| Project/Area Number |
09557094
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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 |
General surgery
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| Research Institution | Tohoku University |
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Principal Investigator |
SUNAMURA Makoto Tohoku University, Hospital, Lecture, 医学部附属病院, 講師 (10201584)
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| Co-Investigator(Kenkyū-buntansha) |
SHIBUYA Kazuhiko Tohoku University, Hospital, Research Associate, 医学部附属病院, 助手 (70260429)
HAMADA Hirofumi Sapporo Medical College, Medicine, Professor, 医学部, 教授 (00189614)
SATO Masaaki Tohoku University, Engineering, Professor, 大学院・工学研究科, 教授 (30111371)
SHIMAMURA Hiromune Tohoku University, Hospital, Research Associate, 医学部附属病院, 助手 (70312585)
江川 新一 東北大学, 医学部・附属病院, 助手 (00270679)
小針 雅男 東北大学, 医学部, 講師 (30170369)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥11,800,000 (Direct Cost: ¥11,800,000)
Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1997: ¥5,700,000 (Direct Cost: ¥5,700,000)
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| Keywords | gene gun / gene therapy / cancer / angiogenesis / IL-12 / 遺伝子治療 / 腫瘍血管新生 / 抗腫瘍免疫 / BAI-1 / 腫瘍免疫 / 細胞死 / P53 / 遺伝子統 / 抗腫瘍療法 |
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| Research Abstract |
In order to establish a gene therapy system without vectors, we checked the efficacy of gene gun for gene transduction. Although we could confirm the expression of LacZ gene in pancreatic cancer cells, the transduction efficacy was very low. It is important to choose the suitable gene which can express the efficient anti-tumor effect with low concentration for gene gun System. As an anti-tumor agent, Interleukin-12 has been revealed to be a key regulator of the immune response, particularly that involving CTL and NK cells. We report herein the anti-angiogenesis effect of IL-12 on human as well as murine tumors in NK-depleted SCID mice using fibroblasts genetically engineered to secrete this cytokine. Although the in vitro growth of tumor cells was not affected by the presence of IL-12, co-inoculation of IL-12 secreting fibroblasts strongly inhibited tumor growth in immunodeficient mice. The neovascularization surrounding the tumor was remarkably inhibited in the area where the IL-12 secreting fibroblasts were implanted, resulting in the suppression of tumor growth. Lectin staining in tumor sample sections also showed a significant reduction in the number of vessels. The RNA expression of IFN-γ and its inducible antiangiogenic chemokine IP-10 was stimulated in endothelial cells cultured with IL-12. It was also found that IL-12 downregulated the expression of the endothelial cell mitogens VEGF and bFGF.The anti-tumor effects of IL-12 were accompanied by interesting histological changes consisting of a high degree of keratinization and apoptosis and a decrease in the proliferation rate of human tumors and extensive necrosis in the murine ones. Therefore, IL-12 is the candidate gene for this gene gun system.
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