Examining the non-homologous repair process following cisplatin and radiation treatments
Examining the non-homologous repair process following cisplatin and radiation treatments
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DOI：
10.1080/09553000110113047
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发表时间：
2002-05-01
影响因子：
2.6
通讯作者：
Raaphorst, GP
中科院分区：
文献类型：
--
作者：
Myint, WK;Ng, C;Raaphorst, GP
目的：探讨非同源末端连接（non-homologous end-joining， NHEJ）在顺铂放射致敏机制中的作用程度。材料与方法：ku80缺陷细胞缺乏非同源DNA双链断裂修复过程，而野生型MEF细胞保持完全的哺乳动物细胞修复能力。两种细胞系在暴露于250千伏x射线之前立即暴露于临床适用剂量的顺铂（1,3和6马克毫升（-1））1小时。绘制每个细胞系和所有剂量的顺铂的辐射反应，以观察放射致敏的相对水平。还对每个细胞系进行了分剂量实验，以测量亚致死损伤修复水平。结果：1马克ml（-1）顺铂与x射线联合处理时，在野生型细胞中观察到放射线致敏，而在Ku80细胞中没有，这表明NHEJ途径可能在顺铂放射线致敏中起重要作用。顺铂剂量与放疗同时使用产生相似水平的放射致敏。相反，在辐射前立即使用3杯和6杯ml（-1）顺铂显示两种细胞系对辐射的抵抗力增加，这可能是由于在随后的致死剂量顺铂后残留的耐药细胞亚群。进一步的实验表明，高浓度的顺铂没有改变细胞周期分布。最后，分剂量实验显示NHEJ通路在亚致死损伤修复中也起着重要作用。结论：本研究揭示临床适用剂量的顺铂治疗由于抑制NHEJ的手术而导致哺乳动物细胞的放射增敏。
Purpose: To investigate the extent of non-homologous end-joining (NHEJ) in the mechanism of cisplatin radiosensitization.Materials and methods: Ku80-deficient cells are deficient in the non-homologous DNA double-strand break repair process, while the wild-type MEF cells maintain full mammalian cell repair capabilities. Both cell lines were exposed to clinically applicable doses of cisplatin (1, 3 and 6 mug ml(-1)) for 1 h immediately before exposure to 250 kV X-rays. Radiation responses were plotted for each cell line and for all doses of cisplatin to observe relative levels of radiosensitization. Split-dose experiments were also performed on each cell line to measure levels of sublethal damage repair.Results: Radiosensitization was observed in the wild-type cells but not in the Ku80 cells when treated with a combination of 1 mug ml(-1) cisplatin followed by X-rays, implying that the NHEJ pathway may play a large role in cisplatin radiosensitization. Concurrent administration of this cisplatin dose with radiation produced similar levels of radiosensitization. Conversely, 3 and 6 mug ml(-1) cisplatin applied immediately before radiation revealed an increasing resistance to radiation in both cell lines possibly due to resistant subpopulations of cells remaining after subsequent lethal doses of cisplatin. Further experiments revealed that the high concentrations of cisplatin did not alter cell cycle distribution. Finally, split-dose experiments revealed that the NHEJ pathway also plays a significant role in sublethal damage repair.Conclusions : The study reveals that clinically applicable doses of cisplatin treatment results in the radiosensitization of mammalian cells due to the inhibition of the operation of NHEJ.