CISPLATIN SENSITIVITY RESISTANCE IN UV REPAIR-DEFICIENT CHINESE-HAMSTER OVARY CELLS OF COMPLEMENTATION GROUP-1 AND GROUP-3
CISPLATIN SENSITIVITY RESISTANCE IN UV REPAIR-DEFICIENT CHINESE-HAMSTER OVARY CELLS OF COMPLEMENTATION GROUP-1 AND GROUP-3
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DOI：
10.1093/carcin/14.10.2177
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发表时间：
1993-10-01
期刊：
影响因子：
4.7
通讯作者：
REED, E
中科院分区：
文献类型：
--
作者：
LEE, KB;PARKER, RJ;REED, E
我们评估了人类修复基因ERCC 1和ERCC 3在抵抗顺铂诱导的细胞毒性中的可能作用。本研究使用了UV修复缺陷型中国仓鼠卵巢（CHO）43：3B [命名为ERCC 1（-）]细胞系及其配对亚系83-J5，后者稳定转染了人DNA切除修复基因ERCC 1 [命名为ERCC 1（+）]。还使用了UV修复缺陷型CHO 27-1细胞[命名为ERCC 3（-）]及其配对亚系命名为“ERCC 3（+）”，其用人DNA切除修复基因ERCC 3稳定转染。在每对细胞系中，我们评估了顺铂的细胞毒性、细胞药物蓄积和药物暴露1小时后的铂- DNA加合物修复。通过原子吸收光谱法与塞曼背景校正评估药物蓄积和DNA修复。ERCC 1（+）细胞（IC 50 = 4.0 μ M）对顺铂的耐药性是ERCC 1（-）细胞（IC 50 = 0.75 μ M）的5倍。ERCC 1（+）细胞在IC 50药物暴露后6小时内修复了细胞DNA中25%的DNA损伤，在24小时内修复了48%。ERCC 1（-）细胞在相同时间段内未观察到DNA修复。两种细胞系显示出相似的药物蓄积模式。对于ERCC 3（-）细胞（IC 50 = 54 μ M）和ERCC 3（+）细胞（IC 50 = 49 μ M），顺铂敏感性和细胞药物累积特征相似。当用50 μ M顺铂处理时，这些细胞显示出相似的药物积累模式，并且在形成和修复细胞DNA中的损伤方面同样有效。这些数据表明，在UV修复缺陷的CHO细胞中，ERCC 1赋予顺铂抗性并赋予从细胞DNA中去除铂的能力。相反，ERCC 3不影响顺铂药物敏感性或加合物修复能力。这表明ERCC 1可能是顺铂耐药的决定因素，而ERCC 3可能不是。
We assessed the possible role of the human repair genes, ERCC1 and ERCC3, in resistance to cisplatin-induced cytotoxicity. The UV repair-deficient Chinese hamster ovary (CHO) 43:3B [designated ERCC1(-), cell line and its paired subline 83-J5, which is stably transfected with the human DNA excision repair gene ERCC1 [designated ERCC1(+)], were used in this study. UV repair-deficient CHO 27-1 cells [designated ERCC3(-)] and its paired subline designated 'ERCC3(+)', which is stably transfected with the human DNA excision repair gene ERCC3, were also used. In each pair of cell lines, we assessed cisplatin cytotoxicity, cellular drug accumulation and platinum - DNA adduct repair after 1 h drug exposures. Drug accumulation and DNA repair were assessed by atomic absorption spectrometry with Zeeman background correction. ERCC1(+) cells (IC50 = 4.0 muM) were 5-fold more resistant to cisplatin than ERCC1(-) cells (IC 50 = 0.75 muM). ERCC1(+) cells repaired 25% of DNA lesions in cellular DNA within a 6 h time period following an IC50 drug exposure and repaired 48% over 24 h. No DNA repair was observed in ERCC1(-) cells during the same time periods. Both cell lines showed similar patterns of drug accumulation. For ERCC3(-) cells (IC50 = 54 muM and ERCC3(+) cells (IC50 = 49 muM), the profiles of cisplatin sensitivity and cellular drug accumulation were similar. When treated with 50 muM cisplatin, these cells showed similar patterns of drug accumulation, and were equally efficient at forming and repairing lesions in cellular DNA. These data show that in UV repair-deficient CHO cells, ERCC1 confers resistance to cisplatin and confers the ability to remove platinum from cellular DNA. In contrast, ERCC3 does not influence cisplatin drug sensitivity or adduct repair capability. This suggests that ERCC1 may be a determinant of cisplatin resistance, whereas ERCC3 is probably not.