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2007 Fiscal Year Final Research Report Summary

Analysis for functional mechanism of peripheral neuropathy induced by anti-cancer drug Paclitaxel

Research Project

Project/Area Number 18590145
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionKagoshima University

Principal Investigator

YAMADA Katsushi  Kagoshima University, Medical and Dental Hospital, Professor (00037491)

Co-Investigator(Kenkyū-buntansha) TAKEDA Yasuo  Kagoshima University, Medical and Dental Hospital, Associate Professor (60245462)
Project Period (FY) 2006 – 2007
Keywordsneuropathy / anti-neoplastic agent / adverse effect
Research Abstract

Paclitaxel-induced painful peripheral neuropathy is a major dose-limiting factor. Recently, it has been reported that macrophages accumulated in the dorsal root ganglion of paclitaxel-treated rats, and their activation is suggested to contribute to generation and development of the neuropathy. However, the mechanism for macrophage activation is still unknown. In this study, to explore candidate genes involved in the mechanism for macrophage activation in the dorsal root ganglion of paclitaxel-treated rats, we developed model rats for paclitaxel-induced neuropathic pain and performed a microarray assay to analyze the changes of gene expressions in the dorsal root ganglion. Among the genes with changed expression levels, we focused on matrix metalloproteinase-3 (MMP-3, stromelysin-1) and CD163, a macrophage marker. By RT-PCR, the expression levels of MMP-3 and CD163 were markedly up-regulated in paclitaxel-treated dorsal root ganglion. As a result of immunohistochemical study, large ganglion neurons, but neither Schwann cells nor macrophages, predominantly expressed MMP-3. This MMP-3 up-regulation occurred prior to macrophage accumulation in the dorsal root ganglion. In addition, recombinant MMP-3 led to the activation of RAW264 macrophages in vitro. Taken together, we suggested that the up-regulation of MMP-3 and following macrophage activation caused in the dorsal root ganglion might be a significant event to trigger a series of reactions developing paclitaxel-induced peripheral neuropathic pain.

  • Research Products

    (8 results)

All 2008 2007 2006

All Journal Article (6 results) (of which Peer Reviewed: 3 results) Presentation (2 results)

  • [Journal Article] Up-regulation of matrix metalloproteinase-3 in the dorsal root ganglion of rats with paclitaxel-induced neuropathy2008

    • Author(s)
      Yamada K, Takeda Y, 他7名
    • Journal Title

      Cancer Sci. (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Up-regulation of matrix metalloproteinase-3 in the dorsal root ganglion of rats with paclitaxel-induced neuropathy2008

    • Author(s)
      Yamada, K, Takeda, Y, et. al.
    • Journal Title

      Cancer Sci. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Effect of pre-treatment with St John's Wort on nephrotoxicity of isplatin in rats2007

    • Author(s)
      Yamada K, Takeda Y, 他10名
    • Journal Title

      Life Science 81

      Pages: 103-108

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Effect of pre-treatment with St John's Wort on nephrotoxicity of cisplatin in rats2007

    • Author(s)
      Yamada, K, Takeda, Y, et. al.
    • Journal Title

      Life Science 81

      Pages: 103-108

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Effect of methotrexate treatment on expression levels of multidrug resis tance protein 2,breast cancer resistance protein and organic anion tran sporters Oatl,Oat2 and Oat3 in rats2006

    • Author(s)
      Yamada K, Takeda Y, 他7名
    • Journal Title

      Cancer Sci. 97

      Pages: 1260-1266

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Effect of methotrexate treatment on expression levels of multidrug resistance protein 2, breast cancer resistance protein and organic anion transporters Oatl, Oat2 and Oat3 in rats2006

    • Author(s)
      Yamada, K, Takeda, Y, et. al.
    • Journal Title

      Cancer Sci. 97

      Pages: 1260-1266

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Paclitaxelによる末梢神経障害ラットの脊髄後根神経節におけるmatrixmetalloproteinase3(MMP3)の発現充進2007

    • Author(s)
      山田 勝士, 他6名
    • Organizer
      第1回次世代を担う若手医療薬科学シンポジウム
    • Place of Presentation
      日本薬学会長井記念館
    • Year and Date
      20071215-16
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Microarray analysis in the dorsal root ganglion of rats with paclitaxel-induced neuropathy2007

    • Author(s)
      Yamada, K, Takeda, Y, et. al.
    • Organizer
      The 1st Symposium of Clinical Pharmaceutical Sciences for Next Generation
    • Place of Presentation
      Tokyo
    • Year and Date
      20071215-16
    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2010-02-04  

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