Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Weiss, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Weiss, M. J.
The Oncologist, Vol. 8, Suppl 3, 18–29, December 2003
© 2003 AlphaMed Press

New Insights Into Erythropoietin and Epoetin Alfa: Mechanisms of Action, Target Tissues, and Clinical Applications

Mitchell J. Weiss

The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

Correspondence: Mitchell J. Weiss, M.D., The Children’s Hospital of Philadelphia, 316B Abramson Research Building, Philadelphia, Pennsylvania 19104, USA. Telephone: 215-590-0565; Fax: 215-590-4834; e-mail: weissmi{at}email.chop.edu


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Mechanism of Action of...
 Erythropoietic Effects of...
 Nonerythroid Functions of EPO
 Potential Functions of EPO...
 Therapeutic Implications
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Discuss the mechanism of action of endogenous erythropoietin and the therapeutic use of epoetin alfa to stimulate red blood cell production and improve the quality of life in patients with cancer.
  2. Explain how epoetin alfa is being investigated in alternate dosing regimens and for anemia prevention in patients with cancer.
  3. Describe how functional endogenous erythropoietin receptor signaling pathways have been demonstrated in numerous nonerythropoietic tissues, including in the central nervous system, and relate evidence for the roles of erythropoietin and epoetin alfa beyond erythropoiesis, including the therapeutic implications of these nonerythroid functions.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Mechanism of Action of...
 Erythropoietic Effects of...
 Nonerythroid Functions of EPO
 Potential Functions of EPO...
 Therapeutic Implications
 Conclusions
 References
 
Recombinant human erythropoietin (epoetin alfa) has proven beneficial for the treatment of various anemias. The mechanism of action of endogenous erythropoietin and the therapeutic use of epoetin alfa to stimulate red blood cell production and improve the quality of life in cancer patients are reviewed here. Epoetin alfa may also attenuate the cognitive dysfunction associated with cancer therapy. Interestingly, functional endogenous erythropoietin receptor signaling pathways have been demonstrated in numerous nonerythropoietic tissues. Of particular importance, epoetin alfa confers neurotrophic and neuroprotective effects in cultured neurons and in several animal models for neurologic disease. In one clinical trial, epoetin alfa appeared to limit functional and histologic damage in patients with stroke. Therefore, in cancer patients receiving chemotherapy, the beneficial effects of epoetin alfa could be mediated not only through enhanced erythrocyte production but also via direct effects on the nervous system. Further investigation into the nonerythropoietic effects of epoetin alfa could broaden its clinical utility for patients with cancer and also provide new therapies for various neurologic disorders.

Key Words. Erythropoietin • Signal transduction • Epoetin alfa • Anemia • Cancer • Central nervous system • Apoptosis


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Mechanism of Action of...
 Erythropoietic Effects of...
 Nonerythroid Functions of EPO
 Potential Functions of EPO...
 Therapeutic Implications
 Conclusions
 References
 
Erythropoietin (EPO) is an endogenous cytokine that is essential for erythrocyte development [1]. In adults, the kidneys produce and release EPO in response to hypoxia [2]. EPO acts by binding to its receptor (EPO-R) and subsequently activating intracellular signal transduction pathways [1]. EPO is essential for life: mice with deletions of the EPO gene or the EPO-R die of anemia in utero [3, 4]. Recombinant human EPO (epoetin alfa) is used in clinical practice to reduce transfusion requirements during surgery [5] and to treat anemia of various etiologies, including anemia of chronic kidney disease [6], cancer-related or cancer treatment-related anemia [7], anemia related to zidovudine therapy in HIV-infected patients [8], and anemia related to ribavirin therapy for hepatitis C virus infection [9].

The mechanism of action of EPO in erythropoiesis and the effects of epoetin alfa in cancer patients are reviewed here. Subsequently, evidence for the roles of EPO and epoetin alfa outside erythropoiesis and potential therapeutic uses of epoetin alfa beyond anemia treatment are explored. This review is based on an educational session presented at the American Society of Hematology (ASH) meeting held in December 2002, updated and expanded as necessary. Accordingly, many abstracts on EPO biology that were presented at the meeting are discussed herein. While these studies have not yet been published in full in peer-reviewed journals, they reflect the current research in this therapeutic area.


   MECHANISM OF ACTION OF EPO IN ERYTHROPOIESIS
Top
 Learning Objectives
 Abstract
 Introduction
 Mechanism of Action of...
Erythropoietic Effects of...
 Nonerythroid Functions of EPO
 Potential Functions of EPO...
 Therapeutic Implications
 Conclusions
 References
 
In adult kidneys, hypoxia gives rise to increased EPO expression stimulated by the DNA binding protein, hypoxia-induced factor-1 (HIF-1) [2, 10]. EPO is secreted into the plasma and, upon arrival in the bone marrow, binds to EPO-Rs on the surface of erythroid progenitor cells [11]. This association triggers a conformational change that brings EPO-R-associated Janus family tyrosine protein kinase 2 (JAK2) molecules into close proximity, stimulating their activation by transphosphorylation [1, 12, 13]. Subsequently, JAK2 molecules phosphorylate eight tyrosine residues in the cytoplasmic domain of the EPO-R, which then serve as docking sites for various Src homology 2-domain-containing intracellular signaling proteins [1]. These proteins, in turn, are tyrosine phosphorylated and activated. One of these proteins is a signal transducer and activator of transcription (STAT5) that, on phosphorylation by JAK2, dissociates from the EPO-R, dimerizes, and then translocates to the nucleus to activate numerous target genes [1], including the apoptosis inhibitor Bcl-x [14].

