| Project/Area Number |
20390339
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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 |
General surgery
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| Research Institution | University of Tsukuba |
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Principal Investigator |
SHODA Junichi University of Tsukuba, 大学院・人間総合科学研究科, 教授 (90241827)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAKAMI Koji 京都大学, 大学院・医学系研究科, 教授 (70422318)
ODA Tatsuya 筑波大学, 大学院・人間総合科学研究科, 講師 (20282353)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Fiscal Year 2010: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2009: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2008: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
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| Keywords | 胆道系悪性腫瘍 / サイトトキシン / インターロイキン-4 / 緑膿菌毒素 / 分子標的治療 / 肝内胆管癌 / 胆道癌 / 陽イオン抗菌ペプチド / ハイブリッドペプチド |
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| Research Abstract |
Immunohistochemical analysis has shown that cancerous epithelia in biliary tract carcinoma (BTC) tissue (e.g., gallbladder carcinoma, extraheaptic cholangiocarcinoma, and intrahepatic cholangiocarcinoma) expressed receptors for IL-4 in situ at high densities. The expression rate is more than 50%. Also, cultured BTC cell lines have been shown to express the receptor. On the other hand, normal gallbladder tissues and bile duct tissues do not express the receptor. Therefore, the receptor can be a novel target for molecular target therapy in future. Targeting cytotoxins or immunotoxins to tumor cell surface receptors represents a new approach for the treatment of carcinomas. In this research project, the antitumor activity of a cytotoxin (IL-4-PE), that is composed of an interleukin-4 (IL-4) targeting moiety and a truncated form of Pseudomonas exotoxin A, was tested against human biliary tract carcinoma (BTC) cells. Eight BTC cell lines expressed IL-4R on the cell surface as determined by radiolabeled ligand binding assays. When these cells were treated with IL-4-PE, significant cytotoxicity was observed as determined by the inhibition of protein synthesis. The concentration of agent causing 50% inhibition of protein synthesis (IC50) was found to be less than 10 ng/mL in 4 of the 8 BTC cell lines studied. The anti-tumor activity of IL-4-PE was assessed for human BTC cells implanted subcutaneously in immunodeficient mice. By intratumoral injection of IL-4-PE, complete disappearance of the established tumors was observed in 40% of animals. Intraperitoneal administration of IL-4-PE at tolerated doses to animals with peritoneally disseminated BTC exhibited significantly prolonged survival compared to untreated animals. Taken together, these results indicate that IL-4 receptor-targeted cytotoxin is a potent agent that may provide a new therapeutic option for BTC.
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