Comparison between anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation: selectivity of anagrelide for the megakaryocytic lineage

Abstract

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 thrombopoietininduced megakaryocytopoiesis in a dose-dependent manner, but with strikingly different potencies (IC 50 ¼ 26 nM for ANA and 30 lM 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 þ 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.

P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis

“…3e). Treatment with pharmacological inhibitors of P2X7R, A740003 (A74; n = 13) [31], after subfailure overstretch injury restored contractile function impairment in RA (Fig. 3a, b).…”

Long-term management of thrombocytosis in essential thrombocythaemia

“…Anagrelide is a cytoreductive agent, with a selective effect on the megakaryocyte cell lineage [62]. It reduces platelet production by inhibiting megakaryocyte colony development, thus reducing megakaryocyte size, ploidy and maturation [63].…”

Essential thrombocytemia progressing to Ph+ chronic myeloid leukemia with megakaryoblastic blasts, following anagrelide withdrawal

“…Previous in vitro studies have shown that when CD34þ cells are stimulated with thrombopoietin, they differentiate towards megakaryocytic lineage. When ANA was added, megakaryocytopoiesis and megakaryocytic differentiation were reduced and so were the number of CD61 positive cells [1]. The presence of ANA was also capable of shifting the hematopoietic cell growth and differentiation to the nonmegakaryocytic compartment.…”