EXPRESSION OF MULTIDRUG RESISTANCE-RELATED GENES (MDRL, MRP, GST-PI AND DNA TOPOISOMERASE-II) IN UROTHELIAL CANCERS

Objective To characterize the multidrug resistance (MDR) phenotype in human urothelial cancers, the expression levels of four MDR-related ge nes (multidrug resistance, mdrl; multidrug resistance-associated prote in, MRP; glutathione S-transferase-pi, GST-pi; and DNA topoisomerase I I, topo II) were analysed in urothelial cancers. Materials and methods Fifty-two tumour tissue and three normal urothelial mucosa samples we re obtained from 44 patients with urothelial cancers. The expression o f each gene was analysed with a reverse-transcription polymerase chain reaction (RT-PCR) method using beta 2-microglobulin (b2m) mRNA as an endogenous control. Levels of expression were expressed as the ratio o f the specific products of the target gene to those specific to b2m. R esults In primary urothelial cancer tissues, the mean (so) expression of mdrl, MRP, GST-pi: and topo II relative to b2m expression were 0.06 7 (0.061), 0.27 (0.23), 0.35 (0.31) and 0.12 (0.05), respectively. The mean expressions of MRP and GST-pi were higher than those of mdrl and topo IT. The mean ratios of mdrl/b2m, MRP/b2m, GST-pi/b2m and topo II /b2m in normal urothelial mucosa were 0.06 (0.03), 0.12 (0.09), 0.30 ( 0.32) and 0.14 (0.01), respectively. There was no significant associat ion of the expression of each gene with either the grade or extent of the primary tumour. The level of MRP expression in each sample was cor related significantly with the expression of mdrl and GST-pi in the ur othelial cancers (r = 0.637 and 0.537, respectively). Chemotherapy did not markedly influence the induction of expression of the MDR-related genes, except for one case in which mdrl expression was 15 times grea ter than before chemotherapy. The expression of GST-pi in the patients not receiving chemotherapy was significantly higher than in those tha t did. Conclusions These results suggest that the activation of MRP an d GST-pi expression occurs during the tumorigenesis of urothelial canc ers and that it may confer de novo and acquired drug resistance on uro thelial cancers. These results should provide further insight into the complex role postulated for MDR-related genes in chemotherapy, carcin ogenesis and tumour progression.