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Doxorubicin sensitizes human bladder carcinoma cells to Fas‐mediated cytotoxicity
Author(s) -
Mizutani Youichi,
Okada Yusaku,
Yoshida Osamu,
Fukumoto Manabu,
Bonavida Benjamin
Publication year - 1997
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/(sici)1097-0142(19970315)79:6<1180::aid-cncr17>3.0.co;2-w
Subject(s) - cytotoxicity , doxorubicin , cytotoxic t cell , apoptosis , fas ligand , cancer research , medicine , cell culture , immunology , pharmacology , biology , programmed cell death , chemotherapy , in vitro , biochemistry , genetics
BACKGROUND The resistance of bladder carcinoma to anticancer chemotherapeutic agents remains a major problem. Hence, several immunotherapeutic approaches have been developed to treat the drug‐resistant cancer cells. Fas antigen (Fas) and Fas ligand participate in cytotoxicity mediated by T lymphocytes and natural killer cells. Like Fas ligand, anti‐Fas monoclonal antibody (MoAb) induces apoptosis of the cells expressing Fas. This study examined whether bladder carcinoma cells are sensitive to cytotoxicity mediated by anti‐Fas MoAb and whether anticancer agents synergize with anti‐Fas MoAb in cytotoxicity. METHODS Cytotoxicity was determined by a 1‐day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. RESULTS The T24 human bladder carcinoma cell line constitutively expressed the Fas on the cell surface; however, T24 line was resistant to anti‐Fas MoAb. Treatment of T24 cells with anti‐Fas MoAb in combination with mitomycin C, methotrexate, or 5‐fluorouracil did not overcome their resistance to these agents. However, treatment of T24 cells with a combination of anti‐Fas MoAb and doxorubicin resulted in a synergistic cytotoxic effect. In addition, the doxorubicin‐resistant T24 cells were sensitive to treatment with a combination of anti‐Fas MoAb and doxorubicin. Synergy was also achieved in three other bladder carcinoma cell lines and four freshly derived human bladder carcinoma cells. Treatment with anti‐Fas MoAb in combination with epirubicin or pirarubicin also resulted in a synergistic cytotoxic effect on T24 cells. The mechanisms of synergy were examined. Anti‐Fas MoAb did not affect the intracellular accumulation of doxorubicin, the expression of P‐glycoprotein, or the expression of the antioxidant glutathione S‐transferase‐π mRNA. However, treatment with doxorubicin enhanced the expression of Fas on T24 cells. CONCLUSIONS This study demonstrated that treatment of bladder carcinoma cells with doxorubicin sensitized the cells to lysis by anti‐Fas MoAb. The synergistic effect obtained with established doxorubicin‐resistant bladder carcinoma cells and freshly isolated bladder carcinoma cells suggests that drug‐resistant bladder carcinoma cells can be sensitized by doxorubicin to Fas‐ and Fas ligant‐mediated cytotoxicity by lymphocytes. Furthermore, the sensitization required low concentrations of doxorubicin, thus supporting the in vivo application of a combination of chemotherapy and immunotherapy in the treatment of drug‐resistant and/or immunotherapy‐resistant bladder carcinoma. Cancer 1997; 79:1180‐9. © 1997 American Cancer Society.