| Project/Area Number |
15591691
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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 | Kagawa University |
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Principal Investigator |
TSUKUDA Fumio (2004) Kagawa University, Faculty of Medicine, Urology, Associate, 医学部, 助手 (40314934)
武田 繁雄 (2003) 香川大学, 医学部, 講師 (10227027)
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| Co-Investigator(Kenkyū-buntansha) |
KAKEHI Yoshiyuki KAGAWA UNIVERSITY, Faculty of Medicine, Urology, Professor, 医学部, 教授 (20214273)
佃 文夫 香川大学, 医学部, 助手 (40314934)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | RCC cells / TRAIL / TRAIL receptor / Anti-DR4 antibody / Anti-DR5 antibody / Apoptosis / Caspase / mouse xenograft / TRAILレセプター / 抗DR4モノクロナル抗体 / アポトーシス / カスパーゼ / ヌードマウス移植モデル / TRAILレセフター / 抗DR4と抗DR5モノクロナル抗体 |
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| Research Abstract |
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells by binding to two receptors, DR4 and DR5. We first investigated the possibility of combination therapy of TRAIL and chemotherapeutic agents against advanced renal cell carcinoma (RCC), hormone-refusal prostate cancer, and advanced bladder cancer. TRAIL in combination with clinically achievable concentrations of anthracyclines exerts a synergistic cytotoxic effect on both RCC and prostate cancer cells, but not in primarily isolated normal kidney cells or normal human prostatic stromal cells. We clarified that this synergistic cytotoxicity was mediated increasing DR4 and DR5 expressions in RCC cells by anthracyclines. The synergistic cytotoxicity was significantly inhibited by caspase inhibitors demonstrating caspase cascade plays an important role in the synergy. We further developed the anti-DR4 and DR5 antibody (ETR1 and ETR2) therapy, which is specific for DR4 and DR5, respectively. ETR2 effectively induced apoptotic cell death in 10 of 11 cell cultures, including two human RCC cell lines and nine human primary RCC cell cultures. In contrast, ETR1 was effective in only one primary RCC cell culture. The increased effectiveness of ETR2 on inducing cell death may have been affected by differences in the cell-surface expression of DR5 but not DR4 was frequently expressed in most of the RCC cells tested. We also demonstrated that the apoptotic cell death of ETR1 and ETR2 was mediated by the activation of caspase cascade. In vivo administration of ETR2 significantly suppressed tumor growth of subcutaneously inoculated human RCC xenografts in SCID and nude mice without causing side effects. The anticancer effect of ETR2 was observed in the prostate cancer DU145, LNCaP cells and bladder cancer T24, J82 cells.
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