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Inhibition of glioma angiogenesis and invasion by anti-microtubule agent in a rat brain tumor model.

Research Project

Project/Area Number 14571340
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionNippon Medical School

Principal Investigator

YOSHIDA Daizo  Nippon Medical School, Neurosurgery, Assistant Professor, 医学部, 講師 (30210701)

Co-Investigator(Kenkyū-buntansha) TERAMOTO Akira  Nippon Medical School, Neurosurgery, Professor, 大学院・医学研究科, 教授 (60231445)
KIM Kyonsong  Nippon Medical School, Neurosurgery, 医学部, 助手 (30339387)
OYAMA Kenichi  Nippon Medical School, Neurosurgery, 医学部, 助手 (70350048)
KANAZAWA Ryuzaburo  Nippon Medical School, Neurosurgery, 医学部, 助手 (20333114)
山王 直子  日本医科大学, 医学部, 講師 (90297862)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywordsbrain tumor / GFP / tumor angiogenesis / microtubule / cell invasion / glioblastoma / glioblastoma / グリオーマ / 血管新生 / MMP / SI-27 / matrix metallo proteinase / レーザー顕微鏡
Research Abstract

We mainly achieved the following two investigations.
(1)OBJECTIVE : We aimed to analyze the anti-invasive effect of the anti-matrix metalloproteinase (anti-MMP) agent SI-27 by quantitative tracking of enhanced green fluorescent protein(EGFP)-labeled human malignant glioma cell lines in a brain slice model. METHODS : Persistent expression of EGFP in human malignant glioma cell clones (U87MG, U251MG, and U373MG) was established with the use of the pEGFP-C1 vector. Tumor spheroid in 1 microl Matrigel was implanted into the caudate nucleus-putamen of a severe combined immunodeficient mouse brain slice. To allow the quantitative assessment of tumor cell invasion, the invasion area index was measured on Days 1,3,5,and 7 with a fluorescence stereomicroscope and an image analyzer in the presence of various concentrations of SI-27(0,1,10,50,or 100 microg/ml). RESULTS : In the control group (0 microg/ml), all glioma cell lines invaded in a fingerlike fashion and reached the contralateral hemisphe … More re through the corpus callosum. SI-27 at concentrations of 10,50,and 100 microg/ml significantly suppressed the invasion area index on Days 5 and 7 in a dose-dependent manner, whereas 1 microg/ml had no effect. Transmission electron microscopy and laser confocal microscopy indicated that the tumor cells had penetrated the brain slice and that the normal structural integrity of the brain was maintained until Day 7. CONCLUSION : This model enabled unequivocal periodic tracking of individual invading tumor cells in normal brain. The significant suppression of glioma cell invasion by noncytotoxic concentrations of SI-27 indicates that anti-MMP treatment may represent an important future therapeutic strategy for malignant cerebral neoplasms.
(2)OBJECTIVE : The matrix metalloproteinase(MMP) inhibitor SI-27 has undergone extensive development because of its effectiveness against glioma invasion and angiogenesis. However, previous studies have been performed in vitro. The present work investigates the potential of SI-27 to inhibit tumor invasion, slow angiogenesis, and prolong survival in rodent brain tumor models. METHODS: Stable enhanced green fluorescent protein-expressing clones of a human malignant glioma cell line, U251MG, were stereotactically xenografted into the periphery of the anterior striatum and corpus callosum of Fischer 944 rats after immunosuppression with cyclosporin A, SI-27(1 or 10 mg/kg) or carrier solution was administered on three successive days by intraperitoneal injection, and tumor invasion and angiogenesis were assessed 3 weeks later by quantitative image analysis. This was performed on whole brain sections analyzed either by direct observation of enhanced green fluorescent protein-expressing glioma cells or by additional immunohistochemistry to detect the endothelial cells with anti-factor VIII monoclonal antibody In situ zymography on frozen sections was used to detect MMP activity. RESULTS : The group receiving a total of 30 mg/kg showed a statistically significant (P<0.001) increase in survival time compared with the controls receiving carrier (median survival, 47.3 versus 32.6 d). There was also a decrease in MMP activity, tumor cell invasion, and neovascularization. In contrast, animals given 3 mg/kg did not show these differences. CONCLUSION : Systemic administration of the anti-MMP agent SI-27 is effective in the treatment of glioma in an animal model. Less

