| Project/Area Number |
15592003
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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 |
Pathobiological dentistry/Dental radiology
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
MIZUGUCHI Junichiro Tokyo Medical University, Medicine, Professor, 医学部, 教授 (20150188)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIMOTO Takayuki Tokyo Medical University, Medicine, Associate Professor, 医学部, 助教授 (80202406)
TAKADA Eiko Tokyo Medical University, Medicine, Research Associate, 医学部, 講師 (50110903)
CHIBA Hiroshige Tokyo Medical University, Medicine, Professor, 医学部, 教授 (80105478)
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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 |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | chemotherapeutic agents / squamous cell carcinoma / new treatment modality / apoptosis / Bcl-2 family proteins / TRAIL / 化学療法剤抵抗性 / Bcl2ファミリータンパク質 / カルボプラチン / 難治性悪性腫瘍 / Bax-α / 併用療法 |
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| Research Abstract |
Although recent advances in chemotherapeutic agents including cisplatin contribute to the increased survival rete of patients with squamous cell carcinoma (SCC), some patients suffer from inherent or acquired resistance to these chemotherapeutic agents during treatment. To overcome the resistance to multiple drugs, development of a new treatment procedure is urgently required. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of TNF family proteins, has been demonstrated to induce apoptosis against diverse tumor cells, but not normal cells. In the preset study, we found that the chemotherapeutic agents including etoposide and cisplatin render SCC cell lines sensitive to TRAIL-induced apoptotic cell death, although either chemotherapeutic agent or TRAIL induces apoptosis to some extent. The drug-induced sensitization could be accounted for by down-regulation of cellular FLICE-inhibitory proteins (cFLIP), resulting in promotion of TRAIL-induced apoptosis. Since combined effect of chemotherapeutic agents with TRAIL was also operative against Bcl-xL-overexpressing SCC cell lines, resistant to multiple chemotherapeutic agents, the combined therapy would be useful for the treatment of patients with SCC. Moreover, Retroviral-mediated transduction of TRAIL in combination with chemotherapeutic agents induces apoptotic cell death in chemotherapeutic resistant cell lines in a synergistic manner. In addition, transient expression of Bax-α lacking the N-terminal region, which is driven by human telomerase reverse transcriptase(hTERT), promotes apoptotic cell death against the Bcl-xL-overexpressing cell lines. Collectively, combined treatment of chemotheratpeutic agent with TRAIL or the truncated Bax would be useful for the treatment of patients with SCC resistant to a variety of chemotherapeutic agents.
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