Recombinant Human Erythropoietin alpha Improves the Efficacy of Radiotherapy of a Human Tumor Xenograft, Affecting Tumor Cells and Microvessels

Tumor-induced anemia often occurs in cancer patients, and is corrected by recombinant human erythropoietins (rHuEPOs). Recent studies indicated that, besides erythroid progenitor cells, tumor and endothelial cells express erythropoietin receptor (EPOR) as well; therefore, rHuEPO may affect their functions. Here, the effect of rHuEPOalpha on irradiation in EPOR-positive human squamous cell carcinoma xenograft was tested.A431 tumor-bearing SCID mice were treated from the tumor implantation with rHuEPOalpha at human-equivalent dose. Xenografts were irradiated (5 Gy) on day 14, and the final tumor mass was measured on day 22. The systemic effects of rHuEPOalpha on the hemoglobin level, on tumor-associated blood vessels and on hypoxia-inducible factor-(HIF-)1alpha expression of the tumor xenografts were monitored. The proliferation, apoptosis and clonogenic capacity of A431 cancer cells treated with rHuEPOalpha and irradiation were also tested in vitro.In vitro, rHuEPOalpha treatment alone did not modify the proliferation of EPOR-positive A431 tumor cells but enhanced the effect of irradiation on proliferation, apoptosis and clonogenic capacity. In vivo, rHuEPOalpha administration compensated the tumor-induced anemia in SCID mice and decreased tumoral HIF-1alpha expression but had no effect on tumor growth. At the same time rHuEPOalpha treatment significantly increased the efficacy of radiotherapy in vivo (tumor weight of 23.9 +/- 4.7 mg and 34.9 +/- 4.6 mg, respectively), mediated by increased tumoral blood vessel destruction.rHuEPOalpha treatment may modulate the efficacy of cancer radiotherapy not only by reducing systemic hypoxia and tumoral HIF-1alpha expression, but also by destroying tumoral vessels.