| Project/Area Number |
17591181
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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 |
Dermatology
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| Research Institution | Jichi Medical University |
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Principal Investigator |
MURAKAMI Takashi Jichi Medical University, School of Medicine, Associate Professor (00326852)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Eiji JICHI MEDICAL UNIVERSITY, School of Medicine, Professor (00245044)
OHTSUKI Mamitaro JICHI MEDICAL UNIVERSITY, School of Medicine, Professor (90185330)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | Melanoma / Tumor immunology / vaccine / Histone deacetylase inhibitor / Adontive immune cell transfer / Interferon-lambda / ヒストン脱アセチル化阻害剤 / interferon-λ |
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| Research Abstract |
With melanoma, as with many other malignancies, aberrant transcriptional repression is a hallmark of refractory cancer. To restore gene expression, use of a histone deacetylase inhibitor (HDACi) is expected to be effective. Our recent DNA micro-array analysis showed that the HDACi depsipeptide (FK228) significantly enhances gp100 antigen expression. Herein, we demonstrate that depsipeptide promotes tumor-specific T-cell-mediated killing of B16/F10 murine melanoma cells. Firstly, by a quantitative assay of caspase-3/7 activity, a sublethal dose of depsipeptide was determined (ED50: 5 nM), in which p21^<Waf1/Cip1> and Fas were sufficiently evoked concomitantly with histone H3 acetylation. Secondly, the sublethal dose of depsipeptide treatment with either a recombinant Fas ligand or tumor-specific T cells synergistically enhanced apoptotic cell death in B16/F10 cells in vitro. Furthermore, we found that depsipeptide increased levels of perforin in T cells. Finally, in vivo metastatic growth of B16/F10 in the lung was significantly inhibited by a combination of depsipeptide treatment and immune cell adoptive transfer from immunized mice using irradiated B16 cells and gp100-specific (Pmel-1) T-cell receptor transgenic mice (p<0.05, vs. cell transfer alone). Consequently, employment of a transcriptional modulation strategy using HDACis might prove to be a useful pretreatment for human melanoma immunotherapy. Furthermore, the latest members of the class II cytokine family, IFN-lambda induced both tumor apoptosis and NK cell-mediated immunological tumor destruction through innate immune responses. We demonstrated that local delivery of IFN-lambda might prove a useful adjunctive strategy in the clinical treatment of human malignancies.
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