Induction of genotoxic and cytotoxic damage by aclarubicin, a dual topoisomerase inhibitor
Induction of genotoxic and cytotoxic damage by aclarubicin, a dual topoisomerase inhibitor
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DOI：
10.1016/j.mrgentox.2005.01.012
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发表时间：
2005-05-02
影响因子：
1.9
通讯作者：
Cortés, F
中科院分区：
文献类型：
--
作者：
Hajji, N;Mateos, S;Cortés, F
蒽环类阿克拉霉素（ACLA）是一种插入性抗生素和抗肿瘤药物，有效地与DNA结合，导致拓扑异构酶II （topo II）对DNA的催化活性的二次抑制。除了这种活性外，据报道ACLA还能对topo I产生伴随的中毒作用，其方式类似于抗肿瘤药物喜树碱及其衍生物。由于ACLA的这种双重（topo II催化抑制/topo I中毒）活性，在DNA损伤和细胞毒性方面的情况有些令人困惑。我们研究了ACLA诱导培养的中国仓鼠V79细胞及其辐射敏感细胞ir -2对topo II的催化抑制能力、细胞毒作用和DNA损伤。最终目的是发现是否可以观察到两种细胞系对ACLA的反应的差异，因为已经广泛报道了用拓扑毒物处理的辐射敏感细胞。我们的结果似乎同意这样的观点，即与辐射修复熟练的V79细胞相比，辐射敏感的ir- 2细胞表现为超敏感的ACLA。对ACLA治疗后的恢复情况也进行了随访，发现irs-2突变体修复ACLA诱导的DNA链断裂的能力不如V79。(c) 2005 Elsevier B.V.版权所有
The anthracycline aclarubicin (ACLA) is an intercalative antibiotic and antineoplastic agent that efficiently binds to DNA, leading to a secondary inhibition of the catalytic activity of topoisomerase II (topo II) on DNA. Besides this activity, ACLA has been reported to exert a concomitant poisoning effect on topo I, in a fashion similar to that of the antitumor drug camptothecin and its derivatives. As a consequence of this dual (topo II catalytic inhibiting/topo I poisoning) activity of ACLA, the picture is somewhat confusing with regards to DNA damage and cytotoxicity. We studied the capacity of ACLA to induce catalytic inhibition of topo II as well as cytotoxic effects and DNA damage in cultured Chinese hamster V79 cells and their radiosensitive counterparts irs-2. The ultimate purpose was to find out whether differences could be observed between the two cell lines in their response to ACLA, as has been widely reported for radiosensitive cells treated with topo poisons. Our results seem to agree with the view that the radiosensitive irs-2 cells appear as hypersensitive ACLA as compared with radiation repair-proficient V79 cells. The recovery after ACLA treatment was also followed-up, and the irs-2 mutant was found to be less proficient than V79 to repair DNA strand breaks induced by ACLA. (c) 2005 Elsevier B.V. All rights reserved.