Erythropoietin – aktueller Stand der Wissenschaft

Zusammenfassung

Im Jahr 1984 gelang erstmals die Rekombination von Erythropoietin (rhEPO) in E.coli. Im folgenden Jahr erfolgte erstmalig die Synthese von rhEPO in Ovarialzellen von Hamstern, welches für die medizinische Applikation besser geeignet ist. Im Jahr 1989 wurde die FDA-Zulassung erteilt. Seitdem wird rhEPO vorwiegend bei der Behandlung von Anämien im Rahmen von chronischen Niereninsuffizienzen und malignen Prozessen eingesetzt. In den letzten 15 Jahren sind in der Forschung zahlreiche Ansätze verfolgt worden, die Bioaktivität von rhEPO und seinen Analoga zu verbessern. Inzwischen gibt es künstlich hergestelltes EPO, in humanen Zelllinien rekombiniertes EPO und Substanzen, die andere Angriffsorte der Erythropoese besitzen. Man spricht in diesem Zusammenhang von „Erythropoese stimulierenden Agenzien” (ESA). Dadurch wird deutlich, dass der Missbrauch von EPO bzw. ESA zu Dopingzwecken, trotz sensitiver Nachweisverfahren für rhEPO, weiterhin möglich ist. Gleichzeitig wurden im Rahmen dieser Forschungen zahlreiche verschiedene Zelltypen verifiziert, die sowohl EPO-Rezeptoren besitzen als auch Syntheseort sind. So konnte unter anderem eine Syntheseleistung in den Tuben, im Herzen und im Gehirn nachgewiesen werden. EPO ist auf diesen nicht blutbildenden Geweben assoziiert mit Funktionen der Transmitter-Freisetzung, Angiogenese, Chemotaxis und Apoptosehemmung. Diese Erkenntnisse haben der Thematik EPO eine große Diversivität hinsichtlich potenzieller, zytoprotektiver Eigenschaften bei Schlaganfall und Myokardinfarkt in Prävention und Rehabilitation gegeben. In den letzten Jahren konnte so ein wachsendes Interesse an der Thematik verzeichnet werden.

Abstract

After a century of research and medical use, erythropoietin (EPO) has more therapeutic approaches than ever in history. After cloning its gene in 1984, EPO obtained FDA license for clinical use in 1989. EPO and its analogues are mainly used for treatment of the anaemias of chronic renal failure and malignancies. Regarding research of the past 15 years, tremendous efforts were made for improvement of bioactivity, half-life and alternative application. Today, there are human cell-lined derived EPO, SEP, CEPO, CERA and drugs which are linked to different pathways of signaling. Due to the fact that these substances are not detectable with standardized methods of detection, it must be assumed that the abuse in sport is still possible. Moreover it was found out that the EPO receptor and EPO synthesis are also expressed by non-hematopoietic tissues, e. g. heart myocytes, ovarian and glial cells. On these tissues EPO is linked to promote cell proliferation and differentiation, angiogenesis or inhibition of apoptosis. This detection offered approaches in treatment for apoplexia and cardiac infarction and even in preventive treatment of cardiovascular diseases which led to an interest of manifold subject categories.

Schlüsselwörter

Erythropoietin - geschichtlicher Überblick - neue therapeutische Aspekte - Doping - Nebenwirkungen

Key words

erythropoietin - historic overview - new therapeutic approaches - doping - side-effects

