Erythropoietin after a century of research: younger than ever.

In the light of the enthusiasm regarding the use of recombinant human erythropoietin (Epo) and its analogues for treatment of the anaemias of chronic renal failure and malignancies it is worth remembering that today's success has been based on a century of laborious research. The concept of the humoral regulation of haematopoiesis was first formulated in 1906. The term 'erythropoietin' for the erythropoiesis-stimulating hormone was introduced in 1948. Native human Epo was isolated in 1977 and its gene cloned in 1985. During the last 15 yr, major progress has been made in identifying the molecules controlling Epo gene expression, primarily the hypoxia-inducible transcription factors (HIF) that are regulated by specific O2 and oxoglutarate requiring Fe2+-containing dioxygenases. With respect to the action of Epo, its dimeric receptor (Epo-R) has been characterised and shown to signal through protein kinases, anti-apoptotic proteins and transcription factors. The demonstration of Epo-R in non-haematopoietic tissues indicates that Epo is a pleiotropic viability and growth factor. The neuroprotective and cardioprotective potentials of Epo are reviewed with a focus on clinical research. In addition, studies utilising the Epo derivatives with prolonged half-life, peptidic and non-peptidic Epo mimetics, orally active drugs stimulating endogenous Epo production and Epo gene transfer are reviewed.