The inhibition of apoptosis by the EPO-activated JAK2/STAT5/Bcl-x pathway (Fig. 1Go) is important for erythroid differentiation. JAK2 deficiency causes embryonic death due to the absence of definitive erythropoiesis [15]. Furthermore, mice deficient in STAT5a/5b have anemia that correlates with the decreased expression of Bcl-x and increased apoptosis in early erythroblasts [16]. Finally, full Bcl-x knockout mice died in embryogenesis with extensive apoptosis of immature hematopoietic cells [17], and conditional hematopoietic-specific Bcl-x knockout mice had severe anemia [18]. In both models, Bcl-x was required for the survival of erythroid cells during terminal maturation [18, 19]. A recent study also demonstrated that enforced Bcl-x expression can rescue maturation of EPO-deprived erythroid progenitors in vitro, suggesting that the major erythropoietic function of EPO is to prevent apoptosis and that Bcl-x is a critical effector gene [20]. However, it is important to note that EPO and EPO-R null mice exhibit a more severe erythropoietic defect than that seen in Bcl-x null animals, indicating that EPO fosters erythropoiesis through additional effectors. In addition, the erythroid defect in the absence of STAT5a/5b is milder than that produced by loss of Bcl-x, indicating that STAT5-independent mechanisms for Bcl-x induction exist.



View larger version (33K):
[in this window]
[in a new window]
  		Figure 1. JAK2/STAT5/Bcl-x signal transduction pathway of the EPO-R. Adapted with permission from Cheung and Miller [1]. Molecular mechanisms of erythropoietin signaling. Nephron 2001;87:215–222.[CrossRef][Medline] Adapted with permission of S. Karger AG, Medical and Scientific Publishers, Basel, Switzerland.

 
In addition to STAT5, EPO induces JAK2-mediated tyrosine phosphorylation and activation of several other intracellular proteins [1]. Examples include: Shc [21], which, in turn, may activate the signaling pathway involved in erythroid cell proliferation [22]; phosphatidylinositol 3-kinase (PI3K) [23], which may promote survival of erythroid cells [22], and phospholipase C-{gamma}1, which may play a role in erythroid cell proliferation [24]. In this regard, loss of the p85{alpha} subunit of PI3K impairs fetal liver erythropoiesis, although this mutation appears to inhibit signaling through the c-Kit receptor to a greater extent than does mutation of the EPO-R [25].


   ERYTHROPOIETIC EFFECTS OF EPOETIN ALFA IN PATIENTS WITH CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Mechanism of Action of...
 Erythropoietic Effects of...
Nonerythroid Functions of EPO
 Potential Functions of EPO...
 Therapeutic Implications
 Conclusions
 References
 
Rationale for Treatment of Cancer-Related Anemia
Up to 75% of patients with cancer experience anemia during the course of their disease, either due to the cancer itself (tumor infiltration of the bone marrow and/or anemia of chronic disease) or to the myelosuppressive effects of chemotherapy or radiation therapy [7, 26]. Several lines of evidence indicate that aggressive treatment of anemia is an important aspect of cancer therapy. First, a quantitative review of published data from patients with cancer suggests that anemia may be an independent prognostic factor for survival, with a 65% overall estimated greater relative risk of death [27]. In a retrospective analysis of patients undergoing chemotherapy and thoracic radiotherapy for stage IIIA/IIIB non-small cell lung cancer, declining hemoglobin (Hb) levels were highly predictive of survival [28]. The 2-year survival rates were 51% for patients whose Hb level decreased <10% from baseline, 33% when Hb declined by 10%-30%, and 0% when Hb declined by >30% [28]. While these observations might simply reflect impaired erythrocyte production in patients with more aggressive malignancies or greater systemic illness, there are some indications that anemia can interfere with cancer therapy. For example, anoxic tumor cells are two to three times more resistant to radiation therapy than are normally oxygenated cells [29, 30]. In addition, low Hb levels have been associated with tumor hypoxia, lower rates of local failures, and lower survival rates during radiation therapy for multiple tumor types [30–36].

In addition to the possible negative effects of anemia on cancer treatment and clinical outcomes, chronic anemia and the resulting fatigue impair the quality of life (QOL) of patients with cancer, and the use of epoetin alfa to boost erythrocyte production in those patients with cancer-related anemia has resulted in clinically important and statistically significant improvements in QOL [37]. Although red blood cell transfusion is also a treatment option for anemia, its associated problems include the potential for transmission of infections, limited availability of adequate blood supplies, and short-term resolution of symptoms. Epoetin alfa is more convenient to administer, reduces infectious risks, and maintains more constant steady-state Hb levels. Epoetin alfa also may offer potential benefits beyond stimulating erythropoiesis (described later).

Clinical Practice Guidelines for the Use of Epoetin Alfa in Cancer-Related Anemia
Evidence-based clinical practice guidelines for the use of epoetin alfa in patients with cancer have been developed by the American Society of Clinical Oncology (ASCO) in conjunction with ASH [38] and by the National Comprehensive Cancer Network (NCCN) [39]. The ASCO/ASH guidelines provide a thorough overview of the use of epoetin alfa therapy in patients with various forms of cancer based on data included in an evidence report assembled by the Blue Cross Blue Shield Association Technology Evaluation Center [38]. The panel reviewed and summarized many clinical studies involving patients with solid tumors or hematologic malignancies and with chemotherapy- or cancer-related anemia. Briefly, the ASCO/ASH guidelines recommend the use of epoetin alfa in patients with chemotherapy-associated anemia when Hb levels decline to <=10 g/dl, with the decision of whether to treat less severe anemia (i.e., Hb of >10 g/dl to <12 g/dl) determined by clinical circumstance [38]. Guidelines published by the NCCN also recommend the use of erythropoietic agents for the treatment of cancer-related anemia, but suggest intervention for Hb levels <=11 g/dl [39]. For anemia associated with hematologic malignancies, the ASCO/ASH guidelines support the use of epoetin alfa therapy in patients with low-grade myelodysplastic syndrome [38]. The authors of those guidelines suggest that evidence for epoetin alfa use is less robust in anemic (Hb <=10 g/dl) patients with multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL), or chronic lymphocytic leukemia (CLL) not receiving chemotherapy, although some significant improvements in Hb levels have been reported with epoetin alfa treatment [38]. To optimize epoetin alfa therapy for the treatment of cancer-related anemia, it is important to monitor iron status regularly and to treat iron deficiency [40].