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (33 results)

All 2005 2004 2003 2002 Other

All Journal Article (22 results) Publications (11 results)

  • [Journal Article] The expression of hypoxia-inducible factor 1α and cathepsin D in, pituitary adenomas2005

    • Author(s)
      D Yoshida
    • Journal Title

      Endocrine Pathology (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Regulation of VEGF by hypoxia inducible factor in pituitary adenoma2005

    • Author(s)
      K Kim
    • Journal Title

      Endocrine Pathology (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Inhibition of cell invasion by indomethacin on glioma cell lines : in vitro study.2005

    • Author(s)
      Wang M, Yoshida D, Liu S, Teramoto A.
    • Journal Title

      J Neurooncol.Mar 72(1)

      Pages: 1-9

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of cathepsin B and microvascular density increases with higher grade of astrocytomas.2005

    • Author(s)
      Wang M, Tang J, Liu S, Yoshida D, Teramoto A.
    • Journal Title

      J Neurooncol.Jan 71(1)

      Pages: 3-7

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A case of pleomorphic xanthoastrocytoma presenting with massive tumoral hemorrhage.2005

    • Author(s)
      Yoshida D, Kogiku M, Noha M, Takahashi H, Teramoto A.
    • Journal Title

      J Neurooncol.Jan 71(2)

      Pages: 169-171

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The expression of hypoxia-inducible factor 1α and cathepsin D in pituitary adenomas2005

    • Author(s)
      D Yoshida
    • Journal Title

      Endocrine Pathology (In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression of cathepsin B and microvascular density increases with higher grade of astrocytomas2005

    • Author(s)
      M Wang
    • Journal Title

      Journal of Neuro-oncology 71(1)

      Pages: 3-7

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A case of pleomorphic xanthoastrocytoma presenting with massive tumoral hemorrhage2005

    • Author(s)
      D Yoshida
    • Journal Title

      Journal of Neuro-oncology 71(2)

      Pages: 169-171

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Inhibition of glioma angiogenesis and invasion by SI-27, an anti-matrix metalloproteinase agent in a rat brain tumor model.2004

    • Author(s)
      D Yoshida
    • Journal Title

      Neurosurgery 54(5)

      Pages: 1213-1220

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Drug-induced apoptosis by a matrix metalloproteinase inhibitor, SI-27 on human malignant glioma cell lines ; in vitro study.2004

    • Author(s)
      M Wang
    • Journal Title

      Journal of Neuro-oncology 66(1)

      Pages: 91-99

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Drug-nduced apoptosis by a matrix metalloproteinase inhibitor, SI-27 on human malignant glioma cell lines ; in vitro study.2004

    • Author(s)
      Kanazawa R, Yoshida D, Takahashi H, Sugisaki Y, Suzuki S, Tearmoto A.
    • Journal Title

      J Neuro-oncol 66

      Pages: 91-99

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of glioma angiogenesis and invasion by SI-27,an anti-matrix metalloproteinase agent in a rat brain tumor model.2004

    • Author(s)
      Yohida D, Takahashi H, Teramoto A.
    • Journal Title

      Neurosurgery 54(5)

      Pages: 1213-1221

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Drug-induced apoptosis by a matrix metalloproteinase inhibitor. SI-27 on human malignant glioma cell lines: in vitro study.2004

    • Author(s)
      R Kanazawa
    • Journal Title

      Journal of Neuro-oncology 66(1)

      Pages: 91-99

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Anti-invasive effect of an anti-matrix metalloproteinase agent in a murine brain slice model utilizing the serial monitoring of green fluorescent protein-labeled glioma cells2003

