AKR-501 (YM477) in combination with thrombopoietin enhances human megakaryocytopoiesis.

Abstract

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.

• Authors: Mari Fukushima-Shintani, Ken-ichi Suzuki, Yoshiyuki Iwatsuki, Masaki Abe, Keizo Sugasawa, Fukushi Hirayama, Tomihisa Kawasaki
• Journal: Experimental hematology (Exp Hematol) Vol. 36 Issue 10 Pg. 1337-42 (Oct 2008) ISSN: 0301-472X [Print] Netherlands
• PMID: 18619724 (Publication Type: Journal Article)

Chemical References

• Antigens, CD
• Antigens, CD34
• Piperidines
• Receptors, Thrombopoietin
• Thiazoles
• Thiophenes
• avatrombopag
• Thrombopoietin

Topics

• Antigens, CD (blood)
• Antigens, CD34 (blood)
• Blood Platelets (drug effects, physiology)
• Cells, Cultured
• Colony-Forming Units Assay
• Flow Cytometry
• Humans
• Piperidines (therapeutic use)
• Receptors, Thrombopoietin (agonists)
• Thiazoles (therapeutic use)
• Thiophenes (therapeutic use)
• Thrombocytopenia (drug therapy)
• Thrombopoiesis (drug effects, physiology)
• Thrombopoietin (therapeutic use)