The expression of drug-resistant genes and the acquirement of drug resistance in human bladder cancer cell lines

Anticancer agents such as cisplatin, vinblastine and adriamycin have been employed in the therapy of human bladder cancer, however their therapeutic effects are not always satisfactory. In order to understand the mechanism underlying drug resistance in bladder cancer, we established two adriamycin resistant cell lines (KK47/ADM and T27/ADM-2), one vincristine resistant cell line (T24/VCR) and two cisplatin resistant cell lines (KK47/DDP20 and T24/DDP10) from human bladder cancer KK47 and T24 cells. KK47/ADM, T24/ADM-2 and T24/VCR cells showed a different multidrug resistance phenotype. T24/ADM 2 cells which had an elevated multidrug resistance-associated protein (MRP) mRNA level but a decreased level of DNA topoisomerase (Topo II), showed a cross-resistance to etoposide. T24/VCR cells which had elevated levels of multidrug resistance 1 (MDR1) mRNA but not of MRP nRNA showed a cross resistance to adriamycin. On the other hand, KK47/ADM cells, which had elevated levels of both MRP and MDR1 mRNA and a decreased level of Topo II mRNA, were found to be cross resistant to etoposide, vincristine and CPT 11. In the two cispatin resistant cell lines (KK47/DDP20 and T24/DDP10), the intracellular platinum concentration was significantly lower than in their parental cells. The intracellular glutathione content of the KK47/DDP20 cells was significantly higher than that of the KK47 parent, whereas that of the T24/DDP10 cells was not significantly different from that of the T24 parent. KK47/DDP20 cells, which had elevated γ glutamyl cycteine synthetase (γ GCS), glutathione S transferase π (GST-π) and metallothionein mRNA levels, showed a cross resistance to adriamycin, mitomycin C, vinblastine and CPT- 11, whereas T24/DDP10 cells which had an elevated DNA topoisomerase I level showed a cross-resistance to vincristine only, while demonstrating collateral sensitivity to both CPT-11 and its active metabolite, SN38. Thus, the mechanism of resistance to anticancer agents in human bladder cancer seems to be complicated and multifactorial. These drug resistant cell lines presented here may provide a useful model for developing new chemotherapeutic strategies against bladder cancer.