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[Clinical use of thrombopoietin (c-Mpl Ligand)].

INTRODUCTION
Results in clinical use of thrombopoietin have been published later than of other hematopoietic growth factors, because until recently the research was the least understood aspect of blood cell development. Reasons for this time gap were numerous, from inconvenient methods for measurement of thrombopoietin activity, to difficulties of its chemical purification. It is claimed recently that the understanding of platelet production has been profoundly advanced by the recombinant-gene synthesis and characterization of c-Mpl ligand (Megakaryocyte Growth and Development Factor), a substance which strongly enhances the proliferation of megakaryocytic line and the production of platelets. In this paper, some historical facts and biology of thrombopoietin are briefly discussed as well as the recent of the clinical use of thrombopoietin.


THE HISTORY OF RESEARCH AND PRODUCTION OF THROMBOPOIETIN
The concept that the platelet production is underlying humoral regulation was first promoted by a group of Hungarian authors and they also named that humoral regulator--thrombopoietin. Further research followed in several countries including our own, and the initial studies proved that the serum of thrombocytopenic animals induced proliferation and maturation of megakaryocytic cell line and thrombocytosis in the peripheral blood of recipient animals. Later, when in vitro techniques were developed, it was shown that this humoral regulator has also a colony stimulating activity on megakaryocytic precursors. During the following two decades, studies of megakarycytopoiesis supported the hypothesis that two types of factors are involved in platelet production: early acting--megakaryocyte colony stimulating factors (Meg-CSF), and late acting--megakaryocyte potentiators, first of all thrombopoietin (TPO). However, extensive attempts on the purification of substances that either stimulate megakaryocyte development or augment platelet production failed to yield a homogeneous protein adequate for protein sequencing and cDNA cloning, the usual route which led to the production of other hematopoietic growth factors. Furthermore, a large number of other cytokines were described that possessed activity in various assays of megakaryocyte development. In spite of great number of accumulated data, it seemed in early 1990s that the production of a distinct, clinically useful lineage specific thrombopoietin will not be soon possible to achieve. The breakthrough occurred in 1994, when four groups of investigators published simultaneously their successful results on production of c-Mpl ligand, a substance which specifically binds to the Mpl receptors on megakaryocytes and has a very potent thrombocytopoietic effect. This production is based on genetic engineering and two companies (Kirin and Amgen) are already able to produce recombinant human thrombopoietin in large amounts, for clinical use. Although this substance is not commercially available yet, it passed the preclinical and clinical trials whose results are presented here.


RESULTS OF THE PRECLINICAL TRIALS OF RECOMBINANT THROMBOPOIETIN
The chemical structure of human recombinant thrombopoietin (rTPO) is well defined, it is a glycoprotein consisting of 353 amino acids and molecular weight of 30 kD. The biologic actions of this molecule are in vitro: stimulation of megakaryocyte colony forming, endoreduplication of chromosomes and megakaryocyte maturation, and in vivo: increase of the number of progenitors and of megakaryocytes in the bone marrow, and an extensive elevation of platelet count in the peripheral blood 4-7 days after its application. Also, in synergism with other pluripotent cytokines, it can stimulate the proliferation of other progenitors including CD34+ stem cells. Based on these data it is considered that c-Mpl ligand is the main physiological humoral regulator of thrombocytopoiesis, having the biological actions both of MegCSF and TPO.