Molecular Medicine rePorTS 3: 95-101, 201095
Abstract. recombinant human erythropoietin (rhePo) has
been used in the eu and the united States for the treatment
of anemia in cancer patients after myelosuppressive chemo-
therapy or radiotherapy. However, several conflicting results
have been reported concerning the detrimental effect of
rhEPO on survival benefit in cancer patients. In experimental
studies, contradictory results were also reported in in vitro
tumor cell proliferation studies and in vivo tumor growth
studies using tumor cells expressing EPO-receptor (EPO-R).
Therefore, we tried to clarify the effect of epoetin β, a product
of rhEPO, on tumor growth in xenograft models using five
ePo-r-positive human cancer cell lines, namely the McF7
breast, 786-O renal, SCH gastric, A549 lung and SK-OV-3
ovarian cancer cell lines. epoetin β was administered once a
week for 3 weeks at doses of 1,000, 3,000 and 10,000 IU/kg
in accordance with the clinical administration schedule and
dosages. As a result, no enhancement of tumor growth from
the administration of epoetin β was observed in any of the
xenograft models throughout the experiment duration. The
effect of epoetin β on the antitumor activity of bevacizumab,
an anti-angiogenic agent, was additionally examined using
A549 and MCF7 xenograft models, since rhEPO reportedly
stimulates tumor neovascularization. epoetin β showed no
significant effect on the antitumor activity of bevacizumab in
either xenograft model. These findings suggest that epoetin β
is not involved in in vivo tumor growth promotion.
Erythropoietin (EPO) is a 30.4-kDa glycoprotein that promotes
the proliferation, differentiation and maturation of erythroid
progenitor cells by binding to its cognate cell surface EPO
receptor (EPO-R) (1-4). Recombinant human EPO (rhEPO) is
an effective treatment modality of anemia associated with
chronic renal failure (5) and is used in the eu and the united
States for the treatment of anemia in cancer patients who have
received myelosuppressive chemotherapy or radiotherapy.
anemia associated with cancer and cancer therapy is one of
the independent prognostic factors in the treatment of malignant
diseases. Several studies have shown that administration of
rhePo to cancer patients with chemotherapy-related anemia
increased hemoglobin (Hb) concentration, resulting in reduced
need for blood transfusions and improved quality of life (Qol)
(6-11). However, conflicting results have been reported
concerning the overall survival of patients who have received
rhEPO therapy. A recent meta-analysis suggested that the
treatment of anemia with rhePo may improve overall survival
in cancer patients (12). Moreover, Glaser et al demonstrated
that overall survival was prolonged in the rhEPO-treated group
compared with the non-treated group in patients with squamous
cell carcinoma of the oral cavity and oropharynx who had
received chemo-radiation therapy (13). on the other hand, data
from several clinical trials indicated adverse outcomes. Henke
et al described that locoregional progression-free survival was
poorer in a rhePo (epoetin β) group than in a placebo group in
patients with advanced head and neck cancer who had received
definitive treatment with radiotherapy or postoperative
radiotherapy (ENHANCE Study) (14). Leyland-Jones et al
reported a higher mortality in a group treated with rhEPO
(epoetin α) compared with a placebo group in patients with
metastatic breast cancer (BEST Study) (15). Wright et al
observed a decrease in overall survival in patients with advanced
non-small cell lung cancer treated with rhEPO (epoetin α)
(16). The disparities may be attributed to differences in study
population, design, target Hb level and risk of thromboembolic
complications, and there is concern that rhePo may stimulate
tumor growth. However, whether or not EPO directly promotes
tumor growth by binding to EPO-R expressed on tumor cells,
which may lead to clinical progression in cancer patients,
remains unclear. The Oncologic Drug Advisory Committee
(USA) has indicated that there are insufficient data from
adequate and well-controlled studies designed to assess the
effects on survival or tumor promotion, and employ the
recommended doses of erythropoiesis-stimulating agents (17).
In addition, the United States Food and Drug Administration
issued a warning against erythropoiesis-stimulating agents for
patients with chemotherapy-associated anemia (18).
Effect of erythropoietin on human tumor
growth in xenograft models
MOTOyUKI KATAOKA, yOICHIRO MORIyA, yOSHIyUKI MORIgUCHI, TOSHIKI IWAI,
KAORI FUJIMOTO-OUCHI, MASATOSHI SHIRANE, KUMIKO KONDOH and KAzUSHIgE MORI
Product Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan
Received June 2009; Accepted September 10, 2009
Correspondence to: Dr Motoyuki Kataoka, Product Research
Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado,
gotemba, Shizuoka 412-8513, Japan
Key words: epoetin β, human cancer xenograft, erythropoietin
Molecular Medicine rePorTS 3: 95-101, 2010101
16. Wright JR, Ung yC, Julian JA, et al: randomized, double-blind,
placebo-controlled trial of erythropoietin in non-small cell lung
cancer with disease-related anemia. J Clin Oncol 25: 1027-1032,
17. Rizzo JD, Somerfield MR, Hagerty KL, et al: use of epoetin
and darbepoetin in patients with cancer: 2007 american Society
of Hematology/American Society of Clinical Oncology clinical
practice guideline update. Blood 111: 25-41, 2008.
