ALTERATIONS IN EXPRESSION OF THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) GENE IN HIGH-GRADE TRANSITIONAL-CELL CARCINOMA OF THE BLADDER

Expression of the MRP gene has been demonstrated in vitro to be a caus al factor in non-P-glycoprotein-mediated multidrug resistance, and is implicated in resistance to a number of the chemotherapeutic agents cu rrently used in the treatment: of high-grade transitional cell carcino ma (TCC) of the bladder (doxorubicin, epirubicin and vinblastine). Usi ng a sensitive RT-PCR-based technique, we have quantified MRP mRNA lev els in a series of untreated TCC (n = 24), normal bladder (n = 5) and control tissue and cell line samples. MRP mRNA was widely expressed an d detectable in all samples analysed, with considerable (up to 190-fol d) variation observed between individual tumour samples. MRP mRNA leve ls found in TCC samples were lower than those determined for normal pe ripheral mononucleocyte (2.3-fold) and testis (4.1-fold) samples, prev iously reported to be high-expressing tissues, and varied over a simil ar range to that observed in normal bladder samples. Results indicate that MRP mRNA levels in a greater proportion of high-grade (G3) bladde r rumours (55%, 6/11) are significantly reduced (P = 0.018) compared w ith low- and moderate-grade (G1/2) bladder tumours (8%, 1/13), and sug gest that MRP mRNA levels frequently become reduced as a consequence o f tumour progression to advanced, poorly differentiated disease. No co rrelation was apparent between MRP and MDR1 mRNA levels, thus providin g no evidence to suggest common regulation of the two genes. In a limi ted number of patients, no evidence was found to support a role for MR P mRNA levels as a determinant of response to chemotherapy in patients being uniformly treated with either cisplatin-methotrexate-vinblastin e (II = 6) or epirubicin- cisplatin-methotrexate (n = 4) regimens. Sim ilarly, no overall pattern of altered MRP mRNA expression was observed following chemotherapy in four patients from whom post chemotherapy b iopsies were taken. This study provides a useful pilot investigation r egarding the level, variation and pattern of MRP mRNA expression in TC C of the bladder, and suggests that further studies to establish the c linical significance of these variations are required.