Cross-resistance and combined cytotoxic effects of paclitaxel and cisplatin in bladder cancer cells

Purpose: We studied the cross-resistance and combined cytotoxic effects of cisplatin and paclitaxel in bladder cancer cells in vitro. Materials and Methods: The cytotoxicity of the 2 agents alone or in combina tion were studied in the bladder cancer cell line NTUB1 and the 2 sublines NTUB1/P, which is cisplatin resistant, and NTUB1/T, which is paclitaxel res istant, using the microculture tetrazolium assay. Schedule dependence of th e 2-drug combination was assayed using 3 treatment schedules, including 1 c oncurrent and 2 sequential exposures. Results: The mean cisplatin concentration plus or minus standard error of t he means inhibiting 50% of the growth of NTUB1, NTUB1/P and NTUB1/T was 1.9 +/- 0.19, 19.3 +/- 2.33 and 2,1 +/- 0.15 muM., respectively, and the mean paclitaxel concentration inhibiting 50% of the growth of the 3 cell lines w as 30 +/- 3.9, 1,033 +/- 120 and 110 +/- 15 nM., respectively. NTUB1/P had strong cross-resistance to paclitaxel. In contrast, NTUB1/T was as sensitiv e as NTUB1 to cisplatin. On median effect analysis the combined effects of the 2 agents given concurrently were sub-additive in the low fraction affec ted range of 0.1 to 0.3 and additive in the median to high fraction affecte d range of 0.4 to 1.0 in the 3 cell lines. Combined cytotoxicity was more s ynergistic when paclitaxel was given 24 hours earlier than cisplatin. The e ffects were less synergistic when cisplatin was given before paclitaxel. Th is phenomenon was noted in sensitive and resistant cells. Conclusions: In our bladder cancer cell model cisplatin resistant cells hav e strong cross-resistance to paclitaxel, whereas paclitaxel resistant cells are sensitive to cisplatin. The combined effects may be optimized by seque ntial use of the 2 agents, preferably paclitaxel given 24 hours before cisp latin. Our results have clinical implications for the treatment of bladder cancer.