Clinical Experience With Epoetin Alfa in the Treatment of Cancer- and Cancer-Treatment-Related Anemia
In both community-based studies and randomized, placebo-controlled clinical trials, epoetin alfa, 150–300 U/kg or 10,000–20,000 U administered three times weekly (TIW) [41–43] or 40,000–60,000 U once weekly (QW) [44–46], has been shown to significantly increase Hb levels and reduce transfusion requirements in anemic patients (generally, Hb <=11 g/dl) with various solid and hematologic malignancies who are undergoing chemotherapy and/or radiation therapy. Overall, approximately two-thirds of patients responded to epoetin alfa treatment, experiencing an increase in Hb of 1 g/dl after 4 weeks or >=2 g/dl (or achieving Hb >=12 g/dl) after 8 weeks of treatment [47]. Epoetin alfa therapy also has been shown to significantly increase Hb levels and significantly improve QOL in anemic (Hb <=11 g/dl) cancer patients who are not undergoing chemotherapy [48].

The effects of epoetin alfa in patients with hematologic malignancies, including MM, lymphoma, and CLL, have been the subjects of more recent investigations. For example, in a randomized, open-label study in patients with these malignancies and mild anemia (Hb >=10 g/dl and <=12 g/dl) undergoing chemotherapy, QW epoetin alfa therapy significantly increased Hb levels and significantly improved QOL [49]. In a pilot study, patients with MM or lymphoma treated with epoetin alfa before high-dose therapy and autologous peripheral stem cell transplantation required fewer transfusions after transplantation, and the median number of units of red blood cells transfused was significantly lower than that of historic controls [50].

Effects of Epoetin Alfa on QOL
Numerous studies have demonstrated that epoetin alfa improves QOL (such as energy level and ability to perform daily activities) in anemic patients with various tumor types. In the community-based studies and the randomized, placebo-controlled clinical trial discussed above, TIW [41–43] or QW [44, 46] epoetin alfa therapy significantly improved QOL. Moreover, in studies that assessed the impact of disease progression as a confounder of QOL, functional improvements with epoetin alfa therapy occurred independently of tumor response [41, 42]. Using data from the randomized, placebo-controlled trial [43], a multivariate analysis revealed a positive correlation between increased Hb levels and improvements in QOL in patients treated with epoetin alfa [51]. Even in patients with mild anemia (Hb >=10.5 g/dl), Hb levels increased significantly and were associated with both statistically and clinically significant improvements in functional status [37, 43]. In two additional studies that evaluated the effect of epoetin-alfa-associated increases in Hb on QOL in anemic cancer patients receiving chemotherapy with or without sequential radiation therapy [52, 53], the greatest incremental gain in QOL occurred when Hb rose from 11 g/dl to 12 g/dl (range, 11–13 g/dl). These data demonstrate that correction of anemia, including mild anemia, leads to significant improvements in functional ability and well-being.

Effects of Epoetin Alfa on Survival of Patients With Cancer
While a positive effect of epoetin alfa on QOL in patients with cancer is firmly established, its effects on tumor progression and survival are less clear. Lower mortality in patients receiving epoetin alfa was reported in a randomized, placebo-controlled study [43]. However, the protocol was not designed or powered to assess this parameter and did not control for factors that could influence survival, such as disease stage, bone marrow involvement, chemotherapy intensity, and disease progression. An association between low Hb level and survival has also been demonstrated. For example, a correlation between Hb level and survival was reported in patients with testicular cancer receiving first-line, sequential, high-dose chemotherapy [54]. Patients whose Hb levels were >=10.5 g/dl after completion of four cycles of chemotherapy had a 3-year overall survival rate of 87%, compared with 68% for patients whose Hb levels were <10.5 g/dl (p < 0.03) [54]. Together, these data suggest that further investigation of the effects of epoetin alfa on survival is warranted.

Early Intervention With Epoetin Alfa for Cancer-Treatment-Related Anemia
Two recent studies have evaluated the impact of early intervention with epoetin alfa therapy on patients with breast cancer and baseline Hb levels of >=9 g/dl and <=14 g/dl receiving or scheduled to receive adjuvant chemotherapy [55, 56]. In both studies, treatment with epoetin alfa, 40,000 U QW for at least 12 weeks, maintained or improved Hb levels and QOL, whereas decreases in Hb levels and deterioration of QOL were observed with historical controls (i.e., no epoetin alfa therapy) and in patients treated with placebo [55–57]. Similar results were found in an interim analysis of a phase III randomized study of early initiation of epoetin alfa, 40,000 U QW, in patients with various tumor types [58]. Patients who received epoetin alfa, 40,000 U QW at the start of chemotherapy, maintained higher Hb levels and reported less fatigue than patients who received epoetin alfa once their Hb levels decreased to <10 g/dl [58]. Together, these data suggest that epoetin alfa treatment initiated at the start of chemotherapy may maintain Hb levels and QOL in patients with cancer. Early intervention with epoetin alfa may be particularly effective during high-dose chemotherapy [59].