18. Juneja V, Keegan P, gootenberg JE, et al: Continuing Reassessment
of the risks of erythropoiesis-stimulating agents in patients with
cancer. Clin Cancer Res 14: 3242-3247, 2008.
19. D'Andrea AD and zon LI: Erythropoietin receptor: subunit
structure and activation. J Clin Invest 86: 681-687, 1990.
20. Farrell F and Lee A: The erythropoietin receptor and its expres-
sion in tumor cells and other tissues. Oncologist 9: 18-30, 2004.
21. Jelkmann W and Wangner K: Beneficial and ominous aspects
of the pleiotropic action of erythropoietin. ann Hematol 83:
22. Anagnostou A, Liu z, Steiner M, Chin K, Lee ES, Kessimian N and
Noguchi CT: Erythropoietin receptor mRNA expression in human
endotherial cells. Proc Natl Acad Sci USA 91: 3974-3978, 1994.
23. Wu H, Lee SH, gao J, Liu X and Iruela-Arispe ML: Inactivation
of erythropoietin leads to defects in cardiac morphogenesis.
development 126: 3597-3605, 1999.
24. Arcasoy MO, Amin K, Karayal AF, Chou SC, Raleigh JA, Varia MA
and Haroon zA: Functional significance of erythropoietin receptor
expression in breast cancer. Lab Invest 82: 911-918, 2002.
25. Acs g, Acs P, Beckwith SM, Pitts RL, Clements E, Wong K and
Verma A: Erythropoietin and erythropoietin receptor expression
in human cancer. cancer res 61: 3561-3565, 2001.
26. yasuda y, Fujita y, Matsuno T, et al: Erythropoietin regulates
tumor growth of human malignancies. Carcinogenesis 24:
27. westenfelder c and Baranowski rl: erythropoietin stimulates
proliferation of human renal carcinoma cells. Kidney Int 58:
28. Arcasoy MO, Jiang X and Haroon zA: Expression of erythropoi-
etin receptor splice variants in human cancer. Biochem Biophys
res commun 362: 999-1007, 2003.
29. Arcasoy MO, Amin K, Vollmer RT, Jiang X, Demark-
Wahnefried W and Haroon zA: Erythropoietin and erythropoietin
receptor expression in human prostate cancer. Mod Pathol 18:
30. Selzer E, Wacheck V, Kodym R, Schlagbauer-Wadl H, Schlegel W,
Pehamberger H and Jansen B: Erythropoietin receptor expression
in human melanoma cells. Melanoma Res 10: 421-426, 2000.
31. Rosti V, Pedrazzoli P, Ponchio L, zibera C, Novella A, Lucotti C,
della cuna Gr and cazzola M: effect of recombinant human
erythropoietin on hematopoietic and non-hematopoietic
malignant cell growth in vitro. Haematologica 78: 208-212,
32. Sugawa M and Fukui H: Effects of recombinant human erythro-
poietin on the growth of various human tumor cells. Biotherapy
19: 181-196, 2005.
33. Tovari J, gilly R, Raso E, Paku S, Bereczky B, Varga N, Vago A
and Timar J: Recombinant human erythropoietin α targets
intratumoral blood vessel, improving chemotherapy in human
xenograft models. Cancer Res 65: 7186-7193, 2005.
34. LaMontagne KR, Butler J, Marshall DJ, Tullai J, gechtman z,
Hall C, Meshaw A and Farrell FX: Recombinant epoetins do not
stimulate tumor growth in erythropoietin receptor-positive breast
carcinoma models. Mol Cancer Ther 5: 347-355, 2006.
35. Silver dF and Piver MS: effects of recombinant human erythro-
poietin on the antitumor effect of cisplatin in SCID mice bearing
human ovarian cancer: a possible oxygen effect. gynecol Oncol
73: 280-284, 1999.
36. Mittelman M, Nemann D, Peled A, Kanter P and Haran-ghera N:
erythropoietin induces tumor regression and antitumor immune
responses in murine myeloma models. Proc natl acad Sci uSa
98: 5181-5186, 2001.
37. Okazaki T, Ebihara S, Asada M, yamanda S, Niu K and Arai H:
Erythropoietin promotes the growth of tumors lacking its receptor
and decreases survival of tumor-bearing mice by enhancing
angiogenesis. Neoplasia 10: 932-939, 2008.
38. Tas F, eralp y, Basaran M, et al: Anemia in oncology practice:
Relation to diseases and their therapies. Am J Clin Oncol 25:
39. Hardee Me, cao y, Fu P, et al: erythropoietin blockade inhibits
the induction of tumor angiogenesis and progression. PLoS One 2:
40. Eskens FA and Sleijfer S: The use of bevacizumab in colorectal,
lung, breast, renal and ovarian cancer: where does it fit. Eur J
Cancer 44: 2350-2356, 2008.