OBJECTIVE: Intrinsic multidrug resistance (MDR) is a major obstacle for effective chemotherapy of advanced transitional cell carcinoma (TCC). The aim of this study was to determine the modulation of cytotoxicity of chemotherapeutic drugs on TCC cells by various modulators.MATERIALS AND METHODS: The cytotoxicities of various anticancer drugs, including
adriamycin and cisplatin, to TCC cell lines were analyzed. Fourteen modulators, including calcium antagonists, a protein kinase C inhibitor, a glutathione transferase inhibitor, protein/peptide synthesis inhibitors, respiratory chain inhibitors, an uncoupling reagent, an ATP synthesis inhibitor,and ionophores, were examined for their MDR-reversing activity using the microplate tetrazolium test. An in vivo animal study was conducted to evaluate the synergistic effect on tumor growth of
modulators of chemotherapeutic agents.RESULTS: Results demonstrated that verapamil, quinidine, tamoxifen, oligomycin, and ouabain had prominent synergistic effects on the cytotoxicity of adriamycin to TCC tumor cells. The enhancement was related to the dosage and treatment duration of the modulators. Further trials on simultaneous additions of these modulators to cocktail mixtures showed no higher synergistic effect. An in vivo study showed that verapamil could enhance the suppression of inoculated tumor growth in mice by adriamycin CONCLUSIONS: The calcium antagonists, tamoxifen, oligomycin, and ouabain, can individually be provided as effective adjunctive chemotherapy for overcoming native drug resistance in
TCC cells. Combination regimens need more study to determine the optimal administration timing,dosage, and frequency of modulators.