Alternate Epoetin Alfa Dosing Regimens
Epoetin alfa, 40,000 U QW, has been shown to be clinically equivalent to 150 U/kg TIW in healthy subjects [1]. In addition, alternate dosing regimens of epoetin alfa are currently under investigation to determine the optimal dose and schedule that will elicit an early and significant increase in Hb level while improving flexibility of administration. In an interim analysis of an open-label, nonrandomized study in 11 anemic (Hb <=11 g/dl) cancer patients receiving chemotherapy with or without concomitant or sequential radiation therapy, epoetin alfa, 60,000 U QW, increased Hb levels by 1.1 g/dl at week 4 and by 2.6 g/dl at week 8 [60]. Similar results were obtained in an open-label, nonrandomized, maintenance study of 20 anemic (Hb <=11 g/dl) cancer patients undergoing chemotherapy [61]. Epoetin alfa administered at a higher starting dose of 60,000 U QW increased Hb levels by 1.0 g/dl at week 4 and by 2.9 g/dl at week 8, with 86% of patients achieving increases in Hb of >=2 g/dl or reaching an Hb level of >=12 g/dl by week 8. In patients who achieved Hb increases of >=2 g/dl and then moved into maintenance therapy, epoetin alfa, 120,000 U every 3 weeks, successfully maintained the Hb levels achieved during initial therapy [61]. These data suggest that epoetin alfa, 60,000 U QW, followed by maintenance dosing of 120,000 U every 3 weeks is a feasible treatment strategy for cancer patients with mild anemia who are undergoing chemotherapy.

In summary, epoetin alfa treatment of anemic cancer patients receiving cytotoxic therapy leads to significant increases in Hb levels and reductions in transfusion utilization, effects associated with both statistically and clinically significant improvements in QOL. Additional data suggest a potential survival benefit associated with epoetin alfa therapy, although it is not known whether this effect could be due to the correction of anemia or whether epoetin alfa may have an intrinsic effect on survival. Administration of epoetin alfa by either the TIW or the more convenient QW regimen results in clinically equivalent effects on Hb, transfusions, and QOL. The availability of darbepoetin alfa, an altered glycosylated form of erythropoietin with an extended circulating half-life, provides additional opportunities to increase dosing intervals in cancer patients with chemotherapy-related anemia. The recommended starting dose is 2.25 mcg/kg SC QW [62], although less frequent dosing regimens may be possible [63, 64]. Additional alternate dosing regimens of epoetin alfa are presently being investigated to further determine their clinical utility.


   NONERYTHROID FUNCTIONS OF EPO
Top
 Learning Objectives
 Abstract
 Introduction
 Mechanism of Action of...
 Erythropoietic Effects of...
 Nonerythroid Functions of EPO
Potential Functions of EPO...
 Therapeutic Implications
 Conclusions
 References
 
The EPO-R is expressed in numerous embryonic and adult tissues in humans and mice. Based on these observations, EPO signaling has been suggested to have various nonerythroid functions. The EPO-R is present in nonerythroid blood lines including myeloid cells, lymphocytes, and megakaryocytes, as well as in multiple nonhematopoietic cells, such as endothelial cells; mesangial, myocardial, and smooth muscle fiber cells; neural cells; prostate cells, and renal cells (Table 1Go) [65–73]. Moreover, many of these cell types exhibit active EPO signaling pathways and biologic responses. For example, EPO stimulates survival and proliferation of endothelial cells in vitro and promotes new blood vessel formation in vivo [66, 67, 70]. In a murine model, EPO stimulated angiogenesis in wound healing [74]. In that model, macrophages in granulation tissue formed during wound healing expressed EPO-R, and EPO was shown to stimulate transforming growth factor (TGF)-ß1 production by activated macrophages [74]. In mice expressing a constitutively active EPO-R, EPO signaling in endothelial cells was found to function in vascular repair [75]. Some additional actions of EPO on nonerythroid tissues, in particular the nervous system, are discussed later.


View this table:
[in this window]
[in a new window]
  		Table 1. EPO-R expression and potential functions in normal nonerythroid cells
 

   POTENTIAL FUNCTIONS OF EPO IN THE CENTRAL NERVOUS SYSTEM
Top
 Learning Objectives
 Abstract
 Introduction
 Mechanism of Action of...
 Erythropoietic Effects of...
 Nonerythroid Functions of EPO
 Potential Functions of EPO...
Therapeutic Implications
 Conclusions
 References
 
Both EPO and the EPO-R are present in the central nervous system [65, 76–79], including the retina [80, 81]. Epoetin alfa has been shown to actively cross the blood-brain barrier in animals (although at significantly higher doses than are conventionally used in the treatment of anemia in humans) [82] and in human subjects at doses of 40,000 U or 1,500 U/kg administered intravenously [83]. In vitro, EPO protects neurons against ischemia-induced glutamate toxicity, the primary factor responsible for neuronal cell death related to hypoxia [65, 84].

In rodent models, the systemic administration of epoetin alfa attenuated the extent of concussive brain injury and the toxicity of kainate, which is representative of the excitotoxicity found in many forms of brain injury [82]. Systemic epoetin alfa also reduced immune damage [82] and inflammation [85] in an experimental model of multiple sclerosis and enhanced neurologic recovery from experimental spinal cord trauma [79, 86]. Systemic epoetin alfa also has been shown to reduce injury from brain ischemia both in an experimental animal model [87] and in patients at doses similar to those used in clinical practice [88]. In addition, epoetin alfa was shown to protect photoreceptors from light-induced damage [81] and retinal neurons from acute ischemia and reperfusion injury in rodents [86].

Mouse embryos with null mutations of EPO or the EPO-R die from severe anemia in midgestation [3, 4] and also exhibit increased apoptosis in the brain [90]. However, mice reported to express EPO-R exclusively in hematopoietic tissues develop normally and exhibit no apparent neurologic deficits [91]. While extended neurologic testing was not reported for these animals, the data indicate that EPO-R may not be required for the development or basal function of the nervous system. Considering the pleiotropic effects of EPO on neuronal tissues discussed previously, it is possible that EPO-R signaling plays an adaptive role in limiting the damage incurred from various neurologic stresses. If this is the case, then mice expressing the EPO-R solely in hematopoietic tissues should be more sensitive to experimentally induced neurotoxicity.

