Altaha Ramin, Liang Xiaobing, Yu Jing Jie, Reed Eddie
Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506-2519, USA.
Int J Mol Med. 2004 Dec;14(6):959-70.
Platinum compounds induce their cytotoxic effect by binding to a DNA molecule in the form of a platinum-DNA-adduct. Many previous studies have shown that the level of platinum-DNA-adduct correlats with response to platinum-based chemotherapy. Although the mechanism of platinum resistance in vivo is not clearly understood, laboratory studies on cancer cell lines suggest that nucleotide excision repair (NER) is the main mechanism responsible for this resistance by increased platinum-DNA-adduct removal. NER pathway is a network of many proteins gathered in a DNA-repair system. The excision repair cross complementing-group 1 (ERCC1) gene has the leading role in NER-pathway because of its damage recognition and excision ability. In this report we reviewed the pathway leading to ERCC1 gene transcription and translation in cancer cells when exposed to cisplatin. We summarized data from different cancer cell lines and human cancers showing that the high level of ERCC1-mRNA and/or ERCC1 protein is associated with resistance to platinum compounds with direct impact on cancer patient survival and finally we analyzed drugs interfering with ERCC1 gene expression and causing the reversal of the platinum resistance when given to cancer cells prior to platinum-based chemotherapy.
铂化合物通过以铂 - DNA加合物的形式与DNA分子结合来诱导其细胞毒性作用。许多先前的研究表明，铂 - DNA加合物的水平与对铂类化疗的反应相关。尽管体内铂耐药的机制尚不清楚，但对癌细胞系的实验室研究表明，核苷酸切除修复（NER）是通过增加铂 - DNA加合物的去除来产生这种耐药性的主要机制。NER途径是聚集在DNA修复系统中的许多蛋白质组成的网络。切除修复交叉互补组1（ERCC1）基因因其损伤识别和切除能力而在NER途径中起主导作用。在本报告中，我们回顾了癌细胞在暴露于顺铂时导致ERCC1基因转录和翻译的途径。我们总结了来自不同癌细胞系和人类癌症的数据，表明高水平的ERCC1 - mRNA和/或ERCC1蛋白与对铂化合物的耐药性相关，这直接影响癌症患者的生存，最后我们分析了在铂类化疗前给予癌细胞时干扰ERCC1基因表达并导致铂耐药逆转的药物。
