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Basic research to explore factors to improve effectiveness of radiation therapy

Research Project

Project/Area Number 24249067
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Radiation science
Research InstitutionNational Institute of Radiological Sciences

Principal Investigator

OKAYASU RYUICHI  国立研究開発法人放射線医学総合研究所, 放射線防護研究センター, 主任研究員 (50356135)

Co-Investigator(Renkei-kenkyūsha) FUJIMORI Akira  放射線医学総合研究所, チームリーダー (50314183)
SAI Sei  放射線医学総合研究所, 主任研究員 (20342735)
YAJIMA Hirohiko  放射線医学総合研究所, 主任研究員 (30261895)
Research Collaborator JEGGO Penny  
NICKOLOFF Jac  
Lee Younghyun  
正岡 綾  
砂田 成章  
平川 博一  
Li Huizi  
Project Period (FY) 2012-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥42,770,000 (Direct Cost: ¥32,900,000、Indirect Cost: ¥9,870,000)
Fiscal Year 2015: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
Fiscal Year 2014: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
Fiscal Year 2013: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
Fiscal Year 2012: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000)
KeywordsHsp90阻害剤 / 重粒子線 / 放射線増感 / TAS-116 / DNA二重鎖切断修復 / DNA-PK阻害剤 / 細胞周期 / 細胞老化 / PU-H71 / Hsp90 阻害剤 / 併用療法 / DNA損傷応答 / Hsp90 阻害剤 / 相同組換修復 / X線 / DNA-PKcs / ヒートショック蛋白90阻害剤 / 17AAG / マウスモデル
Outline of Final Research Achievements

In order to improve the world leading heavy ion radiotherapy, we studied the combination regimen of Hsp90 inhibitor and carbon-ion irradiation. After screening and studying various inhibitors, we found that most Hsp90 inhibitors can cause tumor specific radio-sensitization with heavy ions and the cause of this was shown to be inhibition of DNA double strand break (DSB) repair by the inhibitors. Among these we suggest that an Hsp90 inhibitor TAS-116 might be most recommendable clinically due to its low toxicity.
We also studied the combination effects of a DNA DSB repair inhibitor NU7441 and radiation including heavy ions. Our investigation indicated that a non-toxic concentration of NU7441 radio-sensitized tumor cells and the cause seems to be related to disturbed cell cycle progression. Moreover, some tumor cells show senescence like appearance after the combination treatment. Our study forms a biological basis for a new combination cancer therapy including particle radiation.

Report

(5 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (33 results)

All 2015 2014 2013 2012 Other

All Int'l Joint Research (2 results) Journal Article (13 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 13 results,  Open Access: 6 results,  Acknowledgement Compliant: 7 results) Presentation (15 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results) Book (3 results)

  • [Int'l Joint Research] Colorado State University/Emory University(米国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] GSI (重イオン研究所)(ドイツ)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] VE-821, an ATR inhibitor, causes radiosensitization in human tumor cells irradiated with high LET radiation.2015

    • Author(s)
      Fujisawa H, Nakajima NI, Sunada S, Lee Y, Hirakawa H, Yajima H, Fujimori A, Uesaka M, Okayasu R.
    • Journal Title

      Radiation Oncology

      Volume: 10 Issue: 1 Pages: 175-175

    • DOI

      10.1186/s13014-015-0464-y

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] DNA Damage Response Proteins and Oxygen Modulate Prostaglandin E2 Growth Factor Release in Response to Low and High LET Ionizing Radiation.2015

    • Author(s)
      Allen CP, Tinganelli W, Sharma N, Nie J, Sicard C, Natale F, King M 3rd, Keysar SB, Jimeno A, Furusawa Y, Okayasu R, Fujimori A, Durante M, Nickoloff JA.
    • Journal Title

      Frontiers in Oncology (Radiation Oncology)

      Volume: 5 Pages: 260-260

    • DOI

      10.3389/fonc.2015.00260

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] A comprehensive analysis of radiosensitization targets; functional inhibition of DNA methyltransferase 3B radiosensitizes by disrupting DNA damage regulation.2015

    • Author(s)
      Fujimori H, Sato A, Kikuhara S, Junhui W, Hirai T, Sasaki Y, Murakami Y, Okayasu R, Masutani M.
    • Journal Title

      Sci Rep.

