations may be caused by disruption of cleavable complexes during chromosome condensation. Detection of chromosome bridges during anaphase I/telopahse I may support the hypothesis that induction of aneuploidy by VP-16 is due to failure in decatenation of recombinant homologous chromosomes.
注記
Elsevier Science B.V., Hiroyuki Tateno and Yujiroh Kamiguchi, Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 476(1-2), 2001, 139-148.