Mechanisms of EPO Action in the Central Nervous System
The underlying mechanisms of EPO as a neuroprotective agent are hypothesized to be multifactorial, with both direct and indirect beneficial effects on neurons. EPO may antagonize the cytotoxic effect of glutamate, increase expression of antioxidant enzymes, reduce nitric-oxide-mediated formation of free radicals, normalize cerebral blood flow, influence neurotransmitter release, and promote neoangiogenesis [65]. Hypoxia and injury increase production of EPO and EPO-R in the brain [78, 92, 93]. Hypoxia also induced EPO expression in the retina through the production of HIF-1 [81]. Epoetin alfa may mediate neuroprotection indirectly by restoring blood flow to the injured tissue [94] or act directly on neurons via the activation of several signaling molecules, which also function in EPO signaling in erythropoiesis. EPO downregulates tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase and activates the extracellular signal-regulated kinases ERK1 and ERK2 in cortical neurons, which may enhance the magnitude and duration of signaling [95]. In rat hippocampal neurons, epoetin alfa was shown to protect against hypoxia-induced death through activation of ERK1 and ERK2 and Akt [96]. In rat cortical neurons, EPO-mediated protection from excitotoxin- and nitric-oxide-induced apoptosis involved a novel pathway with crosstalk between the JAK2 and nuclear factor (NF)-{kappa}B signaling cascades; EPO-R-induced activation of JAK2 led to activation of NF-{kappa}B and subsequent increased expression of the inhibitor-of-apoptosis genes, XIAP and c-IAP2 [97]. In the hippocampus of gerbils, EPO was shown to protect neurons against ischemic injury by upregulating the antiapoptotic gene Bcl-x [98]. In addition to inhibition of apoptosis, neuroprotection may also occur through reduction of inflammation [86, 87, 96], which plays a key role in many forms of brain injury. NF-{kappa}B, which is activated by EPO under oxidative or nitrosative stress [97], is a regulator of inflammatory genes [99]. Epoetin alfa has further been shown to have a neurotrophic effect [96] and to affect neuronal excitability [82], a prominent component of many forms of brain injury [100].


   THERAPEUTIC IMPLICATIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Mechanism of Action of...
 Erythropoietic Effects of...
 Nonerythroid Functions of EPO
 Potential Functions of EPO...
 Therapeutic Implications
Conclusions
 References
 
The observed neuroprotective and vascular effects of EPO and epoetin alfa in various experimental models suggest that epoetin alfa may benefit patients with spinal cord injuries, stroke, myocardial infarction, multiple sclerosis, or retinal diseases (macular degeneration, retinitis pigmentosa, and glaucoma [101]). In one recent study of stroke patients, a 33,333-U i.v. dose of epoetin alfa, administered within 8 hours after the onset of symptoms and at 24 hours and also 48 hours later, appeared to limit the extent of histologic damage and improve functional outcomes [88]. Additional clinical trials are required to confirm these findings.

Implications for Cancer Therapy
The discovery that nonerythroid tissues respond to EPO challenges the relatively simple model that its effects in patients with cancer derive exclusively from enhanced red blood cell production. These potential effects of EPO have both positive and negative theoretical implications. For example, epoetin alfa could activate intracellular signaling pathways directly in tumors that express EPO-R. In addition, the ability of EPO to stimulate new blood vessel formation could enhance perfusion to tumors and support their growth or, alternatively, potentiate antitumor therapies by enhancing blood delivery, as previously discussed. The demonstrated neuroprotective effects of EPO could prevent or reduce the neurotoxicities associated with chemotherapy and radiation therapy. These issues are discussed in detail below.

Potential Direct Effects of Epoetin Alfa on EPO-R-Expressing Tumors
Because some cancer cells express EPO-R, treatment with epoetin alfa could produce a variety of direct effects on tumors. For example, it has been suggested that, in certain tumor cell lines and xenografts that express both EPO and EPO-R, EPO signaling may promote cancer progression [73, 102–104]. In cell lines of colon carcinoma, the Ewing’s sarcoma family of tumors, and neuroblastoma, EPO reduced chemotherapy-induced apoptosis through upregulation of antiapoptotic genes [105]. EPO also induced the release of angiogenic growth factors in cell lines of colon carcinoma, the Ewing’s sarcoma family of tumors, glioma, and medulloblastoma [105]. In xenografts and blocks of uterine and ovarian tumors, EPO antagonists induced apoptosis and decreased the number of blood vessels [106, 107]. Phosphorylation of JAK2 and STAT5 appeared to be abolished in tumor blocks treated with EPO antagonists [107].

Despite these studies, only a few rare case reports have been published that describe a possible effect of epoetin alfa on cancer progression in humans, and no causal relationship has been identified. One patient with MM reportedly developed plasma cell leukemia upon receiving treatment with epoetin alfa [108]. In another cancer patient treated with epoetin alfa, rapid growth of a vestibular schwannoma was reported, but the exact cause was not determined [109].

Antitumorigenic effects of EPO and epoetin alfa have also been reported. Epoetin alfa alone had no effect on growth of a lung carcinoma xenograft; however, in synergy with cisplatin, it induced a fivefold reduction in tumor mass [110]. In addition, epoetin alfa treatment, either in the absence of chemotherapy or concomitant with mild chemotherapy for a short duration, produced an antimyeloma effect and prolonged survival in a small study of patients with MM (n = 5) who had advanced disease and an expected survival of less than 6 months [111]. Despite a poor prognosis, patients survived an additional 42–82 months after initiation of epoetin alfa therapy [111]. These findings are consistent with data from a murine model of MM, where tumor regression believed to be mediated via activated CD8+ T cells occurred in 50% of mice inoculated with MM cells [112]. In addition, severe combined immunodeficient (SCID) mice bearing small subcutaneous ovarian cancer xenografts exhibited significantly greater tumor regression (p < 0.05) when treated with epoetin alfa and cisplatin compared with those treated with cisplatin alone [113]. Correction of chemotherapy-induced anemia with epoetin alfa has also been shown to completely restore the antitumor efficacy of photodynamic therapy [114] and increase tumor sensitivity to cyclophosphamide in rodent models [115].

