Cytotoxicity of arsenic trioxide to transitional carcinoma cells

Objectives. To explore the therapeutic efficacy of arsenic trioxide (AS(2)O(3)) in human transitional cell carcinomas, we investigated the potential use of the compound as a chemotherapeutic agent and the possible cross-resistance with cisplatin in this malignancy. Methods. Three bladder transitional carcinoma cell lines, NTUB1, NTUB1/P (cisplatin-resistant), and NTUB1/As (AS(2)O(3)-resistant), were used. The chemosensitivity of the three cell lines to cisplatin and AS(2)O(3) was determined by the microculture tetrazolium assay. The modulatory effect of buthionine sulfoximine (BSO) on AS(2)O(3) cytotoxicity was studied by combining the two agents simultaneously or sequentially and evaluated using the median-effect analysis. Cellular glutathione contents were determined using a biochemical method. Results. There was evident cross-resistance between cisplatin and AS(2)O(3) in the cell model used. BSO significantly enhanced AS(2)O(3) cytotoxicity in the three cell lines, indicating synergism in combination. In the presence of 3 muM BSO, the sensitivity of NTUB1, NTUB1/P, and NTUB1/As to AS(2)O(3) was increased 3, 7.4, and 8.4-fold, respectively. Among the three different combination schedules, greater cytotoxic effects were obtained by concurrent exposure to both agents. A significant dose-response relationship was found between the BSO concentrations and glutathione contents in NTUB1 (P = 0.007) and NTUB1/As (P = 0.05) but not NTUB1/P (P = 0.1) cells. Conclusions. AS(2)O(3) in the presence of BSO may be an active agent against transitional cell carcinoma. Our results have clinical implications and warrant further investigation. (C) 2002, Elsevier Science Inc.