Recombinant human erythropoietin alpha improves the efficacy of radiotherapy of a human tumor xenograft, affecting tumor cells and microvessels

Background and purpose: 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 rHuEPO alpha on irradiation in EPOR-positive human squamous cell carcinoma xenograft was tested. Materials and methods: A431 tumor-bearing SCID mice were treated from the tumor implantation with rHuEPO alpha 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 rHuEPO alpha on the hemoglobin level, on tumor-associated blood vessels and on hypoxia-inducible factor-(HIF-)1 alpha expression of the tumor xenografts were monitored. The proliferation, apoptosis and clonogenic capacity of A431 cancer cells treated with rHuEPO alpha and irradiation were also tested in vitro. Results: In vitro, rHuEPO alpha 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, rHuEPO alpha administration compensated the tumor-induced anemia in SCID mice and decreased tumoral HIF-1 alpha expression but had no effect on tumor growth. At the same time rHuEPO alpha 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. Conclusion: rHuEPO alpha treatment may modulate the efficacy of cancer radiotherapy not only by reducing systemic hypoxia and tumoral HIF-1 alpha expression, but also by destroying tumoral vessels.