Published online 25 August 2008
Haematologica, Vol 93, Issue 10, 1495-1504 doi:10.3324/haematol.12752
Copyright © 2008 by Ferrata Storti Foundation
Wataru Nogami1,2 ,
Hiroshi Yoshida2 ,
Kenzo Koizumi2 ,
Hajime Yamada2 ,
Kenji Abe2 ,
Akinori Arimura2 ,
Noriko Yamane2 ,
Koji Takahashi2 ,
Akiko Yamane1 ,
Atsushi Oda3 ,
Yoshikazu Tanaka2 ,
Hiroshi Takemoto2 ,
Yasuyuki Ohnishi4 ,
Yasuo Ikeda1 ,
Yoshitaka Miyakawa1
Haematologica, Vol 93, Issue 10, 1495-1504 doi:10.3324/haematol.12752
Copyright © 2008 by Ferrata Storti Foundation
Thrombopoiesis |
The effect of a novel, small non-peptidyl molecule butyzamide on human thrombopoietin receptor and megakaryopoiesis
1 Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo
2 Discovery Research Laboratories, Shionogi & Co., Ltd., Osaka
3 Department of Preventive Medicine, Hokkaido University School of Medicine, Hokkaido
4 Central Institute for Experimental Animals, Kanagawa, Japan
Correspondence: Yoshitaka Miyakawa, M.D., Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. E-mail:yoshi{at}sc.itc.keio.ac.jp
Background: Thrombocytopenia is a common problem in the management of patients with cancer and other conditions that affect hematopoietic cells. In previous clinical trials, the polyethylene-glycol-conjugated recombinant human megakaryocyte growth and development factor increased platelet counts in patients with idiopathic thrombocytopenic purpura and solid tumors undergoing chemotherapy. However, antibodies to polyethylene-glycol-conjugated recombinant human megakaryocyte growth and development factor develop in healthy volunteers and patients undergoing chemotherapy and cross-react with endogenous thrombopoietin. As a result, clinical development of polyethylene-glycol-conjugated recombinant human megakaryocyte growth and development factor was discontinued in 1998. The aim of this study was to identify an orally bioavailable human Mpl activator that does not develop autoantibodies against endogenous thrombopoietin.
Design and Methods: We screened our chemical library and created a novel non-peptidyl thrombopoietin receptor, Mpl activator named butyzamide. We evaluated the effect of butyzamide on megakaryopoiesis in vitro using Ba/F3 cells expressing Mpl and human hematopoietic stem cells. For the evaluation of its in vivo effect, we administered butyzamide orally to immunodeficient NOD/Shi-scid,IL-2R
null (NOG) mice transplanted with human fetal liver-derived CD34+ cells and investigated the production of human platelets.
Results: Butyzamide specifically reacted with human Mpl and activated the same signal transduction pathway as thrombopoietin. However, unlike thrombopoietin, butyzamide did not react with murine Mpl and was shown to require the histidine residue in the transmembrane domain of Mpl for its agonistic activity. Butyzamide induced colony-forming unit-megakaryocytes and polyploid megakaryocytes from human CD34+ hematopoietic progenitor cells, and its effects were comparable to those of thrombopoietin. When butyzamide was administered orally at the doses of 10 and 50 mg/kg for 20 days to NOG mice transplanted with human fetal liver-derived CD34+ cells, the human platelet count increased by 6.2- and 22.9-fold, respectively.
Conclusions: Butyzamide is an orally bioavailable human Mpl activator, and appears to have potential for clinical development as a therapeutic agent for patients with thrombocytopenia.
Key words: megakaryocyte, platelet, thrombocytopenia, thrombopoietin, thrombopoietin receptor.
Related Article
Haematologica 2008 93: 1445-1449.
This article has been cited by other articles:
 |
|
 |
|
  J. N. George and D. R. Terrell Novel thrombopoietic agents: a new era for management of patients with thrombocytopenia Haematologica, October 1, 2008; 93(10): 1445 - 1449. [Full Text] [PDF]
|
|