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Clinical Application of Tumor-specific Anti-tumor Immunity Induced by Tumor Cells Expressing Fas (CD95) Ligand

Research Project

Project/Area Number 13557097
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field General surgery
Research InstitutionThe University of Tokyo

Principal Investigator

TAKEDA Yasutaka  The University of Tokyo, Institute of Medical Science, Clinical Associate, 医科学研究所, 助手 (40163422)

Co-Investigator(Kenkyū-buntansha) TSUBURA Airo  The Kansai Medical College, Department of Pathology, Professor, 医学部, 教授 (90098137)
SHIMIZU Motomu  The Tokyo Metropolitan Organization for Medical Research, Medical R&D center, Senior Researcher, 東京都臨床医学総合研究所, 主任研究員 (10124463)
YOSHIMOTO Takayuki  The Tokyo Medical College, Intractable Disease Research Center, Associate Professor, 難病治療研究センター, 助教授 (80202406)
YANAGIE Hironobu  University of Tokyo, Research Center for Advanced Science and Technology, Associate Professor, 先端科学技術研究センター, 特任助教授 (30212278)
ERIGUCHI Masazumi  The University of Tokyo, Research Center for Advanced Science and Technology, Professor, 先端科学技術研究センター, 特任教授 (10114406)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2003: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2002: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2001: ¥5,100,000 (Direct Cost: ¥5,100,000)
KeywordsFasL(CD95L)-transfected tumor cell / Cancer Gene therapy / Nonviral vector / Gene delivery / Liposome / Anti-tumor effect / Apoptosis / Chemokine / Fasリガンド / マクロファージ / 好中球 / 抗腫瘍効果
Research Abstract

CD95 ligand (FasL)-expressing tumors cause immunopotentiation following vigorous neutrophil infiltration. Thus, the induction of neutrophil Infiltration by FasL appears to play an important role in tumor rejection. 1) The mechanism by which FasL-expressing tumors cause neutrophil infiltration has not been well understood. Here, we Investigated the role of chemokines in FasL-induced antitumor activity. CXC chemokine receptor 2 (CXCR2) knockout (KO) mice are a powerful tool for studying CXC chemokine-mediate neutrophil infiltration. Thus, we examined the mechanism for the neutrophil recruitment Induced by FasLcDNA-transfected MethA (MethA+FasL) fibrosarcoma using CXCR2 KO mice. MethA+FasL cells were completely rejected in wild-type (WT) and KO mice. MethA+FasL cells Injected i.p. induced the recruitment of both neutrophils and macrophages in peritoneal cavity (PC) of WT but only macrophages in PC of KO mice, although CXC and CC chemokines were released In PC in both mice. Macrophages Inc … More ubated with MethA+FasL cells released CXC and CC chemokines. F4/80-positive macrophages decreased after injection of MethA+FasL cells. Macrophages derived from WI and KO but not neutrophils from WT mice induced the recruitment of neutrophils when adoptively i.p. transferred with MethA+FasL cells into FasL/Fas-deficient mice. The different recruitment of inflammatory cells between WT and KO mice was attributed to bone marrow (BM) cells by BM transfer experiment. These results demonstrated that CXC chemokines are essential for neutrophil recruitment and that macrophages but not neutrophils play a critical role in FasL-induced infiltration of Inflammatory cells and that chemokines played important roles In eradication of FasL-expressing tumor cells and induction of antitumor immunity. 2) Mouse mammary tumor, BJMC3879, has highly metastatic potential. FasLcDNA-transfected BJMC3879 (BJMC+FasL) was established for clinical application of breast cancer. Although It induced neutrophil recruitment, It was not rejected In WT mice. The reason might be that BJMC+FasL was little expressed FasL-protein on cell surface. It could be indicated that the capability of FasL-protein expression depends on a kind of tumor cell. 3) On the other hand, we were developing non-viral vectors for clinical application. We are investigating the effects of Quarternary complex (Qplex) (cDNA+cationlc liposome+protamine+transferin) or polyethilenimine on transfecting rate of a few cell lines. Several problems for clinical application become clear. Less