Overall, data from more than 10 years of epoetin alfa use in millions of patients indicate that the drug is safe and beneficial for use in cancer [116], with no evidence of associated tumor progression reported in clinical trials. In a randomized, placebo-controlled trial, no differences in adverse events were found between anemic cancer patients receiving epoetin alfa and those receiving placebo TIW for up to 28 weeks [43]. The proportions of deaths in that study were comparable in the epoetin alfa group (14%, 34/251) and the placebo group (18%, 22/124) [43]. Although some patients who died had experienced disease progression, none of the deaths were considered related to the study medication [43], with the possible exception of a stroke that occurred in an elderly patient treated with epoetin alfa who had a history of dyspnea and paresthesia [43]. Hence, while EPO-R has been shown to exist in some tumors and their associated vasculature, the overall broad experience has been that epoetin alfa does not produce major effects, either positive or negative, on tumor growth or progression in most patients.

Potential Neuroprotective Effects of Epoetin Alfa in Patients With Cancer
Neuroprotective effects of EPO could benefit cancer patients, whose neurocognitive function may be affected directly by cancer within the central nervous system or indirectly by paraneoplastic effects, toxicities of certain cancer treatments, or coexisting neurologic or psychiatric disorders [117]. Recently published studies suggest that cognitive dysfunction is experienced by about 10% of breast cancer survivors who did not receive chemotherapy and by approximately 15%-25% of patients with breast cancer treated with chemotherapy [118–124]. Data from a pilot trial in patients with breast cancer receiving adjuvant chemotherapy indicate that those receiving QW epoetin alfa experienced less cognitive decline than patients receiving placebo [56]. At a 6-month follow-up, both the epoetin alfa group and the placebo group exhibited a restoration of cognitive function [56]. Although the difference between groups was not statistically significant, improvements were generally greater in the epoetin alfa group [56]. The cognitive improvement demonstrated by placebo-treated patients may suggest that a learning response occurred with the repeated cognitive assessments. Hence, additional studies are required to determine the efficacy of epoetin alfa as a neuroprotective agent for use in cancer treatment. In particular, it is possible that pretreatment with epoetin alfa could limit some of the neurotoxic effects of radiation therapy or select chemotherapeutic agents.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Mechanism of Action of...
 Erythropoietic Effects of...
 Nonerythroid Functions of EPO
 Potential Functions of EPO...
 Therapeutic Implications
 Conclusions
References
 
The ability of epoetin alfa to stimulate red blood cell production has benefited patients with a variety of anemias, including those of renal and cancer origin. Just how EPO stimulates erythropoiesis is not fully understood, although one important mechanism is by enhancing erythroid precursor survival by inducing the antiapoptotic molecule Bcl-x. More recently, studies have illustrated various biologic effects of EPO on nonerythroid tissues, including vascular endothelial cells, the nervous system, and selected tumors. These observations have clinical implications for patients with cancer as well as neurologic and ischemic disorders. It is likely that further research into EPO-R signaling will enhance insight into its actions outside the hematopoietic system and provide further opportunities to extend the therapeutic role of epoetin alfa within and beyond the oncology practice.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Mechanism of Action of...
 Erythropoietic Effects of...
 Nonerythroid Functions of EPO
 Potential Functions of EPO...
 Therapeutic Implications
 Conclusions
 References
 
The author thanks Rosemary Mazanet for reviewing the manuscript.

Dr. Weiss is the recipient of a Focused Giving Award from Johnson & Johnson and is a consultant for Pfizer.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Mechanism of Action of...
 Erythropoietic Effects of...
 Nonerythroid Functions of EPO
 Potential Functions of EPO...
 Therapeutic Implications
 Conclusions
 References
 

