TY - JOUR
T1 - Comparison between anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation
T2 - Selectivity of anagrelide for the megakaryocytic lineage
AU - Hong, Y.
AU - Wang, G.
AU - Gutierrez del Arroyo, A.
AU - Hernandez, J.
AU - Skene, C.
AU - Erusalimsky, J. D.
PY - 2006/6
Y1 - 2006/6
N2 - Anagrelide (ANA) and hydroxycarbamide (HC) are two distinct pharmacological agents used to treat thrombocythaemia associated with myeloproliferative disorders. Although both drugs have been in clinical use for a number of years, comparative studies of their selectivity and mode of action are still lacking. Here, we have evaluated the activities of ANA and HC on the growth and differentiation of human haematopoietic progenitor cells in liquid culture. Both drugs inhibited thrombopoietin-induced megakaryocytopoiesis in a dose-dependent manner, but with strikingly different potencies (IC50= 26 nM for ANA and 30 μM for HC) and modes of action. Whereas HC inhibited cell proliferation, ANA acted primarily on the differentiation process. At doses that abrogated megakaryocytopoiesis, HC also inhibited the expansion of CD34+ cells stimulated by stem cell factor, interleukin-3 and Flt-3 ligand and also induced apoptosis. Furthermore, HC inhibited erythroid and myelomonocytic cell growth, induced by erythropoietin or granulocyte - macrophage colony-stimulating factor, respectively. In contrast, ANA showed none of these additional effects. Taken together, these results demonstrate that ANA is a potent and selective inhibitor of megakaryocytopoiesis, having no significant activity against haematopoietic progenitor cell expansion or differentiation into other lineages. In contrast, the anti-megakaryocytopoietic activity of HC cannot be dissociated from its more general cytoreductive and cytotoxic actions.
AB - Anagrelide (ANA) and hydroxycarbamide (HC) are two distinct pharmacological agents used to treat thrombocythaemia associated with myeloproliferative disorders. Although both drugs have been in clinical use for a number of years, comparative studies of their selectivity and mode of action are still lacking. Here, we have evaluated the activities of ANA and HC on the growth and differentiation of human haematopoietic progenitor cells in liquid culture. Both drugs inhibited thrombopoietin-induced megakaryocytopoiesis in a dose-dependent manner, but with strikingly different potencies (IC50= 26 nM for ANA and 30 μM for HC) and modes of action. Whereas HC inhibited cell proliferation, ANA acted primarily on the differentiation process. At doses that abrogated megakaryocytopoiesis, HC also inhibited the expansion of CD34+ cells stimulated by stem cell factor, interleukin-3 and Flt-3 ligand and also induced apoptosis. Furthermore, HC inhibited erythroid and myelomonocytic cell growth, induced by erythropoietin or granulocyte - macrophage colony-stimulating factor, respectively. In contrast, ANA showed none of these additional effects. Taken together, these results demonstrate that ANA is a potent and selective inhibitor of megakaryocytopoiesis, having no significant activity against haematopoietic progenitor cell expansion or differentiation into other lineages. In contrast, the anti-megakaryocytopoietic activity of HC cannot be dissociated from its more general cytoreductive and cytotoxic actions.
KW - Anagrelide
KW - Hydroxyurea
KW - Megakaryocyte
KW - Platelet reduction
KW - Thrombocythaemia
UR - http://www.scopus.com/inward/record.url?scp=33646471216&partnerID=8YFLogxK
U2 - 10.1038/sj.leu.2404180
DO - 10.1038/sj.leu.2404180
M3 - Article
C2 - 16557242
AN - SCOPUS:33646471216
SN - 0887-6924
VL - 20
SP - 1117
EP - 1122
JO - Leukemia
JF - Leukemia
IS - 6
ER -
