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A basic study on gene therapy for ovarian cancer to inhibition peritoneal dissemination

Research Project

Project/Area Number 13671740
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Obstetrics and gynecology
Research InstitutionJichi Medical University

Principal Investigator

SUZUKI Mitsuaki  Jichi Medical School, Department of Obstetrics and Gynecology, Professor, 医学部, 教授 (50110870)

Co-Investigator(Kenkyū-buntansha) KOBAYASHI Hiroshi  Hamamatsu University School of Medicine, Department of Obstetrics and Gynecology, Associate professor, 医学部, 助教授 (40178330)
OZAWA Keiya  Jichi Medical School, Department of Center for Molecular Medicine, Professor, 医学部, 教授 (30137707)
OHWADA Michitaka  Jichi Medical School, Department of Obstetrics and Gynecology, Associate professor, 医学部, 助教授 (40203955)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
Keywordsovarian cancer / peritoneal dissemination / angiogenesis / molecular biology / gene therapy / bikunin / IL-10 / soluble Flt-1 / 血管新生抑制 / bikunin / IL-10 / soluble Flt-1 / NK4 / PTEN / AAV / TP / TPI
Research Abstract

To establish molecular targeting therapy and gene therapy for ovarian cancer targeting inhibition of peritoneal dissemination and angiogenesis, we performed a basic study of various molecular targeting factors.
1)An antagonist of hepatocyte growth factor, HGF/NK4, exhibited inhibitory effects on cell migration in vitro and peritoneal dissemination in vivo.
2)A urinary trypsin inhibitor, bikunin, exhibited inhibitory effects on cancer cell invasion and metastasis. We successfully prepared a hybrid gene, ATF-HI8, in which the active site of bikunin, HI8, was bound to ATF that has high affinity for cancer cells. ATF-HI8 markedly inhibited cell migration and invasion.
3)An inflammation-suppressing cytokine, IL-10, inhibited angiogenesis, and tumor growth and peritoneal dissemination were inhibited through the inhibition of angiogenesis in ovarian cancer-bearing mice. We prepared IL-10-expressing AAV vectors(AAV-IL-10), and investigated the effect in vivo. Intramuscular injection of AAV-IL-10 into skeletal muscle decreased the numbers of new blood vessels and peritoneally disseminating tumors in ovarian cancer-bearing mice, and the survival period of the tumor-bearing mice was extended.
4)Theeffects of sFlt-1, the soluble form of a VEGF receptor, Flt-1, were also investigated. Inhibition of tumor growth and peritoneal dissemination through inhibition of angiogenesis was observed in ovarian cancer-bearing mice. sFLT-1-expressing AAV vectors (AAV-sFlt-1) were prepared, and administered in vivo, and the numbers of new blood vessels and peritoneally disseminating tumors were decreased.
The above findings clarified that molecular targeting factors, HGFINK4, bikunin (ATF-HI8), IL-b, and sFlt-1, inhibit peritoneal dissemination of ovarian cancer through inhibition of tumor angiogenesis and migration/invasion. In addition, therapeutic AAV vectors expressing IL-10 and sFlt-1 were successfully prepared, which may lead to gene therapy for ovarian cancer.

Report

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

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Suzuki, M.: "Are DNA mismatch repair deficiencies responsible for accumulation of genetic alterations in epithelial ovarian cancers?"Cancer Genet Cytogenet. 124. 152-158 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saga, Y.: "Expression of HGF/NK4 in ovarian cancer cells suppresses intraperitoneal dissemination and extends host survival."Gene Ther. 8. 1450-1455 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saga, Y.: "Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian cancer cells."Clin Cancer Res. 8. 1248-1252 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suzuki, M.: "Bikunin target genes in ovarian cancer cells identified by microarray analysis."J Biol Chem. 278. 14640-14646 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kohno, T.: "Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer."Cancer Res. 63. 5091-5094 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saga, Y.: "Suppression of cell migration in ovarian cancer cells mediated by PTEN overexpression."Int J Oncol. 23. 1109-1113 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suzuki, M., et al.: "Are DNA mismatch repair deficiencies responsible for accumulation of genetic alterations in epithelial ovarian cancers?"Cancer Genet Cytognet. 124. 152-158 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saga, Y., et al.: "Expression of HGF/NK4 in ovarian cancer cells suppresses intraperitoneal dissemination and extends host survival."Gene Ther. 8. 1450-1455 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saga, Y., et al.: "Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian cancer cells."Cancer Res. 8. 1248-1252 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suzuki, M., et al.: "Bikunin target genes in ovarian cancer cells identified by microarray analysis."J Biol Chem. 278. 14640-14646 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kohno, T., et al.: "Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer."Cancer Res. 63. 5091-5094 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saga, Y., et al.: "Suppression of cell migration in ovarian cancer cells mediated by PTEN overexpression."Int J Oncol. 23. 1109-1113 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suzuki, M.: "Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cell line by overexpression of bikunin."Int J Cancer. 104. 289-302 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tsukagoshi, S.: "Thymidine phosphorylase-mediated angiogenesis regulated by thymidine phosphorylase inhibitor in human ovarian cancer cells in vivo."Int J Oncol. 22. 961-967 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suzuki, M.: "Bikunin target genes in ovarian cancer cells identified by microarray analysis."J Biol Chem. 278. 14640-14646 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Saga, Y.: "Overexpression of thymidylate synthase mediates desensitization for 5-fluorouracil of tumor cells."Int J Cancer. 106. 324-326 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kohno, T.: "Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer."Cancer Res. 63. 5091-5094 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Saga, Y.: "Suppression of cell migration in ovarian cancer cells mediated by PTEN overexpression."Int J Oncol. 23. 1109-1113 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ohwada, M.: "Involvement of microsatellite instability in lymph node metastasis of endometrial carcinoma"Cancer Genet Cytogenet. 132. 152-155 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Saga, Y.: "Establishment of a new cell line(TAYA) of clear cell adenocarcinoma of the ovary and its radiosensitivity"Oncology. 62. 180-184 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Saga, Y.: "Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of topoisomerase I inhibitor irinotecan, in ovarian cancer cells"Clin Cancer Res. 8. 1248-1252 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Itamochi, H.: "Mechanisms of cisplatin resistance in clear cell carcinoma of the ovary"Oncology. 62. 349-353 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Itamochi, H.: "Low proliferation activity may be associated with chemoresistance in clear cell carcinoma of the ovary"Obstet Gynecol. 100. 281-287 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kanamori, Y.: "PTEN expression is associated with prognosis for patients with advanced endometrial carcinoma undergoing postoperative chemotherapy"Int J Cancer. 100. 686-689 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suzuki, M.: "Are DNA mismatch repair deficiencies responsible for accumulation of genetic alterations in epithelial ovarian cancers ?"Cancer Genet Cytogenet. 124. 152-158 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Suzuki, M.: "Micrometastatic p53-positive cells in the lymph nodes of early stage epithelial ovarian cancer : Prognostic significance"Oncology. 60. 170-175 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Suzuki, M.: "Erythropoietin synthesis by tumour tissues in a patient with uterine myoma and erythrocytosis"Brit J Haematol. 113. 49-51 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Saga, Y.: "Expression of HGF/NK4 in ovarian cancer cells suppresses intraperitoneal dissemination and extends host survival"Gene Ther. 8. 1450-1455 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sekine, M.: "Localization of a novel susceptibility gene for familial ovarian cancer to chromosome 3p22-p25"Hum Mol Genet. 10. 1421-1429 (2001)

    • Related Report
      2001 Annual Research Report

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

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