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Application of antisense oligonucleotides for EWS-Flil in Ewing's sarcoma.

Research Project

Project/Area Number 15591586
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

TANAKA Kazuhiro  Kyushu University, Kyushu University Hospital, Research Associate, 大学病院, 助手 (10274458)

Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsEwing's Sarcoma / EWS-Flil / fusion gene / antisense oligonucleotide / molecular target therapy
Research Abstract

The translocation t(11;22)(q24:q12) is a specific chromosomal abnormality detected in Ewing's sarcoma(ES). The translocation results in an EWS-Flil fusion gene. Recent studies have evaluated transforming potentials of the fusion gene products acting as an aberrant transcription factor. However, the biological significance of EWS-Flil is still unknown. We have found that there is a correlation between the expression levels of the EWS-Flil fusion gene and the proliferative activities of ES cells. When the EWS-Flil expression was inhibited by an antisense oligonucleotide (AS) against the fusion gene, the growth of the ES cells was significantly reduced both in vitro and in vivo. The flow cytometry analysis indicated that the growth inhibition of the cells by AS was mediated by G1 arrest in the cell cycle progression. In the present study, we aimed to apply AS against EWS-Flil to inhibit the growth of ES in vivo. To identify the most effective AS sequence, we analyzed EWS-Flil mRNA structure using computer software, and determined mRNA loops which were possible targets of AS. We synthesized these AS and examined whether these AS would inhibit ES cell growth in vitro. We obtained the AS sequence which could most effectively inhibit the growth of ES cells. We also confirmed the growth inhibitory effects of AS in vivo. We next examined the effects of AS on the induction ofapoptosis in ES cells. We found that the effects of AS on ES cell line was cytostatic and apoptosis was not induced in ES cells by AS. Thus, we next examined the combination effects of AS and anti-tumor drugs. Cotreatment with AS and topoisomerase inhibitors showed strong induction ofapoptosis in ES cells. These results suggest that the combination chemotherapy with AS and topoisomerase inhibitors would be effective to maximize the antitumor effects on ES in clinical trial.

Report

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

    (25 results)

All 2004 Other

All Journal Article (16 results) Book (2 results) Publications (7 results)

  • [Journal Article] The prognostic and therapeutic relevance of p27Kip1 in Ewing' s family tumors.2004

    • Author(s)
      Matsunobu T, et al.
    • Journal Title

      Clin.Cancer Res. 10

      Pages: 1003-1012

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] PTEN and other tumor suppressor gene mutations as secondary genetic alterations in synovial sarcoma.2004

    • Author(s)
      Saito T, et al.
    • Journal Title

      Oncol Rep.,11:1011-1015,2004 11

      Pages: 1011-1015

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Low-grade fibromyxoid sarcoma versus low-grade myxofibrosarcoma in the extremities and trunk.2004

    • Author(s)
      Oda Y, et al.
    • Journal Title

      Histopathology 45

      Pages: 29-38

    • 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] E-cadherin mutation and Snail overexpression as alternative mechanisms of E-cadherin inactivation in synovial sarcoma.2004

    • Author(s)
      Saito T, et al.
    • Journal Title

      Oncogene 23

      Pages: 8629-8638

    • 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] The prognostic and therapeutic relevance of p27Kip1 in Ewing's family tumors.2004

    • Author(s)
      Tomoya Matsunobu, Kazuhiro Tanaka, Yoshihiro Matsumoto, Fumihiko Nakatani, Riku Sakimura, Masuo Hanada, Li Xu, Yoshinao Oda, Ichiro Naruse, Hideki Hoshino, Hiromasa Miura, Masazumi Tsuneyoshi, Yukihide Iwamoto
    • Journal Title

      Clin.Cancer Res. 10

      Pages: 1003-1012

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] PTEN and other tumor suppressor gene mutations as secondary genetic alterations in synovial sarcoma.2004

    • Author(s)
      Tsuyoshi Saito, Yoshinao Oda, Ken-ichi Kawaguchi, Tomonari Takahira, Hidetaka Yamamoto, Kazuhiro Tanaka, Shuichi Matsuda, Akio Sakamoto, Yukihide Iwamoto, Masazumi Tsuneyoshi
    • Journal Title

      Oncol Rep. 11

      Pages: 1011-1015

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Low-grade fibromyxoid sarcoma versus low-grade myxofibrosarcoma in the extremities and trunk. A comparison of clinicopathological and immunohistochemical features.2004

