EXPRESSION OF THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) GENE IN PRIMARY NON-SMALL-CELL LUNG-CANCER

Background: One of the major problems in the cure of ad advanced non-s mall-cell lung cancer (NSCLC) is its lack of response to cytotoxic dru g treatment, and the mechanisms underlying this intrinsic drug resista nce are unclear. Patients and methods: We determined the expression of a newly recognised drug resistance gene, the Multidrug Resistance-ass ociated Protein (MRP) gene, in normal lung tissue and in tumour biopsi es from 35 surgically resected NSCLCs (11 adenocarcinomas, 24 squamous cell carcinomas). MRP mRNA levels were quantitated by RNase protectio n assay and expression of the MRP Mr 190,000 glycoprotein was estimate d by immunohistochemistry. Results: Using the MRP-specific monoclonal antibody MRPr1, MRF expression was detected by immunohistochemistry in epithelial cells lining the bronchi in normal lung. In NSCLC approxim ately 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 staini ng (+), and in 34% a strong cytoplasmic as well as membranous staining was observed (++). MRP expression, as estimated by immunohistochemist ry, correlated with the MRP mRNA levels quantitated by RNase protectio n assay (correlation coefficient = 0.745, p = 0.0009), with MRP mRNA l evels (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 differe ntiation: the strongest MRP staining was predominantly found in the we ll differentiated tumours. Conclusions: Hyper expression of MRP is fre quently observed in primary NSCLC, especially in the well differentiat ed squamous cell carcinomas. Further studies are needed to assess the role of MRP in the mechanism of clinical drug resistance in NSCLC.