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Takeda, Y.: "Does the timing of surgery for breast cancer in relation to the menstrual cycle or geomagnetic activity affect prognoses of premenopausal patients ?."Biomed.Pharmacother.. 57(Supp). 96-103 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Eriguchi, M.: "Chronothetrapy for cancer."Biomed.Pharmacother.. 57(Supp). 92-95 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizu, M.: "Modification of tumor cells with Fas (CD95) antigen gene and Fas ligand (CD95L) gene transfection by electroporation for immunotherapy of cancer"Mol.Biotechnol.. 25. 79-87 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yanagie, H.: "Inhibition of growth of human breast cancer cells in culture by neutron capture using liposomes containing 10B"Biomed.Pharmacother.. 56. 93-99 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsuzawa, A.: "Significant role of Fas ligand-binding but defective Fas receptor (CD95) in lymph node hyperplasia composed of abnormal double-negative T cells."Immunology. 106. 470-475 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsuzawa A, Shimizu M, Takeda Y, Nagase H, Sayama K, M.Kimura M.: "Significant role of Fas ligand-binding but defective Fas receptor (CD95) in lymph node hyperplasia composed of abnormal double-negative T cells"Immunology. 106. 470-75 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yanagie H, Kobayashi H, Takeda Y, Yoshizaki I.Nonaka Y, Naka S, Nojiri A, Shinkawa H, Furuya Y, Niwa H, Ariki K, Yasuhara H, Eriguchi M: "Inhibition of growth of human breast cancer cells in culture by neutron capture using liposomes containing 10B."Biomed.Pharmacother. 56. 93-99 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizu M, Yoshimoto T, Matsuzawa A, Takeda T.: "Modification of tumor cells with Fas (CD95) antigen gene and Fas ligand (CD95L) gene transfection by electroporation for Immunotherapy of cancer."Mol.Biotechnol.. 25. 79-87 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takeda T, Yanagie H, Yoshizaki I, Eriuchi, M.: "Does the timing of surgery for breast cancer in relation to the menstrual cycle or geomagnetic activity affect prognoses of premenopausal patients?"Biomed.Pharmacother.. 57(Supp). 96-103 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Eriguchi M, Levi F, Hisa T, Yanagie H, Nonaka Y, Takeda Y.: "Chronothetrapy for cancer."Biomed. Pharmacother.. 57 (Supp). 92-95 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takeda, Y.: "Does the timing of surgery for breast cancer in relation to the menstrual cycle or geomagnetic activity affect prognoses of premenopausal patients?"Biomed.& Pharmacother.. 57(Supp). 96-103 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takeda, Y.: "Investigation on diagnostic parameters for contrast-enhanced breast MR imaging based on histology of invasive ductal carcinoma"Eur.Radiol.. (In press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Eriguchi, M.: "Chronothetrapy for cancer"Biomed.& Pharmacother.. 57(Supp). 92-95 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimizu, M.: "Modification of tumor cells with Fas (CD95) antigen gene and Fas ligand (CD95L) gene transfection by electroporation for immunotherapy of cancer"Mol.Biotechnol.. 25. 79-87 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimizu, M.: "A novel method for modification of tumor cells with bacterial superantigen by heterobifunctional cross-linking agent in immunotherapy of cancer"Mol.Biotechnol.. 25. 89-94 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takeda, Y.: "Investigation on diagnostic parameters for contrast-enhanced breast MR imaging based on histology of invasive ductal carcinoma"Eur. Radiol.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yanagie, H.: "Inhibition of growth of human breast cancer cells in culture by neutron capture using liposomes containing lOB"Biomed. Pharmacother.. 56. 93-99 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hasebe, H.: "Bcl-2, Bcl-xL and c-FLIP(L) potentially regulate the susceptibility of human peripheral blood monocyte-derived dendritic cells to cell death at different developmental stages"Biomed. Pharmacother.. 56. 144-151 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Matsuzawa, A.: "Significant role of Fas ligand-binding but defective Fas receptor (CD95) in lymph node hyperplasia composed of abnormal double-negative T cells"Immunology. 106. 470-475 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Toyota, H.: "Calpain-induced Bax-cleavage product is a more potent inducer of apoptotic cell death than wild-type Bax"Cancer Lett.. 189. 221-230 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 清水本武: "アポトーシスのすべてアポトーシス制御による治療法:悪性腫瘍"臨床免疫. 38巻特別増刊号. 404-408 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 武田泰隆: "気嚢作成法による内視鏡補助下乳腺扇形切除術と広背筋脂肪弁による充填術 乳腺鏡視下手術の実際(沢井清司、福間英祐編)"金原出版. 8(79-87) (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimizu, M.: "Fas/Apo-1 (CD95)-mediated apoptosis of neutrophils with Fas ligand (CD95L)-expressing tumors is crucial for induction of inflammation by neutrophilic polymorphonuclear leukocytes associated with antitumor immunity"Cell. Immunol.. 207. 41-48 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Saegusa, Y.: "Antitumor Effets of a New Lipophilic Platinum Compound, Trans-bis (n-valerato)(1R, 2R-cyclohexane-diamine)(oxalato) platinum (IV) in Mice"Anticancer Res.. 21. 245-252 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takeda, Y.: "Docetaxel alone or orally combined with 5-fluorouracil and its derivatives : effects on mouse mammary tumor cell line MM2 in vitro and in vivo"Anti-Cancer Drugs. 12. 691-698 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takeda, Y.: "Correlation between timing of surgery in relation to the menstrual cycle and prognosis of premenopausal breast cancer patients"Biomed. & Pharmacother. 55-Supplement. 133-137 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yasuda, T.: "Clear suppression of Th1 response but marginal amelioration of autoimmune manifestations by IL-12p40 transene in MRL-Fas^<lprcg>/Fas^<lprcg> mice"Cell. Immunol. 210. 77-86 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakagawa, H.: "Growth inhibitory effects of dialyl disulfide on human breast cancer cell lines"Carcinogenesis. 22. 891-897 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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