      Volume: on-line paper Issue: 1 Pages: 18231-18231

    • DOI

      10.1038/srep18231

    • NAID

      120006987240

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The combination of Hsp90 inhibitor 17AAG and heavy-ion irradiation provides effective tumor control in human lung cancer cells.2015

    • Author(s)
      Hirokazu Hirakawa, Hiroshi Fujisawa, Aya Masaoka, Miho Noguchi, Ryoichi Hirayama, Momoko Takahashi, Akira Fujimori, Ryuichi Okayasu
    • Journal Title

      Cancer Medicine

      Volume: 4 Issue: 3 Pages: 426-436

    • DOI

      10.1002/cam4.377

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The complexity of DNA double strand break is a crucial factor for activating ATR signaling pathway for G2/M checkpoint regulation regardless of ATM function2015

    • Author(s)
      Xue L, Furusawa Y, Okayasu R, Miura M, Cui X, Liu C, Hirayama R, Matsumoto Y, Yajima H, Yu D.
    • Journal Title

      DNA Repair

      Volume: 25 Pages: 72-83

    • DOI

      10.1016/j.dnarep.2014.11.004

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Novel characteristics of CtIP at damage-induced foci following the initiation of DNA end resection.2015

    • Author(s)
      Hiroshi Fujisawa, Akira Fujimori, Ryuichi Okayasu, Mitsuru Uesaka, Hirohiko Yajima
    • Journal Title

      Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis

      Volume: 771 Pages: 36-44

    • DOI

      10.1016/j.mrfmmm.2014.12.001

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Heterochromatin domain number correlates with X-ray and carbon-ion radiation resistance in cancer cells2014

    • Author(s)
      Sato K, Imai T, Okayasu R, Shimokawa T.
    • Journal Title

      Radiat. Res.

      Volume: 182 Issue: 4 Pages: 408-419

    • DOI

      10.1667/rr13492.1

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Parg Deficiency Confers Radio-sensitization through Enhanced Cell Death in Mouse ES Cells Exposed to Various Forms of Ionizing Radiation.2013

    • Author(s)
      Shirai H, Fujimori H, Gunji A, Maeda D, Hirai T, Poetsch AR, Harada H, Yoshida T, Sasai K, Okayasu R, Masutani M.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: Epub ahead of print Issue: 1 Pages: 100-106

    • DOI

      10.1016/j.bbrc.2013.04.048

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Selective enhancing effect of Early mitotic inhibitor 1 depletion on sensi tivity of doxorubicin.2013

    • Author(s)
      Shimizu N, Nakajima NI, Tsunematsu T, Ogawa I, Kawai H, Hirayama R, Fujimori A, Yamada A, Okayasu R, Ishimaru N, Takata T, Kudo Y.
    • Journal Title

      Journal of Biological Chemistry

      Volume: 288 Issue: 24 Pages: 17238-17252

    • DOI

      10.1074/jbc.m112.446351

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chromosome aberrations in normal human fibroblasts analyzed in G0/G1 and G2/M phases after exposure in G0 to radiation with different linear energy transfer (LET).2013

    • Author(s)
      Liu C, Kawata T, et al
    • Journal Title

      Mutat Res

      Volume: 756 Issue: 1-2 Pages: 101-107

    • DOI

      10.1016/j.mrgentox.2013.05.005

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Visualisation of cH2AX Foci Caused by Heavy Ion Particle Traversal; Distinction between Core Track versus Non-Track Damage.2013

    • Author(s)
      Nakajima NI, Brunton H, Watanabe R, Shrikhande A, Hirayama R, Matsufuji N, Fujimori A, Murakami T, Okayasu R, Jeggo P, Shibata A.
    • Journal Title

      PLoS ONE

      Volume: 8 Issue: 8 Pages: e70107-e70107

    • DOI

      10.1371/journal.pone.0070107

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The complexity of DNA double strand breaks is a critical factor enhancing end-resection.2013

    • Author(s)
      Yajima H, Fujisawa H, Nakajima NI, Hirakawa H, Jeggo P, Okayasu R, Fujimori A.
    • Journal Title

      DNA Repair

      Volume: 12 Issue: 11 Pages: 936-946

    • DOI

      10.1016/j.dnarep.2013.08.009

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of the bromodeoxyuridine-mediated sensitization effects between low-LET and high-LET ionizing radiation on DNA double-strand breaks2013

    • Author(s)
      Fujii Y, Genet MD, Roybal EJ, Kubota N, Okayasu R, Fujimori A, Mori T, Mauro K, Kato TA
    • Journal Title

      Oncol Rep

      Volume: 29 Issue: 6 Pages: 2133-2139

    • DOI

      10.3892/or.2013.2354

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] EFFECTS OF HSP90 INHIBITOR PUH71 IN HEAVY ION IRRADIATED HUMAN CANCER CELLS2015

    • Author(s)
      Lee Younghyun, Ryuichi Okayasu, Aya Masaoka, Huizi Li, Shigeaki Sunada
    • Organizer
      放射線ワークショップ(第1回)-未来に繋ぐ放射線研究- 日本放射線影響学会
    • Place of Presentation
      富山
    • Year and Date
      2015-10-16
    • Related Report
      2015 Annual Research Report
  • [Presentation] Radiosensitization effect of Hsp90 inhibitor CAY10607 in human tumor cells2015

    • Author(s)
      Ryuichi Okayasu, Younghyun Lee, Aya Masaoka, Shigeaki Sunada
    • Organizer
      日本癌学会 学術総会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] Radiobiology Update for Radiation Oncologist2015

    • Author(s)
      Ryuichi Okayasu
    • Organizer
      15th International Congress of Radiation Research
    • Place of Presentation
      Kyoto, Japan
    • Year and Date
      2015-05-25
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] DNA Methylation Alterations in Human Lymphocyte Induced by Gamma Radiation in Vitro2015

