The antitumor enediyne C-1027 alters cell cycle progression and induces chromosomal aberrations and telomere dysfunction.
The antitumor enediyne C-1027 alters cell cycle progression and induces chromosomal aberrations and telomere dysfunction.
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DOI：
10.1158/0008-5472.can-05-0015
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发表时间：
2005-06
期刊：
影响因子：
11.2
通讯作者：
M. McHugh;L. Gawron;S. Matsui;T. Beerman
中科院分区：
文献类型：
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作者：
M. McHugh;L. Gawron;S. Matsui;T. Beerman
这项研究检测了抗肿瘤仿射线抗生素C-1027诱导培养的人结肠癌HCT116细胞染色体不稳定的程度。光谱核型分析显示，低至0.035 nmol/L C-1027加入26小时后，染色体内融合和碎裂频繁。当浓度增加到0.14nmol/L C-1027时，92%的细胞出现染色体畸变率，而同等生长抑制剂量的电离辐射(20Gy)处理后，染色体畸变率仅为2.9%。因此，染色体重新连接与C-1027诱导的细胞生长抑制相比，与C-1027诱导的细胞生长抑制的关系要大得多。尽管有这些异常，C-1027处理的细胞中有很大一部分进入了G1期。彗星分析表明，与电离辐射诱导的链断裂相比，这些广泛的染色体异常不是由于C-1027诱导的诱导增加或修复减少所致。荧光原位杂交分析显示，在加入C-1027的26小时内，观察到端粒重复序列的错误连接(即染色体在其端粒上首尾相连或在端粒序列完全丧失后融合在一起)。C-1027的极端细胞毒性可能反映了DNA双链断裂在整个基因组和/或亚基因组靶点如端粒序列中的诱导和错误修复。
This study examined the extent of chromosome instability induced in cultured human colon carcinoma HCT116 cells by the antitumor radiomimetic enediyne antibiotic C-1027. Spectral karyotype analysis showed frequent intrachromosomal fusions and fragmentations 26 hours after addition of as little as 0.035 nmol/L C-1027. When the concentration was increased to 0.14 nmol/L C-1027, 92% of cells showed chromosomal aberrations compared with only 2.9% after treatment with an equivalent growth inhibitory dose of ionizing radiation (20 Gy). Thus, chromosome misrejoining was associated to a much greater extent with C-1027-induced than with ionizing radiation-induced cell growth inhibition. Despite these aberrations, a large fraction of C-1027-treated cells progressed into G1. Comet analysis showed that these extensive chromosomal anomalies were not due to increased induction or reduced repair of C-1027-induced compared with ionizing radiation-induced strand breaks. Fluorescence in situ hybridization analysis showed that misrejoining of telomere repeats (i.e., chromosomes joined end to end at their telomeres or fused together after complete loss of telomere sequences) was observed within 26 hours of C-1027 addition. The extreme cytotoxicity of C-1027 may reflect both induction and erroneous repair of DNA double-strand break in the whole genome and/or in subgenomic targets such as telomere sequences.