Development of novel cytotoxin therapy that targets tumor-associated surface molecules of biliary tract carcinoma
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 |
Section | 一般 |
Research Field |
General surgery
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Research Institution | University of Tsukuba |
Principal Investigator |
SHODA Junichi University of Tsukuba, 大学院・人間総合科学研究科, 教授 (90241827)
|
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)
|
Project Period (FY) |
2008 – 2010
|
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)
|
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 |
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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Report
(4 results)
Research Products
(73 results)
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[Journal Article] Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells.2011
Author(s)
Sugiyama, H., Onuki, K., Ishige, K., Baba, N., Ueda, T., Matsuda, S., Takeuchi, K., Onodera, M., Nakanuma, Y., Yamato, M., Yamamoto, M., Hyodo, I., Shoda, J.
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NAID
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[Journal Article] Proton beam therapy for hepatocellular carcinoma located adjacent to the alimentary tarct.2011
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Nakayama, H., Sugahara, S., Fukuda, K., Abei, M., Shoda, J., Tokita, M., Sakurai, H., Tsuboi, K., Matsuzaki, Y., Tokuue, K.
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Int J Radiat Oncol Biol Phys In press
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[Journal Article] WFA-Positive Sialylated MUC1 is a High-Sensitivity Biliary Marker for Intrahepatic Cholangiocarcinoma.2010
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Matsuda, A., Kuno, A., Kawamoto, K., Matsuzaki, H., Irimura, T., Ikehara, Y., Zen, Y., Nakanuma, Y., Yamamoto, M., Ohkohchi, N., Shoda, J., Hirabayashi, J., Narimatsu, H.
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Hepatology 52
Pages: 174-182
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Sugimoto, H., Okada, K., Shoda, J., Warabi, E., Ishige, K., Ueda, T., Taguchi, K., Yanagawa, T., Nakahara, A., Hyodo, I., Ishii, T., Yamamoto, M.
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[Journal Article] Proton beam therapy for large hepatocellular carcinoma.2010
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Sugahara, S., Oshiro, Y., Nakayama, H., Fukuda, K., Mizumoto, M., Abei, M., Shoda, J., Matsuzaki, Y., Tohno, E., Tokita, M., Tsuboi, K., Tokuue, K.
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Int J Radiat Oncol Biol Phys 76
Pages: 460-466
NAID
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[Journal Article] Nrf2 Counteracts Cholestatic Liver Injury via Stimulation of Hepatic Defense Systems.2009
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Okada, K., Shoda, J., Taguchi, K., Maher, J.M., Ishizaki, K., Inoue, Y., Ohtsuki, M., Goto, N., Sugimoto, H., Utsunomiya, H., Oda, K., Warabi, E., Ishii, T., Yamamoto, M.
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Biochem Biophys Res Commun 389
Pages: 431-436
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[Journal Article] Proton beam therapy for hepatocellular carcinoma : the University of Tsukuba Experience.2009
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Nakayama, H., Sugahara, S., Tokita, M., Fukuda, K., Mizumoto, M., Abei, M., Shoda, J., Sakurai, H., Tsuboi, K., Tokuuye, K.
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Cancer 115
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[Journal Article] Strategy for glycoproteomics : identification of glyco-alteration using multiple glycan profiling tools.2009
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Ito, H., Kuno, A., Sawaki, H., Sogabe, M., Ozaki, H., Tanaka, Y., Mizogami, M., Shoda, J., Angata, T., Sato, T., Hirabayashi, J., Ikehara, Y., Narimatsu, H.
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J Proteome Res 8
Pages: 1358-1367
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[Journal Article] Acarbose, an α-glucosidase inhibitor, prevents obesity and hepatic steatosis in SQSTM1/A170/p62-deficient mice.2009
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Okada, K., Yanagawa, T., Warabi, E., Yamastu, K., Uwayama, J., Takeda, K., Utsunomiya, H., Yoshida, H., Shoda, J., Ishii, T.
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Hepatology Res 39
Pages: 490-500
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[Journal Article] A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma.2009
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Fukumitsu, N., Sugahara, S., Nakayama, H., Fukuda, K., Mizumoto, M., Abei, M., Shoda, J., Thono, E., Tsuboi, K., Tokuuye, K.
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Int J Radiat Oncol Biol Phys 39
Pages: 247-255
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[Journal Article] Choleretic effect of Inchikoto on the cholestatic livers of patients with biliary obstruction due to biliary tract carcinoma : A randomized controlled study.2009
Author(s)
Watanabe, S., Yokoyama, Y., Oda, K., Kokuryo, T., Shoda, J., Okada, K., Utsunomiya, H., Nagino, M.
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Journal Title
Hepatology Res 39
Pages: 247-255
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[Journal Article]2009
Author(s)
正田純一
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胆石診療ガイドライン(編集 財団法人 日本消化器病学会)(南江堂)
Pages: 320-324
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[Journal Article] A new and effective therapeutic option using interleukin-4-conjugated Pseudomonas exotoxin for biliary tract carcinoma.2008
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Ishige, K., Shoda, J., Kawamoto, T., Machida, S., Ueda, T., Hyodo, I., Ohkohchi, N., Puri, R.K., Kawakami, K.
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Int J Cancer 123
Pages: 2915-2922
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[Journal Article] Ursodeoxycholic acid exerts Nrf2-mediated stimulation of hepatobiliary transport, detoxification and antioxidative stress systems.2008
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Okada, K., Shoda, J., Taguchi, K., Goto, N., Takeda, K., Utsunomiya, H., Oda, K., Warabi, E., Ishii, T., Osaka, K., Yamamoto, M.
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[Journal Article] MUC4 Interacts with ErbB2 in Human Gallbladder Carcinoma : Potential Pathobiological Implications.2008
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Miyahara, N., Shoda, J., Ishige, K., Kawamoto, T., Ueda, T., Hyodo, I., Ohkohchi, N., Yamamoto, T., Thomas, M.B., Krishnamurthy, S., Carraway, K.L., Irimura, T.
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Eur J Cancer 44
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[Journal Article] Development of an all-in-one technology for glycan profiling targeting formalin-embedded tissue sections.2008
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Matsuda, A., Kuno, A., Ishida, H., Kawamoto, T., Shoda, J., Hirabayashi, J.
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Biochem Biophys Res Commun 370
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[Presentation] 総胆管結紮による急性胆汁うっ滞におけるKeap1-Nrf2systemの役割2010
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第46回日本肝臓学会総会
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