AKR-501 (YM477) in combination with thrombopoietin enhances human megakaryocytopoiesis
AKR-501 (YM477) in combination with thrombopoietin enhances human megakaryocytopoiesis
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DOI：
10.1016/j.exphem.2008.04.020
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发表时间：
2008-10-01
影响因子：
2.6
通讯作者：
Kawasaki, Tomihisa
中科院分区：
文献类型：
--
作者：
Fukushima-Shintani, Mari;Suzuki, Ken-ichi;Kawasaki, Tomihisa
Objective. AKR-501 (YM477) is an orally active thrombopoietin (TPO) receptor agonist that mimics the biological effect of TPO in vitro and in vivo. Here, we report that AKR-501 in combination with TPO has additive effect on megakaryocytopoiesis.Materials and Methods. Granulocyte colony-stimulating factor-mobilized human peripheral blood CD34(+) cells were cultured with AKR-501, TPO, or a combination of the two in serum-free liquid culture system. The numbers of hematopoietic progenitor cells, megakaryocytic progenitor cells, and megakaryocytes were measured using flow cytometry. Further, the effect of AKR-501 on TPO binding to TPO receptor was examined.Results. Both AKR-501 and TPO alone increased the number of megakaryocytes, and the maximum activities of AKR-501 and TPO were similar. Interestingly, in the presence of TPO concentrations producing maximal stimulation, the addition of AKR-501 increased the number of megakaryocytes to about 200% of that generated with TPO only. In the time course experiment, the combination of AKR-501 and TPO augmented the numbers of hematopoietic progenitor cells and colony-forming unit in culture in the early stages. Thus, the combination of AKR-501 and TPO enhanced not only the differentiation into megakaryocytes, but also the expansion of human hematopoietic progenitor cells. Further, AKR-501 did not inhibit TPO binding to the TPO receptor. This result indicated the possibility that AKR-501 and TPO may act simultaneously on the TPO receptor, and this could be responsible for their additive effect of on megakaryocytopoiesis.Conclusions. This study suggests that AKR-501 would be useful for the treatment of thrombocytopenia even at high plasma levels of endogenous TPO following chemotherapy. (C) 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
