Palo Anil K, Sahoo Diptirani, Choudhury Ramesh C
Department of Zoology, Berhampur University, Berhampur 760 007, Orissa, India.
Mutat Res. 2009 Feb 19;673(1):29-36. doi: 10.1016/j.mrgentox.2008.11.007. Epub 2008 Nov 27.
Cytosine arabinoside (Ara-C), a widely prescribed antineoplastic drug, especially for the treatment of acute myeloid leukaemia, is a pyrimidine analog, in which the ribose sugar of cytidine is replaced by arabinose moiety. Ara-C reportedly competes with dCTP for incorporation into DNA during synthesis and exhibits various cytogenotoxic effects. In the present study, single intraperitoneal treatment of three different doses of Ara-C, 100, 150 and 200 mg/kg b.w. of mice, selected in accordance with its human therapeutic dose, induced statistically significant (p < or = 0.01) and dose dependent increase in the percentages of aberrant metaphases and chromosomal aberrations (CAs) at 24h post-treatment, and micronuclei (MN) in polychromatic erythrocytes (PCEs) at 30 h post-treatment. However, there was no significant change in the mitotic index (MI) at 24h post-treatment, when compared to that of the control mice. In the male germline, all the three doses of Ara-C induced statistically significant (p < or = 0.05 or p < or = 0.01) and dose dependent increase in the percentages of aberrant spermatogonial metaphases and CAs at 24h post-treatment and statistically significant (p < or = 0.01) and dose dependent increase in the percentages of aberrant primary spermatocytes at week 4 post-treatment. However, the induction of abnormal sperm at week 8 post-treatment was decreased, although significantly. The results indicated that Ara-C was clastogenic to both bone marrow and spermatogonial cells of mice, and some of its cytogenotoxic effects were found transmitted through the male germline, at least up to the formation of primary spermatocytes. As the drug is not target specific, the induced cytogenotoxic effects of Ara-C on non-cancerous cells of cancer patients retain possible risk of recurrence of second malignancy among the post-chemotherapeutic cancer survivors. In addition, there is every risk of transmission of some induced genetic alterations to the next generation through the gametes of the cancer survivors pre-treated with this drug. Therefore, Ara-C essentially be made target specific.
阿糖胞苷（Ara-C）是一种广泛应用的抗肿瘤药物，尤其用于治疗急性髓系白血病，它是一种嘧啶类似物，其中胞苷的核糖被阿拉伯糖部分取代。据报道，Ara-C在合成过程中与dCTP竞争掺入DNA，并表现出各种细胞遗传毒性作用。在本研究中，按照人类治疗剂量选择100、150和200mg/kg体重的三种不同剂量的Ara-C对小鼠进行单次腹腔注射，在处理后24小时诱导异常中期相和染色体畸变（CAs）的百分比出现统计学显著（p≤0.01）且呈剂量依赖性增加，在处理后30小时诱导多色红细胞（PCEs）中的微核（MN）出现增加。然而，与对照小鼠相比，处理后24小时有丝分裂指数（MI）没有显著变化。在雄性生殖系中，所有三种剂量的Ara-C在处理后24小时诱导异常精原细胞中期相和CAs的百分比出现统计学显著（p≤0.05或p≤0.01）且呈剂量依赖性增加，在处理后第4周诱导异常初级精母细胞的百分比出现统计学显著（p≤0.01）且呈剂量依赖性增加。然而，处理后第8周异常精子的诱导率虽然显著下降。结果表明，Ara-C对小鼠骨髓和精原细胞具有致断裂作用，并且发现其一些细胞遗传毒性作用通过雄性生殖系传递，至少直至初级精母细胞的形成。由于该药物不是靶向特异性的，Ara-C对癌症患者非癌细胞诱导的细胞遗传毒性作用在化疗后癌症幸存者中保留了二次恶性肿瘤复发的潜在风险。此外，通过用该药物预处理的癌症幸存者的配子将一些诱导的基因改变传递给下一代存在各种风险。因此，Ara-C必须制成靶向特异性的。
