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 thrombopoietin-induced megakaryocytopoiesis in a dose-dependent manner, but with strikingly different potencies (IC50=26 nM for ANA and 30 μ M 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.
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References
Jerushalmy Z, Payta M, Pinkhas J, De Vries A . Alteration of rat bone marrow megakaryocytes following administration of cytosine arabinoside, daunomycin and hydroxyurea. Haemostasis 1977; 6: 110–117.
Mazur EM, Rosmarin AG, Sohl PA, Newton JL, Narendran A . Analysis of the mechanism of anagrelide-induced thrombocytopenia in humans. Blood 1992; 79: 1931–1937.
Solberg Jr LA, Tefferi A, Oles KJ, Tarach JS, Petitt RM, Forstrom LA et al. The effects of anagrelide on human megakaryocytopoiesis. Br J Haematol 1997; 99: 174–180.
Lofvenberg E, Wahlin A . Management of polycythaemia vera, essential thrombocythaemia and myelofibrosis with hydroxyurea. Eur J Haematol 1988; 41: 375–381.
Anagrelide Study Group. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Am J Med 1992; 92: 69–76.
Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995; 332: 1132–1136.
Tefferi A, Silverstein MN, Petitt RM, Mesa RA, Solberg Jr LA . Anagrelide as a new platelet-lowering agent in essential thrombocythemia: mechanism of actin, efficacy, toxicity, current indications. Semin Thromb Hemost 1997; 23: 379–383.
Hong Y, Erusalimsky JD . Comparison of the pharmacological mechanisms involved in the platelet lowering actions of anagrelide and hydroxyurea: a review. Platelets 2002; 13: 381–386.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Hydroxyurea. IARC Monog 2000; 76: 347–386.
Yarbro JW . Mechanism of action of hydroxyurea. Semin Oncol 1992; 19: 1–10.
Gillespie E . Anagrelide: a potent and selective inhibitor of platelet cyclic AMP phosphodiesterase enzyme activity. Biochem Pharmacol 1988; 37: 2866–2868.
Beavo JA . Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995; 75: 725–748.
Wang G, Franklin R, Hong Y, Erusalimsky JD . Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures. Br J Pharmacol 2005; 146: 324–332.
Bobik R, Hong Y, Breier G, Martin JF, Erusalimsky JD . Thrombopoietin stimulates VEGF release from c-Mpl-expressing cell lines and haematopoietic progenitors. FEBS Lett 1998; 423: 10–14.
Mathur A, Hong Y, Wang G, Erusalimsky JD . Assays of megakaryocyte development: surface antigen expression, ploidy, and size. Methods Mol Biol 2004; 272: 309–322.
Beltran B, Mathur A, Duchen MR, Erusalimsky JD, Moncada S . The effect of nitric oxide on cell respiration: a key to understanding its role in cell survival or death. Proc Natl Acad Sci USA 2000; 97: 14602–14607.
Wesierska-Gadek J, Gueorguieva M, Ranftler C, Zerza-Schnitzhofer G . A new multiplex assay allowing simultaneous detection of the inhibition of cell proliferation and induction of cell death. J Cell Biochem 2005; 96: 1–7.
Pescatore SL, Lindley C . Anagrelide: a novel agent for the treatment of myeloproliferative disorders. Expert Opin Pharmacother 2000; 1: 537–546.
Kaushansky K . Thrombopoietin: the primary regulator of platelet production. Blood 1995; 86: 419–431.
Kaushansky K . Thrombopoietin: understanding and manipulating platelet production. Annu Rev Med 1997; 48: 1–11.
Wang Q, Miyakawa Y, Fox N, Kaushansky K . Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1. Blood 2000; 96: 2093–2099.
Villani P, Maserati R, Regazzi MB, Giacchino R, Lori F . Pharmacokinetics of hydroxyurea in patients infected with human immunodeficiency virus type I. J Clin Pharmacol 1996; 36: 117–121.
