Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours
Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours
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DOI：
10.1016/s0960-9822(99)80118-3
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发表时间：
1999-03-11
期刊：
影响因子：
9.2
通讯作者：
Wood, RD
中科院分区：
文献类型：
--
作者：
Köberle, B;Masters, JRW;Wood, RD
成人的转移性癌症通常有致命的结局。相比之下，超过80%的晚期睾丸生殖细胞肿瘤患者使用以顺铂为基础的联合化疗[1]治愈。了解这些细胞对化疗药物敏感的原因可能会对其他类型癌症的治疗产生影响。早期的测量表明，睾丸肿瘤细胞对顺铂过敏，并且从基因组中去除顺铂诱导的DNA损伤的能力较低[2,3]。我们研究了定义明确的833K和GCT27人睾丸肿瘤细胞系提取物的核苷酸切除修复（NER）能力。与已知修复熟练细胞的提取物相比，两者进行NER切口步骤的能力都降低了。免疫印迹结果显示，睾丸肿瘤细胞内大多数NER蛋白含量正常，但着色性干皮病A组蛋白（XPA）和ERCC1-XPF核酸内切酶复合物含量低。添加XPA特异性地赋予睾丸肿瘤提取物完全的NER能力。这些结果表明，睾丸肿瘤细胞系中的低XPA水平足以解释它们从DNA中去除顺铂加合物的能力较差，并可能是睾丸肿瘤对顺铂高敏感性的主要原因。靶向抑制XPA可以使其他类型的细胞和肿瘤对顺铂敏感，并扩大这种化疗药物的用途。(C) Elsevier Science Ltd ISSN 0960-9822。
Metastatic cancer in adults usually has a fatal outcome. In contrast, advanced testicular germ cell tumours are cured in over 80% of patients using cisplatin based combination chemotherapy [1]. An understanding of why these cells are sensitive to chemotherapeutic drugs is likely to have implications for the treatment of other types of cancer. Earlier measurements indicate that testis tumour cells are hypersensitive to cisplatin and have a low capacity to remove cisplatin-induced DNA damage from the genome [2,3]. We have investigated the nucleotide excision repair (NER) capacity of extracts from the well-defined 833K and GCT27 human testis tumour cell lines. Both had a reduced ability to carry out the incision steps of NER in comparison with extracts from known repair-proficient cells. Immunoblotting revealed that the testis tumour cells had normal amounts of most NER proteins, but low levels of the xeroderma pigmentosum group A protein (XPA) and the ERCC1-XPF endonuclease complex. Addition of XPA specifically conferred full NER capacity on the testis tumour extracts. These results show that a low XPA level in the testis tumour cell lines is sufficient to explain their poor ability to remove cisplatin adducts from DNA and might be a major reason for the high cisplatin sensitivity of testis tumours. Targeted inhibition of XPA could sensitise other types of cells and tumours to cisplatin and broaden the usefulness of this chemotherapeutic agent. (C) Elsevier Science Ltd ISSN 0960-9822.