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Erythropoietin (EPO) is commonly used to ameliorate the anemia that results from chemotherapy. However, there is concern that EPO utilization in myeloid malignancies such as leukemia and lymphoma could stimulate growth of tumor cells that express the EPO receptor and/or protect cancer cells from chemotherapy. Recent studies have demonstrated that the EPO receptor is also expressed in some solid tumors such as breast and prostate cancer. To examine the possibility that EPO alters the response to chemotherapy in breast cancer cells, the effects of EPO (10U/ml) on the response to chemotherapeutic agents was assessed in MCF-7 breast tumor cells. EPO produced a detectable stimulation of the growth of MCF-7 breast tumor cells (by approximately 25.7± 7.9%), consistent with the expression of the EPO receptor in this cell line. However, EPO did not reduce the antiproliferative or apoptosis-promoting effects of adriamycin (50nM), tamoxifen (25μM), or taxol (100nM). EPO also failed to interfere with senescence arrest produced by 1μM adriamycin. We further evaluated the influence of EPO (10U/ml) on the response to clinically relevant doses of daunorubicin and cytarabine, two drugs commonly utilized in the treatment of leukemia, in Friend Murine Erythro-Leukemia (F-MEL) cells. F-MEL cells express wild-type EPO receptor and EPO effectively activates signal transduction pathways, but F-MEL cells do not require EPO for proliferation or survival. Only slight growth stimulation (approximately 6.1± 1.3%) was evident in F-MEL cells exposed to EPO. Cytarabine alone, at a concentration of 0.1μM, reduced growth by 42.3± 0.38%. In the presence of EPO, inhibition of proliferation by cytarabine was 32.5± 0.38%, indicating minimal protection by EPO. At cytarabine concentrations of 0.2μM, 0.3μM, and 1μM, where significant apoptosis was evident, EPO appeared to only slightly reduce the extent of apoptotic cell death. Daunorubicin alone, at a concentration of 0.005 μM, reduced growth by 74.7± 0.29%. In the presence of EPO, inhibition of proliferation by daunorubicin was reduced to 36.6± 2.1%, indicative of protection from the drug’s antiproliferative effects. These observations suggest that EPO is unlikely to attenuate the effectiveness of chemotherapy in solid tumors that express the EPO receptor, such as breast cancer. However, EPO does appear to have the capacity to influence distinct signaling pathways that mediate the antiproliferative activity of select drugs in leukemic cells. Although EPO may have utility in the prevention of anemia in patients being treated for leukemia, the effectiveness of some chemotherapeutic agents may be attenuated in the presence of this agent. Supported by United States Research and Materiel Command Award W81XWH-04-1-0659.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]