Cross-resistance, cisplatin accumulation, and platinum-DNA adduct formation and removal in cisplatin-sensitive and -resistant human hepatoma cell lines
Cross-resistance, cisplatin accumulation, and platinum-DNA adduct formation and removal in cisplatin-sensitive and -resistant human hepatoma cell lines
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DOI：
10.1006/excr.1996.0211
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发表时间：
1996-07-10
影响因子：
3.7
通讯作者：
Hamilton, TC
中科院分区：
文献类型：
--
作者：
Johnson, SW;Shen, DW;Hamilton, TC
体外筛选BEL 7404人肝癌细胞系的原发性顺铂耐药。产生了一组四个顺铂耐药亚系，它们对顺铂表现出耐药性（高达34倍），但对阿霉素、紫杉醇、依托泊苷或丝裂霉素C没有交叉耐药性。对这组细胞系的进一步表征显示，相对于亲本BEL 7404细胞系，顺铂耐药性增加与选定亚系中顺铂蓄积减少相关（高达14倍）。在7404-CP 20细胞系中也观察到铂-DNA加合物形成（9倍）和核糖体RNA基因特异性链间交联形成（1 a倍）显著减少。在4小时加载期后，未检测到BEL 7404和7404-CP 20细胞系的铂流出率存在差异，两种细胞系的总铂-DNA加合物和基因特异性链间交联去除率相似。在等毒性顺铂浓度下，BEL 7404细胞中存在的总铂-DNA加合物比7404-CP 20细胞多约3倍，表明DNA损伤耐受性也有助于顺铂抗性表型。总体而言，这些结果表明顺铂蓄积减少是体外选择的细胞系中存在的主要顺铂耐药机制。获得性顺铂耐药的模型系统可能在确定顺铂摄取减少的分子基础方面是有价值的，并且对于潜在的耐药调节剂的研究是有用的。(C)出版社：Academic Press，Inc.
The BEL7404 human hepatoma cell line was selected in vitro for primary cisplatin resistance. A panel of four cisplatin-resistant sublines were generated which exhibited resistance to cisplatin (up to 34-fold) but were not cross-resistant to adriamycin, taxol, etoposide, or mitomycin C. Further characterization of this panel of cell lines revealed that increased cisplatin resistance was associated with decreased cisplatin accumulation in the selected sublines (up to 14-fold) relative to the parental BEL7404 cell line. A significant reduction in platinum-DNA adduct formation (9-fold) and ribosomal RNA gene-specific interstrand crosslink formation (la-fold) were also observed in the 7404-CP20 cell line. No differences in the rate of platinum efflux from the BEL7404 and 7404-CP20 cell lines were detected following a 4-h loading period, and total platinum-DNA adduct and gene-specific interstrand crosslink removal rates were similar in both cell lines. There were approximately 3-fold more total platinum-DNA adducts present in the BEL7404 cells relative to the 7404-CP20 cells at equitoxic concentrations of cisplatin, suggesting that DNA damage tolerance also contributes to the cisplatin resistance phenotype. Overall, these results indicate that decreased cisplatin accumulation is the major cisplatin resistance mechanism present in the in vitro-selected cell lines. This model system of acquired cisplatin resistance may be valuable in determining the molecular basis for decreased cisplatin uptake and be useful for the study of potential resistance modulators. (C) 1996 Academic Press, Inc.