| Project/Area Number |
21390374
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Kyushu University |
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Principal Investigator |
NAKA Nokenjl 九州大学, 先端融合医療レドックスナビ研究拠点, 教授 (00315061)
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| Co-Investigator(Kenkyū-buntansha) |
TAHARA Hideaki 東京大学, 医科学研究所, 教授 (70322071)
NISHIYAMA Nobuhiro 東京大学, 医学系研究院, 准教授 (10372385)
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| Co-Investigator(Renkei-kenkyūsha) |
KATAOKA Kazunori 東京大学, 工学系研究科, 教授 (00130245)
TANI Kenzaburou 九州大学, 生体防御医学研究所, 教授 (00183864)
KUWANO Michihiko 九州大学, 薬学系研究院, 教授 (80037431)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2011: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2010: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2009: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
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| Keywords | TNF一α / YB-1 / CD40L / GM-CSF / 高分子ミセル / miRNA / 遺伝子治療 / TNF-α / TNF-α遺伝子 / ROS / Rac-1 |
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| Research Abstract |
Aim : The purpose of this study is to examine the efficacy of TNF-a, immunogene aYB-lYB-1 miRNA multidisciplinary gene therapy on refractory cancers using non-viral vector of block copolymer micelle. Methods and Results : TNF-a transduction produced reactive oxgen species through activaRae-lac-1 in cancer cells, resulting in cancerpreferential cytotoxicity. We constructed cyclic RGD ligand-fused TNF a expression plasmid to examined the effect of targeting ligand for tumor vessels. The anti-tumor efficacy of RGD-hTNF-a gene therapy using polymer micelle for peritoneally disseminated cancer was greater than TNF-a gene therapy. Among various cytokine and chemokine genes, we found that the combined transduction of CD4OL and GM-CSF induced the prolonged survival for mice with disseminated cancer compared with TNF-a alone and that serum concentrations of IL-2 and IFN-y were increased(Th1 dominant) by the combination therapy. Moreover, we designed RNA silencingYB-lYB-1 by the miRNA expression to prevent cancer EMT triggered by TNFYB-lYB-1 miRNA significantly inhibited tumor growth and prolonged the survival for mice with disseminated canceYB-lYB-1 siRNA induced apoptosis and inhibited tube formation for vascular endothelial cells in vitro, YB-lYB-1 miRNA transduction decreased microvascular density of subcutaneous tumor tissues. After YB-l miRNA or TNF a gene therapy using polymer micelle, body weight and blood examinations revealed no abnormal findings in dissemination mouse model. Doseescalation test in macaca fascicularis also verified no injury for normal organs. Conclusion : Multidisciplinary gene therapy by TNF-a, immunogene and YB-l miRNA transduction using block copolymer micelle vector is a promising therapeutic strategy for intractable cancers.
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