    • Author(s)
      D Yoshida
    • Journal Title

      Neurosurgery 52(1)

      Pages: 187-197

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Anti-invasive effect of an anti-matrix metalloproteinase agent in a murine brain slice model utilizing the serial monitoring of green fluorescent protein-labeled glioma cells.2003

    • Author(s)
      Yoshida D, Watanabe K, Noha M, Takahashi H, Teramoto A.
    • Journal Title

      Neurosurgery 52(1)

      Pages: 187-197

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Osteosarcoma arising from the skull.2003

    • Author(s)
      Kanazawa R, Yoshida D, Takahashi H, Matsumoto K, Teramoto A.
    • Journal Title

      -Case report- Neurol Med Chir (Tokyo) 43(2)

      Pages: 88-91

    • NAID

      110002277092

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Apoptotic induction by BE16627B on human malignant cell lines by anti-matrix metalloproteinase agent.2003

    • Author(s)
      Yoshida D, Watanabe K, Takahashi H, Sugisaki Y, Teramoto A.
    • Journal Title

      Brain Tumor Pathol 20

      Pages: 13-19

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The expression of mstrix metalloproteinase-2 and -9 in human glioma of different pathological grade.2003

    • Author(s)
      Wang M, Wang T, Liu S, Yoshida D, Teramot A.
    • Journal Title

      Brain Tumor Pathol 20

      Pages: 65-72

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] SI-27, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity; detection with a variable-pressure scanning electron microscope.2002

    • Author(s)
      D Yoshida
    • Journal Title

      Neurosurgery 50(3)

      Pages: 578-587

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] SI-27,a novel inhibitor of matrix metalloproteinases with antiangiogenic activity ; detection with a variable-pressure scanning electron microscope.2002

    • Author(s)
      Yoshida D, Noha M, Watanabe K, Sugisaki Y, Teramoto A.
    • Journal Title

      Neurosurgery 50(3)

      Pages: 578-587

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Suppression of matrix metalloproteinase activity by SI-27 : detection by a new activity assay with S-244,a specific chromogenic peptide.2002

    • Author(s)
      Yoshida D, Noha M, Watanabe K, Sugisaki Y, Teramoto A.
    • Journal Title

      Journal of Neuro-oncology 58(1)

      Pages: 1-11

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tracking cell invasion of human glioma cells and the suppression by anti-matrix metalloproteinase agent in rodent brain slice model.2002

    • Author(s)
      Yoshida D, Watanabe K, Noha M, Takahashi H, Teramoto A, Sugisaki Y.
    • Journal Title

      Brain Tumor Pathology 19(2)

      Pages: 69-76

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Yoshida D: "Apoptotic induction by BE16627B"Brain Tumor Pathol. 20・1. 13-19 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida D: "Tracking cell invasion of human glioma cells"Brain Tumor Pathol. 19・2. 69-76 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida D: "Anti-invasive effect of an anti-matrix"Neurosurgery. 52・1. 187-196 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Teramoto A: "Contemporary Transsphenoidal surgery"Biomed Pharmacother. 56.Suppl. 154-157 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Teramoto A: "Complication of Transsphenoidal Pituitary Surgery"No Shikei Geka. 31・11. 1165-1176 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sanno N: "A survey of pituitary incidentaloma in Japan"Eur J Endocrinol. 149・2. 123-127 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida D.: "SI-27, a novel inhibitor of matrix metalloproteinase inhibits"Neurosurgery. 50・3. 578-587 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida. D: "Suppressin of matrix metalloproteinase acting by SI-27"Journal of Neuro-Oncology. 58・1. 1-11 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida. D: "Tracking cell invasion of human glioroma cells"Brain Tumor Pathology. 19・2. 69-76 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 吉田大蔵: "頭蓋外に浸潤発達した髄膜腫"Clinical Neuroscience. 20・5. 595-596 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 吉田大蔵: "新しいmatrix metalleproteluare"日本医大雑誌. 69・2. 211-212 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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