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


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.
Fukushima-Shintani
Mari
M
QA, RA, and Pharmacovigilance, Astellas Pharma Inc., Itabashi-ku, Tokyo, Japan.
Suzuki
Ken-ichi
K
Iwatsuki
Yoshiyuki
Y
Abe
Masaki
M
Sugasawa
Keizo
K
Hirayama
Fukushi
F
Kawasaki
Tomihisa
T
D015703:Antigens, CD / Q000097:blood; D018952:Antigens, CD34 / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D006801:Humans; D010880:Piperidines / Q000627:therapeutic use*; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D013844:Thiazoles / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000188:drug therapy*; D034061:Thrombopoiesis / Q000187:drug effects* / Q000502:physiology; D013926:Thrombopoietin / Q000627:therapeutic use*
D015703:Antigens, CD; D018952:Antigens, CD34; D010880:Piperidines; D053628:Receptors, Thrombopoietin; D013844:Thiazoles; D013876:Thiophenes; C533238:avatrombopag; D013926:Thrombopoietin