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104. A “classical” homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5Y and pheochromocytoma PC-12 cells. Ray-Coquard I, Laplaige P, Vey N, Asselain B, Urbieta M. A prospective, observational study describing the haematological response in patients undergoing chemotherapy treated by tri-weekly darbepoetin alfa for anaemia. Clin Hemorheol Microcirc (2010) 44(2):115–23. European Patent Application EP 2 492 355 A1 (2012). Ann Oncol (2010) 21(10):2029–39. Diseases that may result from lack of EPO include anemia, kidney disease, kidney tumor, or polycythemia. Oncol Rep (2013) 30(3):1455–62. Furthermore, EPORs have been found also on several types of tumors and malignant cells [reviewed in Ref. Does erythropoietin have a dark side? Glycosylation at specific sites of erythropoietin is essential for biosynthesis, secretion, and biological function. Erythropoietin receptor contributes to melanoma cell survival in vivo. Jacobs K, Shoemaker C, Rudersdorf R, Neill SD, Kaufman RJ, Mufson A, et al. Ephrin receptors and their ligands, the ephrins, mediate numerus developmental processes.

doi:10.1002/cncr.25972, 132. By 19 months into the study, when patients were no longer receiving study drug, the proportion of the surviving population in each arm was virtually the same. Eph receptor signalling casts a wide net on cell behaviour. Erythropoietin activates telomerase through transcriptional and posttranscriptional regulation in human erythroleukemic JAS-REN-A cells. Understanding the multifarious functions of EPO and its reciprocal relation with other signaling pathways is crucial for developing more effective agents for cancer therapy and for minimizing risks for cancer patients. To discuss the information in this article with other oncology nurses, visit the ONS Communities. Based on discussed clinical studies, the adverse effect of EPO/ESA in cancer patients during anti-cancer therapy could be related to chronic EPO treatment. Oncology (Williston Park) 16:: Maiese K, Li F, Chong ZZ: New avenues of exploration for erythropoietin. Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, et al. Differences between the two investigators were resolved by consensus. Lancet 362:: Schipper J, Henke M: [Erythropoietin in patients with head and neck carcinomas?]. Muravyov AV, Cheporov SV, Kislov NV, Bulaeva SV, Maimistova AA. A thorough re-examination of the biology of Epo as well as its clinical application for cancer patients is urgently needed. It is tempting to attribute these results to bad luck—a statistical fluke that perhaps happened because the study did not include performance status or the degree of baseline anemia as a stratification factor in the randomization. Furthermore, concurrent administration of EPO and trastuzumab correlated with shorter progression-free and overall survival in patients with HER2-positive metastatic breast cancer (57). Engert A, Josting A, Haverkamp H, Villalobos M, Lohri A, Sökler M, et al. Characteristics of Patients by Treatment Arm and EpoR Status. (2007).

J Biol Chem (1987) 262(35):17156–63. Oncologist (2004) 9(Suppl 5):18–30. Most trials included in this meta-analysis had a relatively short observation period (median, 84 days), and therefore had limited power to uncover a survival advantage with erythropoietin. Table 1. doi:10.1016/j.ygyno.2012.09.002, 144. doi:10.2119/molmed.2011.00414, 49. Improvement in cancer survival with erythropoietin therapy seemed a lofty goal but did not appear to be too much to ask. Importantly, EPO/EPOR levels correlated well with angiogenesis and progression of patients with hepatocellular carcinoma, neuroblastoma, squamous cell carcinoma of the tongue, melanoma, and gastric adenocarcinoma (115–120). Indian J Pathol Microbiol (2011) 54(2):273–8. doi:10.1016/j.cellsig.2006.08.014, 73. 110. Lasne F, Thioulouse J, Martin L, de Ceaurriz J. doi:10.1002/14651858.CD003407.pub5, 125. doi:10.1371/journal.pone.0045122, 81. doi:10.1185/03007995.2011.639352, 127. doi:10.1182/blood-2009-03-211797, 175. Epoetin alpha decreases the number of erythrocyte transfusions in patients with acute lymphoblastic leukemia, lymphoblastic lymphoma, and Burkitt leukemia/lymphoma: results of a randomized clinical trial. In this regard, elevated hemoglobin, increased viscosity, platelet activation, endothelial progenitor mobilization, immunomodulatory effects, and others could play significant roles. We administered 60 Gy following complete resection or 64 Gy subsequent to microscopically incomplete resection; 70 Gy were given following macroscopically incomplete resection or for definitive radiotherapy alone. The gene for the human erythropoietin receptor: analysis of the coding sequence and assignment to chromosome 19p.

