Department of Pharmacology, College of Pharmacy, King Saud University, PO Box 11451 Riyadh, Saudi Arabia.
Mutagenesis. 2012 Jan;27(1):31-9. doi: 10.1093/mutage/ger051. Epub 2011 Aug 6.
The ability of topoisomerase II inhibitor, teniposide, to induce aneuploidy and meiotic delay in somatic and germinal cells of male mice was investigated by fluorescence in situ hybridisation (FISH) assay using labelled DNA probes and 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, respectively. Colchicine and mitomycin C were used as a positive control aneugen and clastogen, respectively, and these compounds produced the expected responses. Using FISH assay with centromeric and telomeric DNA probes for erythrocyte, micronuclei (MN) showed that teniposide is not only clastogenic but also aneugenic in somatic cells in vivo. The assay also showed that chromosomes can be enclosed in the MN before and after centromere separation. By using the BrdU incorporation assay, it could be shown that the meiotic delay caused by teniposide in germ cells was ∼48 h. Disomic and diploid sperms were shown in epididymal sperm hybridised with DNA probes specific for chromosomes 8, X and Y after teniposide treatment. The prevalence of autodiploid (XX88 and YY88) sperm and disomic XX8 or YY8 sperm indicates that the second meiotic division was more sensitive to teniposide than the first meiotic division. The results also suggest that earlier prophase stages contribute relatively less to teniposide-induced aneuploidy. Both the clastogenic and the aneugenic potential of teniposide can give rise to the development of secondary tumours and abnormal reproductive outcomes in cured cancer patients and medical personnel exposing to drug regimens that include teniposide. Thus, genetic counselling of these patients should take place before the start of chemotherapy and should take the present results into consideration.
采用荧光原位杂交（FISH）技术和 5-溴脱氧尿苷（BrdU）掺入试验分别以标记 DNA 探针和 BrdU 掺入试验，研究拓扑异构酶 II 抑制剂依托泊苷（teniposide）在雄性小鼠体细胞核和生殖细胞中诱导非整倍体和减数分裂延迟的能力。秋水仙碱和丝裂霉素 C 分别作为阳性致整倍体和致断裂剂，它们产生了预期的反应。用 FISH 技术以着丝粒和端粒 DNA 探针检测红细胞，微核（MN）表明依托泊苷不仅具有断裂作用，而且在体内体细胞中也具有致整倍体作用。该试验还表明，染色体可以在着丝粒分离前后包含在 MN 中。通过 BrdU 掺入试验，可以显示依托泊苷在生殖细胞中引起的减数分裂延迟约为 48 小时。在经过依托泊苷处理后，与染色体 8、X 和 Y 特异性 DNA 探针杂交的附睾精子中显示出二倍体和二倍体精子。自二倍体（XX88 和 YY88）精子和二倍体 XX8 或 YY8 精子的出现表明，第二次减数分裂比第一次减数分裂对依托泊苷更敏感。结果还表明，早期早前期相对较少参与依托泊苷诱导的非整倍体形成。依托泊苷的断裂和致整倍体潜能可导致接受包括依托泊苷在内的药物治疗方案的治愈癌症患者和医务人员发展继发性肿瘤和异常生殖结局。因此，在开始化疗之前，应对这些患者进行遗传咨询，并应考虑到目前的结果。