Literatur

• 1 Jelkmann W. Erythropoietin after a century of research: younger than ever.  Eur J Haematol. 2007;  78 183-205
• 2 Eckardt K U, Kurtz A. Regulation of erythropoietin production.  Eur J Clin Invest. 2005;  35 (Suppl 3) 13-19
• 3 Bonsdorff E, Jalavista E. A humoral mechanism in anoxic erythrocytosis.  Acta Physiol Scand. 1948;  16 150-170
• 4 Erslev A. Humoral regulation of red cell production.  Blood. 1953;  8 349-357
• 5 Lee-Huang S. Cloning and expression of human erythropoietin cDNA in Escherichia coli.  Proc Natl Acad Sci U S A. 1984;  81 2708-2712
• 6 Levin N. Management of blood pressure changes during recombinant human erythropoietin therapy.  Semin Nephrol. 1989;  9 16-20
• 7 Kawasaki N, Morimoto K, Hayakawa T. Study on evaluating methods for the quality control of glycoprotein products. (1). Erythropoietin products.  Eisei Shikenjo Hokoku. 1995;  69-73
• 8 Stockmann C, Fandrey J. Hypoxia-induced erythropoietin production: a paradigm for oxygen-regulated gene expression.  Clin Exp Pharmacol Physiol. 2006;  33 968-979
• 9 Marxsen J H, Stengel P, Doege K. et al . Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-alpha-prolyl-4-hydroxylases.  Biochem J. 2004;  381 761-767
• 10 Sasaki R, Masuda S, Nagao M. Pleiotropic functions and tissue-specific expression of erythropoietin.  News Physiol Sci. 2001;  16 110-113
• 11 Yoshimura A, Arai K. Physician Education: The Erythropoietin Receptor and Signal Transduction.  Oncologist. 1996;  1 337-339
• 12 Semenza G L. Hypoxia-inducible factor 1 (HIF-1) pathway.  Sci STKE. 2007;  2007 cm8
• 13 Watkins P C, Eddy R, Hoffman N. et al . Regional assignment of the erythropoietin gene to human chromosome region 7pter----q22.  Cytogenet Cell Genet. 1986;  42 214-218
• 14 Choi D, Kim M, Park J. Erythropoietin: physico- and biochemical analysis.  J Chromatogr B Biomed Appl. 1996;  687 189-199
• 15 Narhi L O, Arakawa T, Aoki K H. et al . The effect of carbohydrate on the structure and stability of erythropoietin.  J Biol Chem. 1991;  266 23 022-23 026
• 16 Dame C, Fahnenstich H, Freitag P. et al . Erythropoietin mRNA expression in human fetal and neonatal tissue.  Blood. 1998;  92 3218-3225
• 17 Fisher J W. Erythropoietin: physiology and pharmacology update.  Exp Biol Med. 2003;  228 1-14
• 18 Jelkmann W. Control of erythropoietin gene expression and its use in medicine.  Methods Enzymol. 2007;  435 179-197
• 19 Lappin T R, Maxwell A P, Johnston P G. EPO’s alter ego: erythropoietin has multiple actions.  Stem Cells. 2002;  20 485-492
• 20 Bath P M, Sprigg N. Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke.  Cochrane Database Syst Rev. 2007;  CD005207
• 21 Sasaki H, Bothner B, Dell A. et al . Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA.  J Biol Chem. 1987;  262 12 059-12 076
• 22 Wasley L C, Timony G, Murtha P. et al . The importance of N- and O-linked oligosaccharides for the biosynthesis and in vitro and in vivo biologic activities of erythropoietin.  Blood. 1991;  77 2624-2632
• 23 Yoshimura A, Zimmers T, Neumann D. et al . Mutations in the Trp-Ser-X-Trp-Ser motif of the erythropoietin receptor abolish processing, ligand binding, and activation of the receptor.  J Biol Chem. 1992;  267 11 619-11 625
• 24 Akimoto T, Kusano E, Inaba T. et al . Erythropoietin regulates vascular smooth muscle cell apoptosis by a phosphatidylinositol 3 kinase-dependent pathway.  Kidney Int. 2000;  58 269-282
• 25 Lacombe C, Mayeux P. The molecular biology of erythropoietin.  Nephrol Dial Transplant. 1999;  14 (Suppl 2) 22-28
• 26 Strippoli G F, Navaneethan S D, Craig J C. Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease.  Cochrane Database Syst Rev. 2006;  CD003967
• 27 Lucas C, Carrera F, Jorge C. et al . Effectiveness of weekly darbepoetin alfa in the treatment of anaemia of HIV-infected haemodialysis patients.  Nephrol Dial Transplant. 2006;  21 3202-3206