    • Author(s)
      Yoshinao Oda, Tomonari Takahira, Ken-ichi Kawaguchi, Hidetaka Yamamoto, Sadafumi Tamiya, Shuichi Matsuda, Kazuhiro Tanaka, Yukihide Iwamoto, Masazumi Tsuneyoshi
    • Journal Title

      Histopathology 45

      Pages: 29-38

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] E-cadherin mutation and Snail overexpression as alternative mechanisms of E-cadherin inactivation in synovial sarcoma.2004

    • Author(s)
      Tsuyoshi Saito, Yoshinao Oda, Ken-ichi Kawaguchi, Keishi Sugimachi, Hidetaka Yamamoto, Naomi Tateishi, Kazuhiro Tanaka, Shuichi Matsuda, Yukihide Iwamoto, Marc Ladanyi, Masazumi Tsuneyoshi
    • Journal Title

      Oncogene 23

      Pages: 8629-8638

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The prognostic and therapeutic relevance of p27Kip1 in Ewing's family tumors.2004

    • Author(s)
      Matsunobu T, et al.
    • Journal Title

      Clin.Cancer Res. 10

      Pages: 1003-1012

    • Related Report
      2004 Annual Research Report
  • [Journal Article] PTEN and other tumor suppressor gene mutations as secondary genetic alterations in synovial sarcoma.2004

    • Author(s)
      Saito T, et al.
    • Journal Title

      Oncol Rep., 11:1011-1015, 2004 11

      Pages: 1011-1015

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Transactivation of cyclin E gene by EWS-Fli1 and antitumor effects cyclin dependent kinase inhibitor on Ewing's family tumor.

    • Author(s)
      Li X, et al.
    • Journal Title

      Int.J.Cancer (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] Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors.

    • Author(s)
      Sakimura R, et al.
    • Journal Title

      Int.J.Cancer (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] Transactivation of cyclin E gene by EWS-Flil and antitumor effects of cyclin dependent kinase inhibitor on Ewing's family tumor.

    • Author(s)
      Xu Li, Kazuhiro Tanaka, Fumihiko Nakatani, Tomoya Matsunobu, Riku Sakimura, Masuo Hanada, Takamitsu Okada, Tomoyuki Nakamura, Yukihide Iwamoto
    • Journal Title

      Int.J.Cancer (In Press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors.

    • Author(s)
      Riku Sakimura, Kazuhiro Tanaka, Fumihiko Nakatani, Tomoya Matsunobu, Xu Li, Masuo Hanada, Takamitsu Okada, Tomoyuki Nakamura, Yukihide Iwamoto
    • Journal Title

      Int.J.Cancer (In Press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transactivation of cyclin E gene by EWS-Fli1 and antitumor effects cyclin dependent kinase inhibitor on Ewing's family.

    • Author(s)
      Li X, et al.
    • Journal Title

      Int.J.Cancer (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors.

    • Author(s)
      Sakimura R, et al.
    • Journal Title

      Int.J.Cancer (in press)

    • Related Report
      2004 Annual Research Report
  • [Book] 神中整形外科学改訂22版2004

    • Author(s)
      田仲 和宏, 他(分担執筆)
    • Total Pages
      2124
    • Publisher
      南山堂
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 神中整形外科学改訂22版2004

    • Author(s)
      田仲 和宏他(分担執筆)
    • Total Pages
      2124
    • Publisher
      南山堂
    • Related Report
      2004 Annual Research Report
  • [Publications] Nakatani F, et al.: "Identification of p21(WAF1/CIP1) as a direct target of EWS-Fli1 oncogenic fusion protein"J.Biol.Chem.. 278. 15105-15115 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Saito T, et al.: "PTEN/MMAC1 gene mutationis a rare event in soft tissue sarcomas without specific balanced translocations"Int.J.Cancer. 104. 175-178 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ayyanathan K, et al.: "Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing : a mammalian cell culture model of gene variegation"Genes Develop.. 17. 1855-1869 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Harimaya K, et al.: "Primitive neuroectodermal tumor and extraskeletal Ewing's sarcroma arising primarily in the spinal canal"Spine. 28. 408-412 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Oda Y, et al.: "Altered expression of cell cycle regulators in myxofibrosarcoma, with special emphasis on their prognostic implications"Hum.Pathol.. 34. 1035-1042 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsunobu T, et al.: "The prognostic and therapeutic relevance of p27Kip1 in Ewing's family tumors"Clin.Cancer Res.. (In Press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 田仲 和宏, 他(分担執筆): "別冊整形外科No.43 骨軟部腫瘍の診断と治療-21世紀への展開"南江堂. 230 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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