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Blood, 1 July 2004, Vol. 104, No. 1, pp. 58-64. Prepublished online as a Blood First Edition Paper on March 4, 2004; DOI 10.1182/blood-2003-10-3623. This Article Full Text (PDF) All Versions of this Article: 2003-10-3623v1 104/1/58    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Inagaki, K. Articles by Iwamura, H. Search for Related Content PubMed PubMed Citation Articles by Inagaki, K. Articles by Iwamura, H. Social Bookmarking                   What's this? Submitted October 23, 2003 Accepted February 25, 2004 Induction of megakaryocytopoiesis and thrombocytopoiesis by JTZ-132, a novel small molecule with thrombopoietin mimetic activities Koji Inagaki, Tomohiro Oda, Yuichi Naka, Hisashi Shinkai, Norio Komatsu, and Hiroyuki Iwamura* Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki, Osaka, Japan Division of Hematology, Department of Medicine, Jichi Medical School, Kawachi-gun, Tochigi, Japan * Corresponding author; email: hiroyuki.iwamura{at}ims.jti.co.jp. We report in this paper that a novel small molecule, JTZ-132, induced growth and differentiation of megakaryocytic progenitor cells, and improved thrombocytopenia in myelosuppressed mice. JTZ-132 stimulated proliferation of UT-7/TPO cells, a cell line highly sensitive to thrombopoietin (TPO), and exhibited full efficacy comparable to TPO with an approximate EC50 value of 0.43 µmol/L, whereas little proliferation was observed in a TPO-insensitive cell line, UT-7/EPO, and human carcinoma cell line, HCT116. Signal transduction studies revealed that JTZ-132 induced tyrosine phosphorylation of c-Mpl, JAK2 and STAT5 in UT-7/TPO cells as well as TPO. JTZ-132 increased the number of megakaryocyte-specific marker, CD61 and CD41-positive cells in cultures of mouse and human bone marrow cells, respectively, and the colony-forming unit megakaryocytes in mouse bone marrow cells. In vivo experiments in x-ray irradiation or busulfan-injection induced myelosuppressed mice demonstrated that subcutaneously injected JTZ-132 at 30 mg/kg showed significantly higher platelet number at nadir, and accelerated platelet recovery without affecting white blood cell number. These data suggest that JTZ-132 is a novel stimulator of megakaryocytopoiesis and thrombocytopoiesis in vitro and in vivo with TPO mimetic activities, and that it is useful for the treatment of thrombocytopenia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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