Molecular analysis of acquired multidurg resistance in non-small cell lung cancer

我们研究了人多药耐药基因MDR1编码的p -糖蛋白（P-Gp）表达增加是否与体内肺癌获得性多药耐药有关。肺癌异种移植物（LC-6，腺癌和Lu-24，小细胞癌）最初对长春新碱（VCR,1.6 mg/kg: LC-6,45%; Lu-24,39%）和阿霉素（DOX,12mg/kg: LC-6,29%; Lu-24,26%）的体内化学敏感性试验均敏感。与VCR （0.4mg/kg, x 9）选择的耐药变体（LC-6R，66%和Lu-24R，68%）获得了对DOX的交叉抗性（分别为51%和55%）。同时给药环孢素A可避免LC-6R对VCR/DOX的获得性耐药（CysA,35%/14%）。逆转录聚合酶链反应结果显示，LC-6R和Lu-24R中MDR1表达水平升高，经4代无VCR处理后MDR1表达水平稳定。P-Gp表达水平升高，LC-6R和Lu-24R中P-Gp阳性肿瘤细胞增多。这些结果进一步表明P-Gp/MDR1过表达与体内肺癌获得性多药耐药有关。在104例非小细胞肺（NSCLC）标本（59例腺癌，Ad； 40例鳞状细胞癌，Sq； 4例大细胞癌，La； 1例腺鳞状细胞癌，AdSq）中，我们检测了多药耐药相关蛋白（MRP）基因的表达水平，并将其与RT-PCR检测的MDR1基因的表达水平进行了比较。104例NSCLC中有33例（31.7%）表达不同程度的MRP基因。MRP基因高表达的NSCLC（++, 19 / 33,57.6%）主要为鳞状细胞癌（Ad 5, Sq 13, La 1） （p<0.05）。在8例MRP mRNA高表达而不表达MDR1 （MRP++、MDR1-）的NSCLC中，有6例为鳞状细胞癌。104例NSCLC患者中有61例接受了mrp相关抗癌药物（vindesine， VDS和依托泊苷，VP-16）的化疗。23例（37.7%）MRP高或中表达肿瘤患者预后明显差于MRP不表达或低表达肿瘤患者（p<0.05）。这些结果提示MRP基因表达水平与NSCLC的组织病理及预后有关。少

We examined whether the increased expression of P-glycoprotein (P-Gp) encoded by the human multidrug resistance gene MDR1 is related to acquired multidrug resistance of lung cancer in vivo. The lung cancer xenografts (LC-6, adenocarcinoma and Lu-24, small cell carcinoma) were initially sensitive to both vincristine (VCR,1.6 mg/kg : LC-6,45% ; Lu-24,39%) and doxorubicin (DOX,12mg/kg : LC-6,29% ; Lu-24,26%) by in vivo-chemosensitivity test. Resistant variants (LC-6R,66% and Lu-24R,68%) selected with VCR (0.4mg/kg, x 9) acquired cross-resistance to DOX (51%, and 55%, respectively) . The acquired resistance to VCR/DOX in LC-6R was circumvented by coadministration of cyclosporin A (CysA,35%/14%) . Reverse transcriptasepolymerase chain reaction assay showed increased levels of MDR1 expression in LC-6R and Lu-24R with stable MDR1 expression levels after 4 passages without VCR.P-Gp expression levels were elevated, and P-Gp positve tumor cells increased in both LC-6R and Lu-24R.These results su … More ggest that P-Gp/MDR1 overexpression is related to acquired multidrug resistance in lung cancer in vivo.We examined the levels of expression of the multidrug resistance-associated protein (MRP) gene quantified by Northern blot analysis in comparison with those of the MDR1 gene determined by RT-PCR in 104 non-small cell lung (NSCLC) specimens (59 adenocarcinoma, Ad ; 40 squamous cell carcinoma, Sq ; 4 large cell carcinoma, La ; and 1 adenosquamous carcinoma, AdSq) . Thirty-three (31.7%) of the 104 NSCLC expressed the MRP gene at various levels. The NSCLC showing high levels of MRP gene expression (++, 19 of 33,57.6%) were predominantly squamous cell carcinomas (Ad 5, Sq 13, La 1) (p<0.05) . Six of the 8 NSCLC expressing high levels of MRP mRNA and no MDR1 (MRP++, MDR1-) were squamous cell carcinomas. Sixty-one of the 104 NSCLC patients received chemotherapy with MRP-related anticancer drugs (vindesine, VDS and etoposide, VP-16) . Twenty-three patients (37.7%) with tumor expressing high or moderate levels of MRP showed significantly worse prognoses than those with non or low-MRP-expressing tumours (p<0.05) . These results suggest that the level of MRP gene expression is related to the histopathology and prognosis of NSCLC. Less