Gaver RC, Deeb G, Pittman KA, Smyth RD . Disposition of anagrelide, an inhibitor of platelet aggregation. Clin Pharmacol Ther 1981; 29: 381–386.
Silverstein MN, Petitt RM, Solberg Jr LA, Fleming JS, Knight RC, Schacter LP . Anagrelide: a new drug for treating thrombocytosis. N Engl J Med 1988; 318: 1292–1294.
Kornblihtt LI, Vassallu PS, Heller P, Molinas FC . Treatment of essential thrombocythemia with anagrelide: a ten-year experience. Medicina (B Aires) 2002; 62: 231–236.
Birgegard G, Bjorkholm M, Kutti J, Larfars G, Lofvenberg E, Markevarn B et al. Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders. Haematologica 2004; 89: 520–527.
Storen EC, Tefferi A . Long-term use of anagrelide in young patients with essential thrombocythemia. Blood 2001; 97: 863–866.
Andreasson B, Swolin B, Kutti J . Hydroxyurea treatment reduces haematopoietic progenitor growth and CD34 positive cells in polycythaemia vera and essential thrombocythaemia. Eur J Haematol 2000; 64: 188–193.
Fruchtman SM, Mack K, Kaplan ME, Peterson P, Berk PD, Wasserman LR . From efficacy to safety: a Polycythemia Vera Study group report on hydroxyurea in patients with polycythemia vera. Semin Hematol 1997; 34: 17–23.
Finazzi G, Ruggeri M, Rodeghiero F, Barbui T . Efficacy and safety of long-term use of hydroxyurea in young patients with essential thrombocythemia and a high risk of thrombosis. Blood 2003; 101: 3749.
Rafii S, Meeus S, Dias S, Hattori K, Heissig B, Shmelkov S et al. Contribution of marrow-derived progenitors to vascular and cardiac regeneration. Semin Cell Dev Biol 2002; 13: 61–67.
Sterkers Y, Preudhomme C, Lai JL, Demory JL, Caulier MT, Wattel E et al. Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion. Blood 1998; 91: 616–622.
Penninga E, Jensen BA, Hansen PB, Clausen NT, Mourits-Andersen T, Nielsen OJ et al. Anagrelide treatment in 52 patients with chronic myeloproliferative diseases. Clin Lab Haematol 2004; 26: 335–340.
Steurer M, Gastl G, Jedrzejczak WW, Pytlik R, Lin W, Schlogl E et al. Anagrelide for thrombocytosis in myeloproliferative disorders: a prospective study to assess efficacy and adverse event profile. Cancer 2004; 101: 2239–2246.
Petrides PE . Anagrelide: a decade of clinical experience with its use for the treatment of primary thrombocythaemia. Expert Opin Pharmacother 2004; 5: 1781–1798.
Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005; 353: 33–45.
Rameshwar P, Narayanan R, Qian J, Denny TN, Colon C, Gascon P . NF-κB as a central mediator in the induction of TGF-β in monocytes from patients with idiopathic myelofibrosis: an inflammatory response beyond the realm of homeostasis. J Immunol 2000; 165: 2271–2277.
Wagstaff AJ, Keating GM . Anagrelide: a review of its use in the management of essential thrombocythaemia. Drugs 2006; 66: 111–131.
Kaushansky K . On the molecular origins of the chronic myeloproliferative disorders: it all makes sense. Blood 2005; 105: 4187–4190.
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We thank Dr Richard Franklin and Dr Maggi Moss for their valuable advice during the course of this work.
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Hong, Y., Wang, G., del Arroyo, A. et al. Comparison between anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation: selectivity of anagrelide for the megakaryocytic lineage. Leukemia 20, 1117–1122 (2006). https://doi.org/10.1038/sj.leu.2404180
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DOI: https://doi.org/10.1038/sj.leu.2404180
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