Effect of concentration on the cytotoxic mechanism of doxorubicin-apoptosis and oxidative DNA damage
Effect of concentration on the cytotoxic mechanism of doxorubicin-apoptosis and oxidative DNA damage
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DOI：
10.1006/bbrc.1996.5898
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发表时间：
1997-01-13
影响因子：
3.1
通讯作者：
Halliwell, B
中科院分区：
文献类型：
--
作者：
Muller, I;Jenner, A;Halliwell, B
蒽环类药物衍生物如阿霉素是许多化疗方案的一部分，其血药浓度最高可达5 μ m。我们研究了不同阿霉素浓度对MOLT-4 all细胞的细胞毒性机制。在培养的MOLT-4细胞中，高达100 μ M的阿霉素达到了类似的细胞毒性作用，但通过不同的机制起作用。阿霉素诱导细胞凋亡（在1 μ M时效果最大），细胞凋亡依赖于RNA合成并涉及氧化应激。浓度高于3 μ M不诱导细胞凋亡，但显著抑制RNA合成。在1 ~ 5 μ M阿霉素的作用下，MOLT-4细胞的DNA链断裂程度相似，但在较高浓度下表现出剂量依赖性。在凋亡细胞中没有GC/ ms检测到DNA碱基的氧化，在高达100 μ M的阿霉素存在下，13种DNA碱基氧化产物中只有1种8-羟基鸟嘌呤显著增加。这些结果表明，在药理学上相关的浓度下，凋亡而非DNA氧化损伤是阿霉素对ALL细胞的主要杀伤机制。(C) 1997学术出版社
Anthracycline derivatives such as doxorubicin are part of many chemotherapeutic regimens and reach peak plasma concentrations of 5 mu M. We investigated the cytotoxic mechanisms of various doxorubicin concentrations in MOLT-4 ALL-cells. Concentrations of up to 100 mu M doxorubicin achieved similar cytotoxic effects in cultures of MOLT-4 cells, but acted via different mechanisms. Doxorubicin induced apoptosis (maximum effect at 1 mu M), which was dependent on RNA synthesis and involved oxidative stress. Concentrations higher than 3 mu M did not induce apoptosis, but significantly inhibited RNA synthesis. DNA strand breaks in MOLT-4 cells occurred in the presence of 1 to 5 mu M doxorubicin to a similar extent, but showed a dose-dependence at higher concentrations. There was no GC/MS-detectable oxidation of DNA bases in apoptotic cells and only 1 out of 13 DNA base oxidation products, 8-hydroxyguanine, increased significantly in the presence of as much as 100 mu M doxorubicin. These results suggest that at pharmacologically relevant concentrations apoptosis and not oxidative DNA damage is the main killing mechanism of doxorubicin against ALL cells. (C) 1997 Academic Press