EXPRESSION OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP), MDR1 ANDDNA TOPOISOMERASE TT IN HUMAN MULTIDRUG-RESISTANT BLADDER-CANCER CELL-LINES

The acquisition of the multidrug resistance phenotype in human tumours is associated with an overexpression of the 170 kDa P-glycoprotein en coded by the multidrug resistance 1 (MDR1) gene, and also with a 190 k Da membrane ATP-binding protein encoded by a multidrug resistance-asso ciated protein (MRP) gene. Human bladder cancer is a highly malignant neoplasm which is refractory to anti-cancer chemotherapy. In order to understand the mechanism underlying multidrug resistance in bladder ca ncer, we established three doxorubicin-resistant cell lines, T24/ADM-1 , T24/ADM-2 and KK47/ADM, and one vincristine-resistant cell line, T24 /VCR, from human bladder cancer T24 and KK47 cells respectively. Both T24/ADM-1 and T24/ADM-2 cells which had elevated MRP mRNA levels showe d both a cross-resistance to etoposide and a decreased intracellular a ccumulation of etoposide. T24/VCR cells which had elevated levels of M DR1 mRNA and P-glycoprotein but not of MRP mRNA, showed cross-resistan ce to doxorubicin. On the other hand, KK47/ADM cells, which had elevat ed levels of both MRP and MDR1 mRNA and a decreased level of topoisome rase II mRNA, were found to be cross-resistant to etoposide, vincristi ne and a camptothecin derivative, CPT-11. Our present study demonstrat es a concomitant induction of increased levels of MRP mRNA, decreased levels of topoisomerase II mRNA and decreased drug accumulation during development of multidrug resistance in human bladder cancer cells. Th e enhanced expression of the MRP gene is herein discussed in a possibl e correlation with the decreased expression of the topoisomerase II ge ne.