• 28 Bokemeyer C, Aapro M S, Courdi A. et al . EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update.  Eur J Cancer. 2007;  43 258-270
• 29 Miskowiak K, O’Sullivan U, Harmer C J. Erythropoietin enhances hippocampal response during memory retrieval in humans.  J Neurosci. 2007;  27 2788-2792
• 30 Ehrenreich H, Fischer B, Norra C. et al . Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis.  Brain. 2007;  130 2577-2588
• 31 Grunfeld J F, Barhum Y, Blondheim N. et al . Erythropoietin delays disease onset in an amyotrophic lateral sclerosis model.  Exp Neurol. 2007;  204 260-263
• 32 Bogoyevitch M A. An update on the cardiac effects of erythropoietin cardioprotection by erythropoietin and the lessons learnt from studies in neuroprotection.  Cardiovasc Res. 2004;  63 208-216
• 33 Egrie J C, Dwyer E, Browne J K. et al . Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin.  Exp Hematol. 2003;  31 290-299
• 34 Long D L, Doherty D H, Eisenberg S P. et al . Design of homogeneous, monopegylated erythropoietin analogs with preserved in vitro bioactivity.  Exp Hematol. 2006;  34 697-704
• 35 Dumont J A, Low S C, Peters R T. et al . Monomeric Fc fusions: impact on pharmacokinetic and biological activity of protein therapeutics.  BioDrugs. 2006;  20 151-160
• 36 Fiordaliso F, Chimenti S, Staszewsky L. et al . A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury.  Proc Natl Acad Sci U S A. 2005;  102 2046-2051
• 37 Martin K J. The first human cell line-derived erythropoietin, epoetin-delta (Dynepo), in the management of anemia in patients with chronic kidney disease.  Clin Nephrol. 2007;  68 26-31
• 38 Pascual J A, Belalcazar V, Bolos de C. et al . Recombinant erythropoietin and analogues: a challenge for doping control.  Ther Drug Monit. 2004;  26 175-179
• 39 Liu Z, Stoll V S, Devries P J. et al . A potent erythropoietin-mimicking human antibody interacts through a novel binding site.  Blood. 2007;  110 2408-2413
• 40 Hsieh M M, Linde N S, Wynter A. et al . HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques.  Blood. 2007;  110 2140-2147
• 41 Battaglia A, Fattorossi A, Pierelli L. et al . The fusion protein MEN 11 303 (granulocyte-macrophage colony stimulating factor/erythropoietin) acts as a potent inducer of erythropoiesis.  Exp Hematol. 2000;  28 490-498
• 42 Lee D E, Son W, Ha B J. et al . The prolonged half-lives of new erythropoietin derivatives via peptide addition.  Biochem Biophys Res Commun. 2006;  339 380-385
• 43 Tsutsui H, Sugioka Y, Takaku F. et al . A double-blind dose ranging study of weekly subcutaneous administration of rHuEPO (KRN5702) on post-phlebotomy anemia of patients scheduled for predeposit autologous blood transfusion (multicenter late PhII study).  Nippon Seikeigeka Gakkai Zasshi. 1993;  67 919-934
• 44 Luft F C. Erythropoietin and arterial hypertension.  Clin Nephrol. 2000;  53 S61-S64
• 45 Sytkowski A J. Does erythropoietin have a dark side? Epo signaling and cancer cells.  Sci STKE. 2007;  2007 pe38
• 46 Casadevall N. What is antibody-mediated pure red cell aplasia (PRCA)?.  Nephrol Dial Transplant. 2005;  20 Suppl 4 iv3-iv8
• 47 Parisotto R, Gore C J, Emslie K R. et al . A novel method utilising markers of altered erythropoiesis for the detection of recombinant human erythropoietin abuse in athletes.  Haematologica. 2000;  85 564-572
• 48 Gaudard A, Varlet-Marie E, Bressolle F. et al . Drugs for increasing oxygen and their potential use in doping: a review.  Sports Med. 2003;  33 187-212
• 49 Minuto F, Barreca A, Melioli G. Indirect evidence of hormone abuse. Proof of doping?.  J Endocrinol Invest. 2003;  26 919-923
• 50 Schmidt W, Prommer N. The optimised CO-rebreathing method: a new tool to determine total haemoglobin mass routinely.  European journal of applied physiology. 2005;  95 486-495