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Gene therapy for hepatocellular carcinoma

Research Project

Project/Area Number 11670516
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionMiyazaki Medical College

Principal Investigator

IDO Akio  Miyazaki Medical College, Research Associate, 医学部, 助手 (30291545)

Co-Investigator(Kenkyū-buntansha) 堀 剛  宮崎医科大学, 医学部, 助手 (00281220)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥800,000 (Direct Cost: ¥800,000)
Keywordsgene therapy / hepatoma / α-fetoprotein / hypoxia / VEGF / HSV-tk gene / gancyclovir / suicide gene / 血管新生
Research Abstract

We previously reported that the retroviral vector expressing the herpes simplex virus-thymidine kinase (HSV-tk) gene under the control of 0.3-kb human α-fetoprotein (AFP) gene promoter (AF0.3) provided the cytotoxicity to ganciclovir (GCV) in high-AFP-producing human hepatoma cells but not in low-AFP-producing cells. Therefore, specific enhancement of AFP promoter activity is likely to be required to induce enough cytotoxicity in low-AFP-producing hepatoma cells. In this study, we constructed a hybrid promoter, [HRE]AF, in which a 0.4-kb fragment of human vascular endothelial growth factor (VEGF) 5'-flanking sequences containing hypoxia responsive element (HRE) was fused to AF0.3 promoter. By means of the reporter gene transfection assay, hypoxia-inducible transcriptions that were mediated by [HRE]AF promoter were detected in low- and non-AFP-producing human hepatoma cells, but not in nonhepatoma cells. When the HSV-tk gene controlled by [HRE]AF promoter was transduced into hepatoma and nonhepatoma cells by a retroviral vector, the exposure to 1% O2 induced GCV-cytotoxicity specifically in the hepatoma cells. Moreover, in nude mice bearing solid tumor xenografts, only the tumors consisting of the virus-infected hepatoma cells gradually disappeared by GCV administration. These results indicate that the hypoxia-inducible enhancer of the human VEGF gene, which is directly linked to human AFP promoter, involves selective and enhanced tumoricidal activity in gene therapy for hepatocellular carcinoma.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (8 results)

All Other

All Publications (8 results)

  • [Publications] Hirofumi Uto et al..: "Hepatoma-specific gene therapy through retrovirus-mediated and targeted gene transfer using an adenovirus carrying the ecotropic receptor gene."Biochem.Biophys.Res.Commun.. 265. 550-555 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akio Ido et al.: "Gene therapy targeting for hepatocellular carcinoma : selective and enhanced suicide gene expression regulated by hypoxia-inducible enhancer linked to human a-fetoprotein promoter."Cancer Research. 61(in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 坪内博仁 他2名: "肝細胞癌の遺伝子治療-将来の展望"臨床消化器内科. 14・7. 268-278 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Uto H, Ido A, Hori T, et al.: "Hepatoma-specific gene therapy through retrovirus-mediated and targeted gene transfer using an adenovirus carrying the ecotropic receptor gene"Biochem Biophys Res Commun. 265. 550-555 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ido A, Uto H, et al.: "Gene therapy targeting for hepatocellular carcinoma : Selective and enhanced gene expression regulated by hypoxia-inducible enhancer linked to human α-fetoprotein promoter"Cancer Research. 61 (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hirofumi Uto et al..: "Hepatoma-specific gene therapy through retrovirus-mediated and targeted gene transfer using an adenovirus carrying the ecotropic receptor gene."Biochem.Biophys.Res.Commun.. 265. 550-555 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Akio Ido et al.: "Gene therapy targeting for hepatocellular carcinoma : selective and enhanced suicide gene expression regulated by hypoxia-inducible enhancer linked to human a-fetoprotein promoter."Cancer Research. 61(in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 坪内博仁 他2名: "肝細胞癌の遺伝子治療-将来の展望"臨床消化器内科. 14・7. 268-278 (1999)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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