| Project/Area Number |
07671719
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
MIZUTANI Youichi Kyoto University, Urology, Lecturer, 医学研究科, 助手 (10243031)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIDA Osamu Kyoto University, Urology, Professor, 医学研究科, 教授 (70025584)
OKADA Yusaku Kyoto University, Urology, Assistant Professor, 医学研究科, 助教授 (20127062)
TERACHI Toshiro Kyoto University, Urology, Associate Professor, 医学研究科, 講師 (50207487)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1996: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1995: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Bladdr cancer / BCG / Immunity / Lymphocyte / Cytotoxicity / Autologors tumor / Fas / ADR / cytotoxicity / Immunity / T lymphocyte / NK cell / IL-6 / c-myc / G-CSF / lymphocyte |
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| Research Abstract |
The resistance of bladder cancer 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 T lymphocyte-and natural killer cell-mediated cytotoxicity, which are activated by BCG immunotherapy. Like Fas ligand, anti-Fas monoclonal antibody (mAb) induces apoptosis of the cells expressing Fas. This study has examined whether bladder cancer cells are sensitive to anti-Fas mAb-mediated cytotoxicity and whether anticancer agents synergize with anti-Fas mAb in cytotoxicity. The T24 human bladder cancer cell line constitutively expressed the Fas on the cell surface, however, T24 line was resistant to anti-Fas mAb. Treatment of T24 cells with anti-Fas mAb in combination with mitomycin C,methotrexate or 5-fluorouracil did not overcome their resistance to these agents. However, treatment of T24 cells with combination of anti-Fas mAb and adr
… More
iamycin (ADR) resulted in a synergistic cytotoxic effect. In addition, the ADR-resistant T24 cells (T24/ADR) was sensitive to treatment with combination of anti-Fas mAb and ADR.Synergy was also achieved in three other bladder cancer lines and four freshly derived human bladder cancer cells. Treatment with anti-Fas mAb in combination with epirubicin or pirarubicin also resulted in a synergistic cytotoxic effect on T24 cells. The mechanisms of synergy were examined. Intracellular accumulation of ADR,the expression of P-glycoprotein, or the expression of the anti-oxidant glutathione S transferase-pi mRNA was not affected by anti-Fas mAb. However, treatment with ADR enhanced the expression of Fas on T24 cells. This study demonstrates that treatment of bladder cancer cells with ADR sensitizes the cells to lysis by anti-Fas mAb. The synergistic effect obtained with established ADR-resistant bladder cancer cells and freshly isolated bladder cancer cells suggests that drug-resistant bladder cancer cells can be sensitized by ADR to Fas-Fas ligand-mediated cytotoxicity by lymphocytes. Furthermore, the sensitization required low concentrations of ADR,thus supporting the in vivo application of combination of drug and BCG immunotherapy in the treatment of drug-and/or BCG immunotherapy-resistant bladder cancer. Less
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