| Project/Area Number |
10671325
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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 |
Cerebral neurosurgery
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| Research Institution | Jikei University School of Medicine |
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Principal Investigator |
TANAKA Toshihide Department of Neurosurgery, Jikei University School of Medicine, Clinical fellow, 医学部, 助手 (90301530)
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| Co-Investigator(Kenkyū-buntansha) |
AKASAKI Yasuharu Department of Neurosurgery, Jikei University School of Medicine, Clinical fellow, 脳神経外科, 助手 (00256322)
MANOME Yoshinobu Department of Microbiology 1, Jikei University School of Medicine, Assistant Professor, 第一細菌学, 講師 (30219539)
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| Project Period (FY) |
1998 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
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| Keywords | Angiogenesis / Gene Therapy / Viral Vectors / Tumor Dormancy / angiostatin / endostatin / endothelial cells / apoptosis / ascites tumor / glioma / endostain |
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| Research Abstract |
The aim of this study is to verify whether viral vector mediated transduction of angiogenesis inhibitor genes containing signal peptide is effective for therapeutics of brain tumor and ascites tumor models.
VEGF (vascular endothelial growth factor) plays a major role as stimulator as well as vascular permeability, which result in peritumoral edema, ascites and pleural effusion. First of all, the transduction efficiency to tumor cells and endothelial cells by adenoviral vector expressing β galactosidase was examined. Endothelial cells as well as tumor cells tunied out to be attractive target for gene transduction. Then adenoviral vectors encoding angiogenesis inhibitor such as platelet factor 4 (PF4), angiostatin and endostatin fused to signal peptide was assessed. Vectors mediated therapy against brain and ascites tumor models led to prolonged survival and inhibition of angiogenesis and tumor growth. Secretable form of PF4 (sPF4) was the most effective inhibitor of tumor growth among the all of the angiogenesis inhibitors.
In addition, interestingly, gene therapy by sPF4 not only inhibited ascites formation, but also turned bloody tumor associated ascites into yellow and serous fluid. Immunohi stochemical analyzes showed the decreased microvascular density and induction of apoptosis by transduction of angiogenesis inhibitor genes, however, they did not have any effects on growth potency of tumor cells.
These results suggest that viral vector mediated anti angiogenesis gene therapy achieved to maintain tumor dormancy. These studies were published in Nature Medicine, Cancer Research, Neurologia Medico-Chirurgica, and Human Gene Therapy.
In the future, we will continue to develop further system utilizing other angiogenesis inhibitors such as soluble form of VEGF and Tie-2 receptor to examine whether they have more potent inhibitory effect on tumor growth.
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