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2007 Fiscal Year Annual Research Report

チロシンキナーゼ阻害剤の至適併用療法を予測するサロゲートマーカーの確立

Research Project

Project/Area Number 18014010
Research InstitutionNagoya University

Principal Investigator

清井 仁  Nagoya University, 医学部・附属病院, 講師 (90314004)

Co-Investigator(Kenkyū-buntansha) 冨田 章裕  名古屋大学, 医学部・附属病院, 助教 (80378215)
Keywordsチロシンキナーゼ / 阻害剤 / 分子標的療法 / サロゲートマーカー / 白血病 / シグナル伝達
Research Abstract

本研究においては、白血病の治癒を得るために、チロシンキナーゼ阻害剤を含む併用療法を分子基盤に基づき適切に選択する上でのサロゲートマーカーを確立することを目的として検討を行い、下記の成果を得た。
1.チロシンキナーゼ阻害剤の標的分子阻害効果をin vitroで評価するにあたり、ヒト血漿中蛋白との結合により、フリー体としての阻害剤濃度が低下することによる阻害活性に及ぼす影響を考慮する必要性が指摘されている。中でも主たる結合物質であるアルブミンとα1-acid-glycoprotein (AGP)濃度の阻害活性に及ぼす影響を検討したところ、多くのチロシンキナーゼ阻害剤においてAGPが濃度依存性に阻害活性を低下させることを明らかにした。担がん患者、特に白血病患者における血中AGP濃度は健常人の2倍以上に上昇しているとの報告があることより、現在、イマチニブにより治療中の慢性白血病患者におけるAGP濃度、イマチニブ血中濃度と治療効果との相関性につき多数例での検討を開始した。
2.チロシンキナーゼ阻害剤の併用による治療効果を評価するために、イマチニブ治療中の患者血漿を用いて標的分子に対する阻害活性を評価するplasma inhibitory activity (PIA)アッセイを確立した。
3.PIAアッセイにより、BCR/ABL、CrkL、STAT5、MAPKに対する脱リン酸化効果を評価したところ、細胞増殖抑制効果と最も相関し、かつ最も鋭敏な評価系としてはSTAT5に対する阻害効果であることが示されたが、細胞種類によっては、CrkLへの効果が有用であることが明らかになった。
4.以上の検討によりイマチニブ治療中の患者に対する併用療法の評価においては、PIAアッセイにより評価する必要性が示された。

  • Research Products

    (23 results)

All 2008 2007

All Journal Article (16 results) (of which Peer Reviewed: 16 results) Presentation (7 results)

  • [Journal Article] Response: Mutations of JAK2, JAK3 and GATA1 in acute megakaryobla stic leukemia of Down syndrome2008

    • Author(s)
      Asahito Hama
    • Journal Title

      Blood 111

      Pages: 2493-2494

    • Peer Reviewed
  • [Journal Article] Clinical characteristics and outcomes in patients with t(8;21)acute myel oid leukemia in Japan2008

    • Author(s)
      Hiroto Narimatsu
    • Journal Title

      Leukemia 22

      Pages: 432-434

    • Peer Reviewed
  • [Journal Article] Clinical significance of nuclear non-phosphorylated beta-catenin in acute myeloid leukaemia and myelodysplastic syndrome2008

    • Author(s)
      Jinglan Xu
    • Journal Title

      Br J Haematol 140

      Pages: 394-401

    • Peer Reviewed
  • [Journal Article] FLT3 regulates beta-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells2007

    • Author(s)
      Tomohiro Kajiguchi
    • Journal Title

      Leukemia 21

      Pages: 2476-2484

    • Peer Reviewed
  • [Journal Article] High incidence of secondary failure of platelet recovery after autologous and syngeneic peripheral blood stem cell transplantation in acute promyelocytic leukemia2007

    • Author(s)
      Hiroto Narimatsu
    • Journal Title

      Bone Marrow Transplant 40

      Pages: 773-778

    • Peer Reviewed
  • [Journal Article] LRP16 is fused to RUNX1 in monocytic leukemia cell line with t(11;21)(q13;q22)2007

    • Author(s)
      Shizuka Imagama
    • Journal Title

      Eur J Haematol 79

      Pages: 25-31

    • Peer Reviewed
  • [Journal Article] A novel FLT3 inhibitor FI-700 selectively suppress the growth of leukemia cells with FLT3 mutations2007

    • Author(s)
      Hitoshi Kiyoi
    • Journal Title

      Clin Cancer Res 13

      Pages: 4575-4582

    • Peer Reviewed
  • [Journal Article] Epegenetic regulation of CD20 protein expression in a novel B-cell lymp homa cell line, RRBL1, established from a patient treated repeatedly with Rituximab-containing chemotherapy2007

