Cytotoxicity of arsenic trioxide to transitional carcinoma cells.
OBJECTIVE
To explore the therapeutic efficacy of arsenic trioxide (As2O3) 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 (As2O3-resistant), were used. The chemosensitivity of the three cell lines to cisplatin and As2O3 was determined by the microculture tetrazolium assay. The modulatory effect of buthionine sulfoximine (BSO) on As2O3 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 As2O3 in the cell model used. BSO significantly enhanced As2O3 cytotoxicity in the three cell lines, indicating synergism in combination. In the presence of 3 microM BSO, the sensitivity of NTUB1, NTUB1/P, and NTUB1/As to As2O3 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
As2O3 in the presence of BSO may be an active agent against transitional cell carcinoma. Our results have clinical implications and warrant further investigation.
Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China.
Yeong-Shiau
YS
Pu
Tzyh-Chyuan
TC
Hour
Jun
J
Chen
Chao-Yuan
CY
Huang
Jing-Yi
JY
Guan
Shiu-Hui
SH
Lu
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D010087:Oxides / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D019328:Buthionine Sulfoximine; D005978:Glutathione; D002945:Cisplatin; D000077237:Arsenic Trioxide