Palo Anil K, Sahu Prajyoti, Choudhury Ramesh C
Department of Zoology, Berhampur University, 760 007, Orissa, India.
J Appl Toxicol. 2005 Mar-Apr;25(2):94-100. doi: 10.1002/jat.1040.
As cancer chemotherapeutic agents are cytogenotoxic but not target-specific during systemic treatment, they affect all the encountered cells including the non-cancerous ones and consequently lead to the recurrence of second malignancy in post-chemotherapeutic cancer survivors. The effects would be persistent if the stem cells were affected. These drugs also may affect germline cells during therapeutic treatments. There is every chance that the effects are transmitted through the germline cells to the gametes and to the next generation if the gonadal mother cells are affected. Such transmission of effects from the post-chemotherapeutic childhood cancer survivors is of serious concern but very little attention has been given so far to such studies. Etoposide (VP-16)--a semi-synthetic epipodophyllotoxin derivative, a DNA non-intercalating agent and a topoisomerase II inhibitor--is prescribed frequently for the treatment of various types of cancers. It is a potent clastogen inducing chromosomal damage both in vitro and in vivo. Its clastogenic effect is indirect through inhibition of the catalytic activity of topoisomerase II enzymes, which maintain the topology of DNA during replication, recombination, transcription, etc. by forming a 'cleavable complex' and facilitate the cleaving and re-ligation of the cleaved DNA to relieve the torsional stress during such events. Transient stabilization of the cleavable complex by etoposide leads to illegitimate ligation of the cleaved DNA. Consequently, single- and double-strand breaks occur. In the present study, the clastogenic potential of three different doses of etoposide (10, 15 and 20 mg kg(-1)) in the male germline of mice was assessed from the dividing spermatogonia after a single exposure for one cell cycle duration at 24 h post-treatment. Transmission of such effects was assessed from the frequency of aberrant primary spermatocytes at week 4 post-treatment and of abnormal sperm at week 8 post-treatment. All three doses of etoposide were found to be clastogenic to the dividing spermatogonia of mice, and mostly chromatid breaks were induced. The effects also were transmitted through the male germline of mice, which was evident from the prevalence of statistically significant increased percentages of aberrant primary spermatocytes at week 4 posttreatment and the higher percentages of abnormal sperm at week 8 post-treatment. Thus, there is every chance that the cytogenotoxic effects of etoposide are transmitted to the next generation through the male germline of post-chemotherapeutic cancer survivors, therefore it is essential to make etoposide target-specific or modulate its effects.
由于癌症化疗药物在全身治疗过程中具有细胞遗传毒性但无靶向特异性，它们会影响所有接触到的细胞，包括非癌细胞，从而导致化疗后癌症幸存者出现第二原发性恶性肿瘤复发。如果干细胞受到影响，这些影响将持续存在。这些药物在治疗过程中也可能影响生殖细胞。如果性腺母细胞受到影响，那么这些影响极有可能通过生殖细胞传递给配子和下一代。化疗后儿童癌症幸存者的这种影响传递令人严重担忧，但迄今为止此类研究很少受到关注。依托泊苷（VP - 16）——一种半合成的表鬼臼毒素衍生物、一种DNA非嵌入剂和一种拓扑异构酶II抑制剂——经常被用于治疗各种类型的癌症。它是一种强效的断裂剂，在体外和体内均可诱导染色体损伤。其断裂作用是间接的，通过抑制拓扑异构酶II酶的催化活性，该酶在复制、重组、转录等过程中通过形成“可裂解复合物”来维持DNA的拓扑结构，并促进裂解后的DNA的切割和重新连接以缓解此类事件中的扭转应力。依托泊苷使可裂解复合物短暂稳定会导致裂解后的DNA发生异常连接。因此，会出现单链和双链断裂。在本研究中，在处理后24小时对小鼠雄性生殖细胞单次暴露一个细胞周期持续时间后，从分裂的精原细胞评估三种不同剂量（10、15和20 mg kg⁻¹）的依托泊苷在小鼠雄性生殖细胞中的断裂潜力。在处理后第4周从异常初级精母细胞的频率以及处理后第8周从异常精子的频率评估这种影响的传递。发现所有三种剂量的依托泊苷对小鼠分裂的精原细胞均具有断裂作用，并且主要诱导染色单体断裂。这些影响也通过小鼠雄性生殖细胞传递，这从处理后第4周异常初级精母细胞百分比的统计学显著增加以及处理后第8周异常精子百分比的升高可以明显看出。因此，依托泊苷的细胞遗传毒性影响极有可能通过化疗后癌症幸存者的雄性生殖细胞传递给下一代，所以使依托泊苷具有靶向特异性或调节其作用至关重要。
