EXPRESSION OF THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) GENE IN UROTHELIAL CARCINOMAS

The intrinsic or acquired resistance of urothelial cancer to chemother apy is one major obstacle to successful treatment. Generally, the expr ession level of P-glycoprotein in urothelial cancer is low, so we acco rdingly investigated the expression of multidrug resistance-associated protein (MRP). We examined the expression of MRP mRNA by means of slo t-blotting samples of 11 renal pelvic and/or ureteral tumors, 33 bladd er tumors, one lung metastasis from a ureter tumor, 7 non-cancerous ur othelia from patients with transitional-cell carcinoma (TCC) and one u rothelium from a patient with renal-cell carcinoma (RCC). We also esti mated, by Southern blotting, whether or not the MRP gene was amplified in clinical specimens that overexpressed MRP mRNA. MRP was detected i mmunohistochemically using a polyclonal antibody against MRP. In all, 5 of 11 renal pelvic and/or ureter tumors (45.5%), 17 of 33 bladder tu mors (51.5%) and 4 of 7 non-cancerous urothelia of TCC patients (57.1% ) expressed more than 2-fold the MRP mRNA levels of drug-sensitive hum an KB cells. There was no significant difference in the MRP mRNA level between primary and recurrent tumors. Low-grade urothelial carcinomas (G1 and G2 TCCs) expressed significantly higher levels of MRP mRNA th an the high-grade G3 TCC. The MRP gene was not amplified in urothelial carcinomas, irrespective of their expression levels of MRP mRNA. Immu nohistochemically, MRP was located mainly on the plasma membrane, but also detected on the cytoplasm of cancer cells. MRP may be one mechani sm responsible for intrinsic drug resistance in low-grade urothelial c ancer. (C) 1996 Wiley-Liss, Inc.