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Establishment of a new strategy for colorectal cancer gene therapy by controlling Wnt-signal molecules

Research Project

Project/Area Number 11470126
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionTohoku University

Principal Investigator

SHIBATA Hiroyuki  Tohoku Univ., Inst. Dev. Aging and Cancer, Assistant Professor, 加齢医学研究所, 助手 (50260071)

Co-Investigator(Kenkyū-buntansha) ISHIOKA Chikashi  Tohoku Univ., Inst. Dev. Aging and Cancer, Associate Professor, 加齢医学研究所, 助教授 (60241577)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2001: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1999: ¥7,600,000 (Direct Cost: ¥7,600,000)
KeywordsAPC gene / beta-Catenin / Wntシグナル / APC / 大腸癌
Research Abstract

Recent studies indicate that the activation of Wnt-signal pathway, which is composed of the sequential reactions including loss of APC function, resulting accumulation of beta-Catenin and the activation of the down-stream target gene such as c-Myc via transcriptional factors, is deeply involved in the colorectal carcinogenesis. It might be possible to suppress the tumor growth by controlling theses Wnt-signal molecules.
For this purpose, two strategies are planned. One is to construct some vector systems, which enable to decrease the level of beta-Catenin in colon cancer cells. The other is to set up the toxic gene therapy, where the up-regulated signal pathway toward c-Myc is connected to express some toxic genes such as DT-A.
Strategy 1. Construction of the beta-Catenin down-regulation vector and its application of gene therapy
The entire length of APC gene is very huge and disadvantageous for gene transfer. On the other hand, the central one third portion of APC gene (1260-2056 a.a.) i … More s essential for beta-Catenin degradation. This smaller portion (it is called, APC-Core) functions like a scaffold protein. The APC-Core was put under the control of the various promoters including CMV and MT promoter. These vectors have some potential to induce the apoptosis, when introduced into the colorectal cancer cell lines. Then, in vivo utility of theses vectors were examined. One colorectal cancer cell line, DLD-1 was inoculated in the nude mice to analyze the in vivo gene transfer efficiency. Adenoviral gene transfer and electroporation were adapted. It was indicated that the adenovial method was much more efficient than the electroporation. In the view point of the curability, even by the adenovial method, cancer cell could not be driven away completely from the host. Repetitious use of the adenovirus is thought to diminish its effectiveness mainly due to its immunogenisity. The APC-Core has some potential to induce the apoptosis in the colorectal cancer, but some efficient gene transfer methods into colorectal cancer must be established.
Strategy 2. Construction of the colorectal cancer specific toxic gene therapy
The signal to c-Myc activation was utilized to this strategy. The 5' promoter region of c-Myc was connected to the minimum promoter and DT-A gene. This regulation is not so tight and specific toxicicity in the colorectal cancer cell lines could not be achieved. Less

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Hasegawa S., et al.: "Apoptosis in neuronal crest cells by functional loss of APC tumor supressor gene"PNAS. 99(1). 297-302 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Han SY., et al.: "Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay"Cancer Res.. 60. 3147-3151 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kato H., et al.: "Functional evaluation of p53 and PTEN gene mutatios in gliomas"Clinical Cancer Res.. 6. 3937-3943 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamashita Y., et al.: "BRCA1 mutation testing for Japanese patients with ovarian cancer in breast cancer screening"Breast Cancer Research and Treatment. 58. 11-17 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kato S., et al.: "Effects of p51/p63 missense mutations on transcriptional activities of p53 downstream gene promoters"Cancer Res.. 59. 5908-5911 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoshioka T, et al.: "A new combination chemotherapy with cis-diammine-glycolatoplatinum (Nedaplatin) and 5-fluorouracil for advanced esophageal cancers"Intern Med.. 38(11). 844-848 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hasegawa S., et al.: "Apoptosis in neuronal crest cells by functional loss of APC tumor supressor gene."PNAS. 99(1). 297-302 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Han SY., et al.: "Functional evaluation of PTEN missense mutations using in vitro phosphoinositide hosphatase assay."Cancer Res.. 60. 3147-3151 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kato H., et al.: "Functional evaluation of p53 and PTEN gene mutatios in gliomas"Clinical Cancer Res.. 6. 3937-3943 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamashita Y., et al.: "BRCA1 mutation testing for Japanese patients with ovarian cancer in breast cancer screening"Breast Cancer Research and Treatment. 58. 11-17 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kato S., et al.: "Effects of p51/p63 missense mutations on transcriptional activities of p53 downstream gene promoters."Cancer Res.. 59. 5908-5911 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoshioka T., et al.: "A new combination chemotherapy with cis-diammine-glycolatoplatinum (Nedaplatin) and 5-fluorouracil for advanced esophageal cancers."Intern Med.. 38(11). 844-848 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nichols KE., et al.: "Heterozygous germline ATM mutations do not contribute to radiation-associated malignancies after Hodgikin's disease"Journal of Clinical Oncology. 17. 1259-1266 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Bell D, et al.: "Common nonsense mutations in RAD52"Cancer Res.. 59. 3883-3888 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sunahara M., et al.: "Mutational analysis of p51A/TAp63 gamma, a p53 homolog, in non-small cell lung cancer and breast cancer."Oncogene. 18. 3761-3765 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shimada A., et al.: "The transcriptional activities of p53 and its homologue p51/p63: similarities and differences"Cancer Res.. 59. 2781-2786 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sumitaka Hasegawa et al.: "Apoptosis in neuronal crest cells by functional loss of APC tumor suppressor gene"PNAS. 99(1). 297-302 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ham SY,Koto H,Kato S,Suzuki T,Shibata H, et al.: "Functional evaluation of PTEN missense mutations using in vitro phosphinositide phosphatase a ssay"Cancer Res.. 60. 3147-3151 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kato H,Kato S,kumaba T, et al.: "Functional evaluation of p53 and PTEN gene mutations in gliomas."Clinical cancer reseach. 6. 3937-3943 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shimada A. et al.: "The transcriptional activities of p53 and its homologue p51/p63: similarities and differences"Cancer Research. 59. 2781-2786 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kato S. et al.: "Effects of p51/p63 missense mutations on transcriptional activities of p53 downstream gene promoters"Cancer Research. 59. 5908-5911 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sunahara M. et al.: "Mutational analysis of p51A/TAp63 gamma, a p53 homolog, in non-small cell lung cancer and breast cancer"Oncogene. 18. 3761-3765 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamashita Y. et al.: "BRCAl mutation testing for Japanese patients with ovarian cancer in breast cancer screening"Breast Cancer Research and Treatment. 58. 11-17 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Bell D. et al.: "Common nonsense mutations in RAD52"Cancer Research. 59. 3883-3888 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nichols KE. et al.: "Heterozygous germline ATM mutations do not contribute to radiation-associated malignancies atter Hodgikin's disease"Journal of Clinical Oncology. 17. 1259-1266 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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