Free radical scavengers can differentially modulate the genotoxicity of amsacrine in normal and cancer cells
Free radical scavengers can differentially modulate the genotoxicity of amsacrine in normal and cancer cells
复制标题
DOI：
10.1016/s1383-5718(02)00289-9
复制
发表时间：
2003-02-05
影响因子：
1.9
通讯作者：
Pertynski, T
中科院分区：
文献类型：
--
作者：
Blasiak, J;Gloc, E;Pertynski, T
安吖啶是一种吖啶衍生物药物，用于治疗血液系统恶性肿瘤。它靶向拓扑异构酶R，增强可切割DNA-酶复合物的形成，并导致分裂癌细胞中的DNA片段化。安吖啶与DNA相互作用的其他模式知之甚少，通过这种模式，它也可以影响正常细胞。使用碱性彗星试验，我们表明，安吖啶在浓度范围为0.01至10 μ M诱导正常人淋巴细胞，人早幼粒细胞白血病HL-60细胞缺乏p53基因和小鼠前B淋巴细胞BaF 3表达BCR/ABL癌基因的DNA损伤，测量为增加的尾部DNA的百分比。该效应呈剂量依赖性。经处理的细胞能够在120分钟孵育内恢复。14 mM氨磷汀降低正常淋巴细胞中DNA损伤的水平，对HL-60细胞没有影响，并增强药物在BCR/ABL转化细胞中的DNA损伤作用。10和50 RM的维生素C降低了正常淋巴细胞的DNA损伤程度，但对癌细胞没有影响。用硝酮自旋阱、N-叔丁基-α-苯基硝酮或依布硒啉预处理细胞，其模拟。谷胱甘肽过氧化物酶降低了安吖啶在所有类型细胞中引起的DNA损伤程度。细胞暴露于安吖啶和处理核酸内切酶III和3-甲基腺嘌呤-DNA糖基化酶11，酶识别氧化和烷基化的碱基，分别显示出更大程度的DNA损伤比那些没有用这些酶处理。结果表明，自由基可能参与安吖啶引起的DNA损伤的形成。该药物也可以甲基化DNA碱基。我们的研究结果表明，继发性恶性肿瘤的诱导应考虑到安吖啶的各种副作用。氨磷汀可以增强安吖啶在癌细胞中的DNA损伤作用，并降低这种作用在正常细胞中，维生素C可以被认为是一种保护剂，防止正常细胞中的DNA损伤;（C）2002 Elsevier Science B. V.保留所有权利。
Amsacrine is an acridine derivative drug applied in haematological malignancies. It targets topoisomerase R enhancing the formation of a cleavable DNA-enzyme complex and leading to DNA fragmentation in dividing cancer cells. Little is known about other modes of the interaction of amsacrine with DNA, by which it could affect also normal cells. Using the alkaline comet assay, we showed that amsacrine at concentrations from the range 0.01 to 10 muM induced DNA damage in normal human lymphocytes, human promyelocytic leukemia HL-60 cells lacking the p53 gene and murine pro-B lymphoid cells BaF3 expressing BCR/ABL oncogene measured as the increase in percentage tail DNA. The effect was dose-dependent. Treated cells were able to recover within a 120-min incubation. Amifostine at 14 mM decreased the level of DNA damage in normal lymphocytes, had no effect on the HL-60 cells and potentiated the DNA-damaging effect of the drug in BCR/ABL-transformed cells. Vitamin C at 10 and 50 RM diminished the extent of DNA damage in normal lymphocytes, but had no effect in cancer cells. Pre-treatment of the cells with the nitrone spin trap, N-tert-butyl-alpha-phenylnitrone or ebselen, which mimics. glutathione peroxidase reduced the extent of DNA damage evoked by amsacrine in all types of cells. The cells exposed to amsacrine and treated with endonuclease III and 3-methyladenine-DNA glycosylase 11, the enzymes recognizing oxidized and alkylated bases, respectively, displayed greater extent of DNA damage than those not treated with these enzymes. The results obtained suggest that free radicals may be involved in the formation of DNA lesions induced by amsacrine. The drug can also methylate DNA bases. Our results indicate that the induction of secondary malignancies should be taken into account as diverse side effects of amsacrine. Amifostine may potentate DNA-damage effect of amsacrine in cancer cells and decrease this effect in normal cells and Vitamin C can be considered as a protective agent against DNA damage in normal cells; (C) 2002 Elsevier Science B.V. All rights reserved.