CORRELATION OF INTRINSIC CHEMORESISTANCE OF NON-SMALL-CELL LUNG-CANCER CELL-LINES WITH HER-2/NEU GENE-EXPRESSION BUT NOT WITH RAS GENE-MUTATIONS
CORRELATION OF INTRINSIC CHEMORESISTANCE OF NON-SMALL-CELL LUNG-CANCER CELL-LINES WITH HER-2/NEU GENE-EXPRESSION BUT NOT WITH RAS GENE-MUTATIONS
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DOI：
10.1093/jnci/85.11.897
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发表时间：
1993-06-02
期刊：
影响因子：
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通讯作者：
GAZDAR, AF
中科院分区：
文献类型：
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作者：
TSAI, CM;CHANG, KT;GAZDAR, AF
背景资料：在诊断时，大多数小细胞肺癌（SCLC）是化学敏感的，而非小细胞肺癌（NSCLC）通常是耐药的。ras基因和HER-2/neu基因（也称为ERBB 2）的激活见于NSCLC亚群，但不见于SCLC，并与生存期缩短有关。因此，这些基因的激活可能与NSCLC的内在耐药性相关。研究还表明，MDR 1基因（也称为PGY 1）表达的多药耐药表型与NSCLC细胞的体外化疗敏感性或对治疗的临床反应无关，也不能解释药物交叉耐药谱。目的：本研究的目的是探讨化疗耐药与ras基因点突变和HER-2/neu基因在NSCLC细胞系中的过度表达之间的关系，这表明基因激活。研究方法：使用一组20个从未经治疗的患者中建立的NSCLC细胞系，我们评估了有或没有ras突变的细胞系中HER-2/neu信使RNA（mRNA）表达的差异。我们通过基于四唑的MTT [即，3-（4，5-二甲基-2-噻唑基）-2，5-二苯基-2H-溴化四唑]测定，并且我们确定了IC 50值的差异（即，抑制细胞生长50%所需的药物浓度）。结果如下：我们发现所有6种药物的IC 50值与所有20种细胞系中HER-2/neu基因表达程度之间存在统计学显著相关性（r = 0.67 - 0.86; P
Background: At diagnosis, most small-cell lung cancers (SCLCs) are chemosensitive, whereas non-small-cell lung cancers (NSCLCs) are usually chemoresistant. Activation of ras genes and HER-2/neu genes (also known as ERBB2) is encountered in subpopulations of NSCLC but not in SCLC and has been linked to shortened survival. Therefore, activation of these genes may be associated with intrinsic chemoresistance in NSCLC. Studies have also suggested that the multidrug-resistant phenotype expressed by the MDR1 gene (also known as PGY1) does not correlate with the in vitro chemosensitivity of NSCLC cells or with clinical response to therapy and does not explain the spectrum of cross-resistance to drugs. Purpose: The purpose of this study was to investigate the relationships between chemoresistance and the presence of ras gene point mutations and overexpression of the HER-2/neu gene in NSCLC cell lines, which indicates gene activation. Methods: Using a panel of 20 NSCLC cell lines established from untreated patients, we assessed the differences in HER-2/neu messenger RNA (mRNA) expression in the cell lines with or without ras mutations. We performed in vitro drug sensitivity testing by the tetrazolium-based MTT [i.e., 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assay with doxorubicin, carmustine, cisplatin, melphalan, mitomycin, and etoposide, and we determined the differences in IC50 values (i.e., the drug concentrations required to inhibit cell growth by 50%) for the cell lines. Results: We found a statistically significant correlation between the IC50 values for all six drugs and the degree of HER-2/neu gene expression in all 20 cell lines (r = .67-.86; P