1998 Fiscal Year Final Research Report Summary
Cancer gene therapy by the in vivo transfer of cytokine-genes in to the artery that leads to tumors with fusogenic liposomes.
| Project/Area Number |
09557194
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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 | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
MAYUMI Tadanori School of Pharmaceutical Sciences Osaka University Professor, 薬学研究科, 教授 (00098485)
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| Co-Investigator(Kenkyū-buntansha) |
TSUTSUMI Yasuo School of Pharmaceutical Sciences Research Associate, 薬学研究科, 助手 (50263306)
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| Project Period (FY) |
1997 – 1998
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| Keywords | Genethetrapy / tumor immune / Cytokine / Fusogenic liposomes |
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| Research Abstract |
We report that tumor necrosis factor (TNF) alpha induced a strong antitumor immune reaction when it was produced in arteries leading to tumors by gene transfer in vivo. We used a mouse model carrying a sarcoma-18O tumor in the right footpad and injected the fusogenic liposomes encapsulating the human TNF-alpha gene into the right femoral artery. Under this condition, human TNF-alpha was detected only in the artery leading to the tumor and in the tumor. There was a significant regression in tumor growth when the TNF-alpha gene was delivered into the right femoral artery, with 4 of 11 mice completely cured. No regression was observed when the TNF-alpha gene was delivered into the left femoral artery or into the tumor or when the luciferase gene was administered. Tumor regression was inhibited by the injection of anti-TNF-alpha, anti-CD4, or anti-CD 8 monoclonal antibody, and CD8+ T cells accumulated in the tumors of TNF-alpha-treated mice. These results suggest that TNF-alpha expressed l
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ocally in the arteries leading to tumors efficiently suppresses tumor growth through reinforcement of an antitumor immune reaction. Additionally, Development of methodologies for gene transfer into the central nervous system (CNS) is important for fundamental research as well as clinical studies for gene therapy. Cationic liposomes (CL) are attractive vectors because of their safety and ease of use. However, to date only low rates of success have been reported. We succeeded in obtaining high transfection efficiencies into the newborn mouse brain in vivo by CL and a cytoplasmic gene expression system based on T7 RNA polymerase and T7 RNA polymerase- and the luciferase-gene with the T7 promoter sequence. This system showed an efficiency rate 2 orders of magnitude higher than the standard system, which used CL and luciferase genes with a Rous sarcoma virus promoter, pRSVL.In addition, in vitro experiments using LLCMK2 cells showed that cytoplasmic gene expression occurred rapidly (within 6 h) after transfection. In contrast, pRSVL required 24-48 h for induction of luciferase expression. Less
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[Publications] Mizuguchi H., Nakagawa T., Toyosawa S., Nakanishi M., Imazu S., Nakanishi T., Tsutsumi Y., Nakagawa S., Hayakawa T., Ijuhin N., and Mayumi T.: "Tumor necrosis factor alpha-mediated tumor regression by the in vivo transfer of genes in to the artery that leads to tumors." Cancer Res.58. 5725-5730 (1998)
Description
「研究成果報告書概要(欧文)」より
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