    • Author(s)
      Lee Younghyun, Ryuichi Okayasu
    • Organizer
      15th International Congress of Radiation Research
    • Place of Presentation
      Kyoto, Japan
    • Year and Date
      2015-05-25
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Investigation of a new Hsp90 inhibitor as combined with low and high LET radiation2014

    • Author(s)
      正岡 綾、砂田成章、平川博一、根井 充、藤森 亮、岡安 隆一
    • Organizer
      日本癌学会
    • Place of Presentation
      パシフィコ 横浜
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Effectiveness of the combined treatment with Hsp90 inhibitor and heavy ion irradiation2014

    • Author(s)
      Ryuichi OKayasu, Aya Masaoka, Hirokazu Hirakawa, Hiroshi Fujisawa, Shigeaki Sunada, Ryoichi Hirayama, Miho Noguchi, Huizi Li, and Akira Fujimori
    • Organizer
      American Association for Cancer Research Annual Meeting
    • Place of Presentation
      San Diego Convention Center, CA USA
    • Year and Date
      2014-04-05 – 2014-04-09
    • Related Report
      2014 Annual Research Report
  • [Presentation] Hsp90 inhibitor is a good candidate for effective combination therapy with carbon ions2013

    • Author(s)
      Ryuichi Okayasu, Hirokazu Hirakawa, Aya Masaoka, Miho Noguchi, Ryoichi Hirayama, Huizi Li, Yoshitaka Matsumoto, Akira Fujimori
    • Organizer
      HITSRS 2013
    • Place of Presentation
      Chiba, Japan
    • Related Report
      2013 Annual Research Report
  • [Presentation] Biological basis for heavy ion radiotherapy2013

    • Author(s)
      Ryuichi Okayasu
    • Organizer
      International Symposium on Radiation Sciences
    • Place of Presentation
      Taipei, Taiwan
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Hsp90阻害剤PU-H71と炭素線照射の併用による癌抑制効果2013

    • Author(s)
      岡安 隆一, 正岡 綾, 李 惠子, 平川 博一, 松本 孔貴, 藤森 亮
    • Organizer
      日本癌学会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
  • [Presentation] Hsp90阻害剤と重粒子線照射併用処理によるがん細胞の反応2013

    • Author(s)
      正岡 綾, 平川 博一, 李 惠子, 岡安 隆一
    • Organizer
      日本分子生物学会
    • Place of Presentation
      神戸
    • Related Report
      2013 Annual Research Report
  • [Presentation] Significant tumor radio-sensitization by the combined treatment of hsp90 inhibitor and heavy ion irradiation in vivo2012

    • Author(s)
      Ryuichi Okayasu
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      札幌芸文館(北海道)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Hsp90 inhibitor may enhance the effectiveness of heavy ion treatment2012

    • Author(s)
      Ryuichi Okayasu
    • Organizer
      Radiation Research Society 58th Annual Meeting
    • Place of Presentation
      プエルトリコ, San Juan
    • Related Report
      2012 Annual Research Report
  • [Presentation] Radiosensitization by inhibition of homologous recombination repair combined with high LET heavy ion irradiation2012

    • Author(s)
      Hirokazu Hirakawa
    • Organizer
      日本放射線影響学会第55回大会
    • Place of Presentation
      東北大学(宮城県)
    • Related Report
      2012 Annual Research Report
  • [Presentation] 複雑な損傷構造を持つDNA二本鎖切断の誘発によるDNA末端の削り込み反応の解析2012

    • Author(s)
      矢島 浩彦
    • Organizer
      第35回日本分子生物学会年会
    • Place of Presentation
      福岡国際会議場(福岡県)
    • Related Report
      2012 Annual Research Report
  • [Presentation] マウス胚繊維芽細胞におけるクロマチン関連蛋白HMGN1とPARP-1との相互作用2012

    • Author(s)
      正岡 綾
    • Organizer
      第35回日本分子生物学会年会
    • Place of Presentation
      福岡国際会議場(福岡県)
    • Related Report
      2012 Annual Research Report
  • [Book] HIMAC20年の歩み: HIMAC20周年記念 研究成果要覧 1セクション担当 (p27-34)2015

    • Author(s)
      岡安隆一
    • Total Pages
      245
    • Publisher
      放射線医学総合研究所
    • Related Report
      2015 Annual Research Report
  • [Book] Stress-Induced Mutagenesis2013

    • Author(s)
      Allen, C. P., Fujimori, A., Okayasu, R., & Nickoloff, J. A.
    • Publisher
      Springer New York
    • Related Report
      2013 Annual Research Report
  • [Book] Stress-Induced Mutagenesis.Ch9: Radiation-Induced Delayed Genome Instability and hypermutation in Mammalian Cells2013

    • Author(s)
      Chris Allen
    • Publisher
      Springer
    • Related Report
      2012 Annual Research Report

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Published: 2013-05-15   Modified: 2022-01-28  

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