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

我们研究了体内多药耐药基因MDR 1编码的P-糖蛋白（P-Gp）表达的增加是否与肺癌获得性多药耐药有关。体内药敏试验表明，肺癌移植瘤（LC-6，腺癌和Lu-24，小细胞癌）对长春新碱（VCR，1.6 mg/kg：LC-6，45%; Lu-24，39%）和阿霉素（DOX，12 mg/kg：LC-6，29%; Lu-24，26%）均表现出初步的敏感性。用VCR（0.4mg/kg，× 9）筛选的耐药变异株（LC-6 R，66%）与DOX交叉耐药（分别为51%和55%）。LC-6 R对VCR/DOX的获得性耐药可通过与环孢素A（CysA，35%/14%）联合给药而逆转。逆转录-聚合酶链反应（RT-PCR）结果显示，LC-6 R和Lu-24 R细胞的MDR 1表达水平升高，无VCR作用4代后，MDR 1表达水平稳定，P-Gp表达水平升高，P-Gp阳性肿瘤细胞增多。 ...更多信息 为了探讨P-GP/MDR 1基因过表达与肺癌获得性多药耐药的关系，我们采用北方印迹法检测了104例非小细胞肺癌（NSCLC）组织中MRP基因的表达水平，并与RT-PCR法检测的MDR 1基因的表达水平进行比较（59例腺癌，Ad ; 40例鳞状细胞癌，Sq ; 4例大细胞癌，La ; 1例腺鳞癌，AdSq）。104例NSCLC中33例（31.7%）表达不同水平的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）。8例非小细胞肺癌中MRP mRNA高表达而无MDR 1表达（MRP++，MDR 1-）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（长春地辛、VDS和依托泊苷、VP-16）化疗。23例（37.7%）MRP高表达或中表达的肿瘤患者的肿瘤表现出明显差于无MRP表达或低MRP表达的肿瘤患者（p<0.05）。结果提示MRP基因表达水平与非小细胞肺癌的组织病理学及预后有关。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