  1. Cheung JY, Miller BA. Molecular mechanisms of erythropoietin signaling. Nephron 2001;87:215–222.
  2. Graber SE, Krantz SB. Erythropoietin: biology and clinical use. Hematol Oncol Clin North Am 1989;3:369–400.[Medline]
  3. Wu H, Liu X, Jaenisch R et al. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 1995;83:59–67.[CrossRef][Medline]
  4. Lin CS, Lim SK, D’Agati V et al. Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev 1996;10:154–164.[Abstract/Free Full Text]
  5. Faris PM, Ritter MA, Abels RI. The effects of recombinant human erythropoietin on perioperative transfusion requirements in patients having a major orthopaedic operation. The American Erythropoietin Study Group. J Bone Joint Surg Am 1996;78:62–72.[Abstract/Free Full Text]
  6. National Kidney Foundation. K/DOQI clinical practice guidelines for anemia of chronic kidney disease, 2002. Am J Kidney Dis 2002;39(suppl 1):S1–S266.[CrossRef][Medline]
  7. Rizzo JD, Seidenfeld J, Piper M et al. Erythropoietin: a paradigm for the development of practice guidelines. Hematology (Am Soc Hematol Educ Program) 2001;10–30.
  8. Saag MS, Levine AM, Leitz GJ et al. Once-weekly epoetin alfa increases hemoglobin and improves quality of life in anemic HIV+ patients [abstract]. In: Program and Abstracts of the 39th Annual Meeting of the Infectious Diseases Society of America. San Francisco, California 2002:160.
  9. Sulkowski M, Wasserman R, Brau N et al. Once-weekly recombinant human erythropoietin (epoetin alfa) facilitates optimal ribavirin (RBV) dosing in hepatitis C virus-infected patients receiving interferon-{alpha}-2b(IFN)/RBV therapy [poster]. Presented at the Hepatitis Single Topic Conference (AASLD). Chicago, Illinois, June 15, 2001.
  10. Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 1993;90:4304–4308.[Abstract/Free Full Text]
  11. Broudy VC, Lin N, Brice M et al. Erythropoietin receptor characteristics on primary human erythroid cells. Blood 1991;77:2583–2590.[Abstract/Free Full Text]
  12. Remy I, Wilson IA, Michnick SW. Erythropoietin receptor activation by a ligand-induced conformation change. Science 1999;283:990–993.[Abstract/Free Full Text]
  13. Livnah O, Stura EA, Middleton SA et al. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science 1999;283:987–990.[Abstract/Free Full Text]
  14. Silva M, Benito A, Sanz C et al. Erythropoietin can induce the expression of bcl-xL through Stat5 in erythropoietin-dependent progenitor cell lines. J Biol Chem 1999;274:22165–22169.[Abstract/Free Full Text]
  15. Parganas E, Wang D, Stravopodis D et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998;93:385–395.[CrossRef][Medline]
  16. Socolovsky M, Nam H, Fleming MD et al. Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood 2001;98:3261–3273.[Abstract/Free Full Text]
  17. Motoyama N, Wang F, Roth KA et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 1995;267:1506–1510.[Abstract/Free Full Text]
  18. Wagner KU, Claudio E, Rucker EB 3rd et al. Conditional deletion of the Bcl-x gene from erythroid cells results in hemolytic anemia and profound splenomegaly. Development 2000;127:4949–4958.[Abstract]
  19. Motoyama N, Kimura T, Takahashi T et al. bcl-x prevents apoptotic cell death of both primitive and definitive erythrocytes at the end of maturation. J Exp Med 1999;189:1691–1698.[Abstract/Free Full Text]
  20. Dolznig H, Habermann B, Stangl K et al. Apoptosis protection by the Epo target Bcl-XL allows factor-independent differentiation of primary erythroblasts. Curr Biol 2002;12:1076–1085.[CrossRef][Medline]
  21. He TC, Jiang N, Zhuang H et al. Erythropoietin-induced recruitment of Shc via a receptor phosphotyrosine-independent, Jak2-associated pathway. J Biol Chem 1995;270:11055–11061.[Abstract/Free Full Text]
  22. Koury MJ, Sawyer ST, Brandt SJ. New insights into erythropoiesis. Curr Opin Hematol 2002;9:93–100.[CrossRef][Medline]
  23. Damen JE, Cutler RL, Jiao H et al. Phosphorylation of tyrosine 503 in the erythropoietin receptor (EpR) is essential for binding the P85 subunit of phosphatidylinositol (PI) 3-kinase and for EpR-associated PI 3-kinase activity. J Biol Chem 1995;270:23402–23408.[Abstract/Free Full Text]
  24. Ren HY, Komatsu N, Shimizu R et al. Erythropoietin induces tyrosine phosphorylation and activation of phospholipase C-gamma 1 in a human erythropoietin-dependent cell line. J Biol Chem 1994;269:19633–19638.[Abstract/Free Full Text]
  25. Huddleston H, Tan B, Yang FC et al. Functional p85{alpha} gene is required for normal murine fetal erythropoiesis. Blood 2003;102:142–145.[Abstract/Free Full Text]
  26. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999;91:1616–1634.[Abstract/Free Full Text]
  27. Caro JJ, Salas M, Ward A et al. Anemia as an independent prognostic factor for survival in patients with cancer: a systematic, quantitative review. Cancer 2001;91:2214–2221.[CrossRef][Medline]
  28. MacRae R, Shyr Y, Johnson D et al. Declining hemoglobin during chemoradiotherapy for locally advanced non-small cell lung cancer is significant. Radiother Oncol 2002;64:37–40.[CrossRef][Medline]
  29. Teicher BA. Physiologic mechanisms of therapeutic resistance. Blood flow and hypoxia. Hematol Oncol Clin North Am 1995;9:475–506.[Medline]
  30. Harrison LB, Chadha M, Hill RJ et al. Impact of tumor hypoxia and anemia on radiation therapy outcomes. The Oncologist 2002;7:492–508.[Abstract/Free Full Text]
  31. Fyles AW, Milosevic M, Wong R et al. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol 1998;48:149–156.[CrossRef][Medline]
  32. Girinski T, Pejovic-Lenfant MH, Bourhis J et al. Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of the cervix treated by radiation therapy: results of a retrospective study of 386 patients. Int J Radiat Oncol Biol Phys 1989;16:37–42.[Medline]
  33. Grogan M, Thomas GM, Melamed I et al. The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 1999;86:1528–1536.[CrossRef][Medline]
  34. Takigawa N, Segawa Y, Okahara M et al. Prognostic factors for patients with advanced non-small cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation. Lung Cancer 1996;15:67–77.[CrossRef][Medline]
  35. Fein DA, Lee WR, Hanlon AL et al. Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol 1995;13:2077–2083.[Abstract/Free Full Text]
  36. Glaser CM, Millesi W, Kornek GV et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001;50:705–715.[CrossRef][Medline]
  37. Cella D, Zagari MJ, Vandoros C et al. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol 2003;21:366–373.[Abstract/Free Full Text]
