Nooter K, Bosman F T, Burger H, van Wingerden K E, Flens M J, Scheper R J, Oostrum R G, Boersma A W, van der Gaast A, Stoter G
Department of Medical Oncology, University Hospital Rotterdam and Rotterdam Cancer Institute, The Netherlands.
Ann Oncol. 1996 Jan;7(1):75-81. doi: 10.1093/oxfordjournals.annonc.a010484.
One of the major problems in the cure of advanced non-small-cell lung cancer (NSCLC) is its lack of response to cytotoxic drug treatment, and the mechanisms underlying this intrinsic drug resistance are unclear.
We determined the expression of a newly recognised drug resistance gene, the Multidrug Resistance-associated Protein (MRP) gene, in normal lung tissue and in tumour biopsies from 35 surgically resected NSCLCs (11 adenocarcinomas, 24 squamous cell carcinomas). MRP mRNA levels were quantitated by RNase protection assay and expression of the MRP Mr 190,000 glycoprotein was estimated by immunohistochemistry.
Using the MRP-specific monoclonal antibody MRPr1, MRP expression was detected by immunohistochemistry in epithelial cells lining the bronchi in normal lung. In NSCLC approximately 35% of the samples showed elevated MRP mRNA levels. Based on MRP-specific immunohistochemical staining the tumours were divided into 4 groups: 12% were scored as negative (-), 14% showed weak cytoplasmic staining of the tumour cells (+/-), 40% had a clear cytoplasmic staining (+), and in 34% a strong cytoplasmic as well as membranous staining was observed (++). MRP expression, as estimated by immunohistochemistry, correlated with the MRP mRNA levels quantitated by RNase protection assay (correlation coefficient = 0.745, p = 0.0009), with MRP mRNA levels (mean +/- SD) of 3.0 +/- 1.0 U, 3.5 +/- 0.7 U, 7.5 +/- 5.9 U, and 19.3 +/- 10.7 U, in the (-), (+/-), (+), and (++) immunohistochemistry expression groups, respectively. Among the squamous cell carcinomas a correlation was observed between MRP staining and tumour cell differentiation: the strongest MRP staining was predominantly found in the well differentiated tumours.
Hyperexpression of MRP is frequently observed in primary NSCLC, especially in the well differentiated squamous cell carcinomas. Further studies are needed to assess the role of MRP in the mechanism of clinical drug resistance in NSCLC.
晚期非小细胞肺癌（NSCLC）治疗中的主要问题之一是其对细胞毒性药物治疗缺乏反应，而这种内在耐药性的潜在机制尚不清楚。
我们测定了一种新发现的耐药基因——多药耐药相关蛋白（MRP）基因在正常肺组织以及35例手术切除的NSCLC（11例腺癌、24例鳞状细胞癌）肿瘤活检组织中的表达。通过核糖核酸酶保护试验对MRP mRNA水平进行定量，并通过免疫组织化学法评估Mr 190,000糖蛋白的MRP表达。
使用MRP特异性单克隆抗体MRPr1，通过免疫组织化学在正常肺支气管内衬上皮细胞中检测到MRP表达。在NSCLC中，约35%的样本显示MRP mRNA水平升高。根据MRP特异性免疫组织化学染色，肿瘤分为4组：12%评分为阴性（-），14%显示肿瘤细胞胞质弱阳性染色（+/-），40%有明显的胞质染色（+），34%观察到强胞质及膜染色（++）。通过免疫组织化学评估的MRP表达与通过核糖核酸酶保护试验定量的MRP mRNA水平相关（相关系数 = 0.745，p = 0.0009），在免疫组织化学表达（-）、（+/-）、（+）和（++）组中，MRP mRNA水平（平均值 +/- 标准差）分别为3.0 +/- 1.0 U、3.5 +/- 0.7 U、7.5 +/- 5.9 U和19.3 +/- 10.7 U。在鳞状细胞癌中，观察到MRP染色与肿瘤细胞分化之间存在相关性：最强的MRP染色主要见于高分化肿瘤。
在原发性NSCLC中经常观察到MRP的过表达，尤其是在高分化鳞状细胞癌中。需要进一步研究以评估MRP在NSCLC临床耐药机制中的作用。