    • Author(s)
      Akihiro Tomita
    • Journal Title

      Int J Hematol 86

      Pages: 49-57

    • Peer Reviewed
  • [Journal Article] Successful second cord blood transplantation using fludarabine and cyclophosphamide as a preparative regimen for graft rejection following reduced-intensity cord blood transplantation2007

    • Author(s)
      Emi Mizutani
    • Journal Title

      Bone Marrow Transplant 40

      Pages: 85-87

    • Peer Reviewed
  • [Journal Article] Prognostic analysis of aberrant somatic hypermutation of RhoH gene in diffuse large B cell lymphoma2007

    • Author(s)
      Junji Hiraga
    • Journal Title

      Leukemia 21

      Pages: 1846-1847

    • Peer Reviewed
  • [Journal Article] A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML・RAR{alpha} transcript after consolidation therapy: The Japan Adult Leukemia study Group (JALSG)APL97 study2007

    • Author(s)
      Noirio Asou
    • Journal Title

      Blood 110

      Pages: 59-66

    • Peer Reviewed
  • [Journal Article] JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults2007

    • Author(s)
      Hitoshi Kiyo
    • Journal Title

      Leukemia 21

      Pages: 574-576

    • Peer Reviewed
  • [Journal Article] Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the reatment of AML with FLT3/ITD2007

    • Author(s)
      Mitsuhiro Okamoto
    • Journal Title

      Leukemia 21

      Pages: 403-410

    • Peer Reviewed
  • [Journal Article] Establishment of a Stroma-Dependent Human Acute Myelomonocytic Leukemia Cell Line, NAMO-2, with FLT3 Tandem Duplication2007

    • Author(s)
      Akihiro Abe
    • Journal Title

      Int J Hematol 84

      Pages: 328-336

    • Peer Reviewed
  • [Journal Article] Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice2007

    • Author(s)
      Manabu Ninomiya
    • Journal Title

      Leukemia 21

      Pages: 136-142

    • Peer Reviewed
  • [Journal Article] Clinical features and outcome of T-lineage acute lymphoblastic leukemia in adults: A low initial white blood cell count, as well as a high count predict decreased survival rates2007

    • Author(s)
      Masamitsu Yanada
    • Journal Title

      Leuk Res 31

      Pages: 907-914

    • Peer Reviewed
  • [Presentation] KW-2449, a Novel Multi-Kinase Inhibitor Against FLT3, Abl, FGFR1 and Aurora, Suppresses the Growth of AML Both In Vitro and In Vivo2007

    • Author(s)
      Yukimasa Shiotsu
    • Organizer
      The American Society of Hematology 49th Annual Meeting
    • Place of Presentation
      Atlanta USA
    • Year and Date
      20071208-11
  • [Presentation] Epigenetic Regulation of CD20 Protein Expression in B-Cell Lymphoma Cells after Rituximab-Containing Chemotherapy2007

    • Author(s)
      Akihiro Tomita
    • Organizer
      The American Society of Hematology 49th Annual Meeting
    • Place of Presentation
      Atlanta USA
    • Year and Date
      20071208-11
  • [Presentation] Activating JAK3 Mutations in Transient Myeloproliferative Disorder and Acute Megakaryoblastic Leukemia Accompanying Down Syndrome2007

    • Author(s)
      Tomohiko Sato
    • Organizer
      The American Society of Hematology 49th Annual Meeting
    • Place of Presentation
      Atlanta USA
    • Year and Date
      20071208-11
  • [Presentation] Prognostic Implications and Biological Roles of RhoH in Acute Myeloid Leukemia2007

    • Author(s)
      Toshihiro Iwasaki
    • Organizer
      The American Society of Hematology 49th Annual Meeting
    • Place of Presentation
      Atlanta USA
    • Year and Date
      20071208-11
  • [Presentation] Clinical Characteristics and Outcomes in Patients with t(8;21) Acute Myeloid Leukemia in Japan2007

    • Author(s)
      Hiroto Narimatsu
    • Organizer
      The American Society of Hematology 49th Annual Meeting
    • Place of Presentation
      Atlanta USA
    • Year and Date
      20071208-11
  • [Presentation] Comprehensive Analysis of Genetic Alterations in Acute Myeloid Leukemia According to the WHO Classification2007

    • Author(s)
      Yuichi Ishikawa
    • Organizer
      The American Society of Hematology 49th Annual Meeting
    • Place of Presentation
      Atlanta USA
    • Year and Date
      20071208-11
  • [Presentation] Analysis of the Role of Wnt Signaling for the Interaction between Leukemia Cells and Stroma2007

    • Author(s)
      Akihiro Abe
    • Organizer
      The American Society of Hematology 49th Annual Meeting
    • Place of Presentation
      Atlanta USA
    • Year and Date
      20071208-11

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Published: 2010-02-04   Modified: 2016-04-21  

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