Biology of erythropoietin

Hypoxia induces tissue-specific gene products such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF), which improve the peripheral O₂ supply, and glucose transporters and glycolytic enzymes, which adapt cells to reduced O₂ availability. EPO has been the fountainhead in research on pO₂-dependent synthesis of proteins. The EPO gene enhancer (like the flanking DNA-elements of several other pO₂-controlled genes) contains a consensus sequence (CGTG) that binds the trans-acting dimeric hypoxia-inducible factor 1 (HIF-1 α/β). The α-subunit of HIF-1 is rapidly degraded by the proteasome under normoxic conditions, but it is stabilized on occurrence of hypoxia. HIF-1 DNA-binding is also increased by insulin, and by interleukin-1 and tumor necrosis factor. Thus, in some aspects there is synergy in the cellular responses to hypoxia, glucose deficiency and inflammation. In viewing clinical medicine recombinant human EPO (rHu-EPO) has become the mainstay of treatment for renal anemia. Endogenous EPO and rHu-EPO are similar except for minor differences in the pattern of their 4 carbohydrate chains. RHu-EPO is also administered to patients suffering from non-renal anemias, such as in autoimmune diseases or malignancies. The correction of anemia in patients with solid tumors is not merely considered a palliative intervention. Hypoxia promotes tumor growth. However, the benefits of the administration of rHu-EPO to tumor patients with respect to its positive effects on tumor oxygenation, tumor growth inhibition and support of chemo- and radiotherapy is still debatable ground.