doi:10.1038/nrn1687, 48. Leyland-Jones B, Semiglazov V, Pawlicki M, et al: Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. Comparisons were done separately for patients, with cancer staining positive for EpoR and for patients whose cancers did not. (64–67)] questioning the use of recombinant EPO in cancer patients (68). Paradoxes of the EphB4 receptor in cancer. The ASCO Post For the most part, characteristics of patients assigned to treatment with epoetin beta were similar to those assigned placebo. This is followed by a more detailed presentation of both pre-clinical and clinical data that demonstrate EPO’s action on cancer cells, as well as tumor angiogenesis and lymphangiogenesis. Van Belle S, Karanikiotis C, Labourey JL, Galid A, Wheeler T, Pujol B. Until 1990, erythropoietin (EPO) was considered to have a single biological purpose and action, the stimulation of red blood cell growth and differentiation. Although the methodology of this study was heavily criticized in a series of letters published in The Lancet in 2004, the results are still noteworthy. Many clinical trials have looked at the benefits of using erythropoietin to treat people with cancer. ASCO Daily News PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer – results at the time of surgery.

Lancet (2009) 373(9674):1532–42. Institutions Adding epoetin alfa to intense dose-dense adjuvant chemotherapy for breast cancer: randomized clinical trial. Epoetin alfa in patients with advanced-stage Hodgkin’s lymphoma: results of the randomized placebo-controlled GHSG HD15EPO trial. doi:10.3892/ijmm.2013.1231, 56. Beschorner R, Psaras T, Meyermann R, Bremer J, Schmidt T, Mittelbronn M, et al. Erythropoietin and its receptor in breast cancer: correlation with steroid receptors and outcome. doi:10.1016/j.yexcr.2011.03.003, 123. doi:10.1038/onc.2011.366, 113. Erythropoietin resistance as surrogate marker of graft and patient survival in renal transplantation: 3-year prospective multicenter study. Int J Clin Oncol (2004) 9(3):184–8. doi:10.1185/03007995.2010.542134, 153. Oncogene 23:: Acs G, Zhang PJ, Rebbeck TR, et al: Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma. Curr Med Res Opin (2011) 27(5):987–94. 40. Oxford, England, Cochrane Library, CD003407, 2004. It appears that the problems surrounding Epo treatment of cancer patients stem from the biology of Epo itself.4 Once thought to act solely on the erythroid compartment, it is now becoming increasingly clear that Epo has pleiotropic effects.1 High levels of Epo and Epo R are found in many different cell types and the Epo/Epo R system is known to induce proliferation, chemotaxis, and angiogenesis, and inhibit apoptosis.1,2 Epo and Epo R are expressed in head-and-neck tumors,6 breast, colon, lung, prostate,7 ovary,7,8 uterine,8 and cervical9 cancer cells, neuroblastomas, astrocytomas, and other solid nervous system tumors,10 and numerous malignant cell lines.11,12 Additionally, the Epo/Epo R system appears to be functioning in these cells and tissues.8,10-12 Epo added to cancer cell lines in vitro elicits secretion of angiogenic growth factors and promotes proliferation and chemotaxis of endothelial cells.10 Neutralizing anti-Epo monoclonal antibody and soluble Epo R antagonist injected into ex vivo cultured tumor tissue blocks,8 and soluble Epo R antagonist injected into mice possessing cancer cell xenografts,11 reduce angiogenesis and tumor cell survival. 1. doi:10.3892/mmr.2014.2044, 90. Custom Services for Cell & Gene Therapies, Good Manufacturing Practice (GMP) Antibody Services. It is probably not necessary for such a trial to enroll patients with an identical tumor type and stage, as long as well-recognized general prognostic features such as performance status are balanced, and the study is large enough that tumor types and other characteristics are evenly distributed. Figure 1. doi:10.1016/S0140-6736(09)60502-X, 137. EPO is secreted into the bloodstream, circulates to the bone marrow, and binds to EPOR situated on the cell surface of erythroid progenitors promoting their survival, proliferation, and differentiation (27). If the treatment plan is more conservative or palliative, consider ESAs for anemia treatment, but proceed with great caution. Grau C, Overgaard J: Significance of Hemoglobin Concentration for Treatment Outcome .

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