Abstract:
: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 EC(50) (median effective concentration) value of 0.43 microM, 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, Janus kinase-2 (JAK2), and signal transducers and activators of transcription 5 (STAT5) in UT-7/TPO cells as well as TPO. JTZ-132 increased the number of megakaryocyte-specific marker, CD61(+) and CD41(+), 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.
journal_name
Bloodjournal_title
Bloodauthors
Inagaki K,Oda T,Naka Y,Shinkai H,Komatsu N,Iwamura Hdoi
10.1182/blood-2003-10-3623subject
Has Abstractpub_date
2004-07-01 00:00:00pages
58-64issue
1eissn
0006-4971issn
1528-0020pii
2003-10-3623journal_volume
104pub_type
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