  38. Rizzo JD, Lichtin AE, Woolf SH et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. Blood 2002;100:2303–2320.[Abstract/Free Full Text]
  39. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. v.1.2003. Cancer and Treatment-Related Anemia. Rockledge, PA: National Comprehensive Cancer Network, Inc., January 2003.
  40. Henry DH. Supplemental iron: a key to optimizing the response of cancer-related anemia to rHuEPO? The Oncologist 1998;3:275–278.[Abstract/Free Full Text]
  41. Demetri GD, Kris M, Wade J et al. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 1998;16:3412–3425.[Abstract]
  42. Glaspy J, Bukowski R, Steinberg D et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 1997;15:1218–1234.[Abstract/Free Full Text]
  43. Littlewood TJ, Bajetta E, Nortier JW et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001;19:2865–2874.[Abstract/Free Full Text]
  44. Gabrilove JL, Cleeland CS, Livingston RB et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001;19:2875–2882.[Abstract/Free Full Text]
  45. Sloan JA, Witzig T, Silberstein P et al. Quality of life, blood transfusions, and toxicity, in anemic patients with advanced cancer receiving weekly erythropoietin while on chemotherapy: results from a phase III randomized double-blind placebo-controlled study [abstract]. Proc Am Soc Hematol 2002;100:287a.
  46. Shasha D, George MJ, Harrison LB. Once-weekly dosing of epoetin-{alpha} increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy. Cancer 2003;98:1072–1079.[CrossRef][Medline]
  47. Shasha D, George M. Rapid hemoglobin response in anemic cancer patients undergoing chemotherapy or chemoradiation therapy receiving once-weekly epoetin alfa treatment [abstract]. Blood 2002;100:17b.
  48. Quirt I, Robeson C, Lau CY et al. Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy. J Clin Oncol 2001;19:4126–4134.[Abstract/Free Full Text]
  49. Straus DJ, Turner RR, Testa MA et al. Epoetin alfa treatment improves quality of life and increases hemoglobin levels during chemotherapy for lymphoma, chronic lymphocytic leukemia (CLL), and multiple myeloma (MM) patients with mild-to-moderate anemia [abstract]. Blood 2002;100:220a–221a.
  50. Hunault-Berger M, Lévy V, Dib M et al. Recombinant human erythropoietin (rHuEpo) before high dose therapy (HDT) allows autologous peripheral stem cell transplantation (APSCT) without red blood cell (RBC) transfusion. A pilot study [abstract]. Proc Am Soc Hematol 2002;100:841a.
  51. Fallowfield L, Gagnon D, Zagari M et al. Multivariate regression analyses of data from a randomised, double-blind, placebo-controlled study confirm quality of life benefit of epoetin alfa in patients receiving non-platinum chemotherapy. Epoetin Alfa Study Group. Br J Cancer 2002;87:1341–1353.[CrossRef][Medline]
  52. Crawford J, Cella D, Cleeland CS et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 2002;95:888–895.[CrossRef][Medline]
  53. Shasha D, George MJ, Harrison LB. Significant relationship between hemoglobin (Hb) levels and quality of life (QOL) during chemoradiation: findings from an incremental analysis of a 442-patient prospective, community-based epoetin alfa study [abstract]. Int J Radiat Oncol Biol Phys 2002;54(suppl 1):48.[CrossRef]
  54. Bokemeyer C, Oechsle K, Hartmann JT et al. Treatment-induced anaemia and its potential clinical impact in patients receiving sequential high dose chemotherapy for metastatic testicular cancer. Br J Cancer 2002;87:1066–1071.[CrossRef][Medline]
  55. Hudis C, Williams D, Gralow JR et al. Epoetin alfa maintains hemoglobin and quality of life in breast cancer patients receiving conventional adjuvant chemotherapy: final report [abstract]. PROCRIT Study Group. Proc Am Soc Clin Oncol 2003;22:767.
  56. O’Shaughnessy J, Vukelja S, Savin M et al. Impact of epoetin alfa on cognitive function, asthenia, and quality of life in women with breast cancer receiving adjuvant or neoadjuvant chemotherapy. Analysis of 6-month follow-up data [abstract]. Breast Cancer Res Treat 2002;76(suppl 1):S138.
  57. Lawless GD, Ford JM. Cumulative prevalence of anemia in early-stage breast cancer (ESBC) patients [abstract]. Blood 2000;96:390b.
  58. Richart JM, Petruska PJ, Klebert KS et al. A phase III trial of epoetin-alfa: early vs late administration in patients treated with chemotherapy [abstract]. Blood 2002;100:175b.
  59. Henry DH. Epoetin alfa and high-dose chemotherapy. Semin Oncol 1998;25(suppl 7):54–57.
  60. Chap L, George M, Glaspy JA. Evaluation of epoetin alfa (Procrit®) 60,000 U once weekly in anemic cancer patients receiving chemotherapy [abstract]. Proc Am Soc Clin Oncol 2002;21:264b.
  61. Patton J, Kuzur M, Liggett W et al. Epoetin alfa 60,000 U once-weekly followed by 120,000 U every three weeks to maintain hemoglobin levels in anemic cancer patients receiving chemotherapy: final report [abstract]. Proc Am Soc Clin Oncol 2003;22:754. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology. Chicago, Illinois, May 31–June 3, 2003.
  62. Aranesp® (darbepoetin alfa) Prescribing Information. Amgen Inc. Thousand Oaks, CA. December 17, 2002.
  63. Glaspy JA, Jadeja JS, Justice G et al. A randomized, active-control, pilot trial of front-loaded dosing regimens of darbepoetin-alfa for the treatment of patients with anemia during chemotherapy for malignant disease. Cancer 2003;97:1312–1320.[CrossRef][Medline]
  64. Kotasek D, Steger G, Faught W et al. Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind, placebo-controlled, randomized study. Eur J Cancer 2003;39:2026–2034.
  65. Buemi M, Cavallaro E, Floccari F et al. The pleiotropic effects of erythropoietin in the central nervous system. J Neuropathol Exp Neurol 2003;62:228–236.[Medline]
  66. Jaquet K, Krause K, Tawakol-Khodai M et al. Erythropoietin and VEGF exhibit equal angiogenic potential. Microvasc Res 2002;64:326–333.[CrossRef][Medline]
  67. Ribatti D, Presta M, Vacca A et al. Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 1999;93:2627–2636.[Abstract/Free Full Text]
  68. Anagnostou A, Liu Z, Steiner M et al. Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci USA 1994;91:3974–3978.[Abstract/Free Full Text]
  69. Anagnostou A, Lee ES, Kessimian N et al. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci USA 1990;87:5978–5982.[Abstract/Free Full Text]
  70. Yasuda Y, Masuda S, Chikuma M et al. Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J Biol Chem 1998;273:25381–25387.[Abstract/Free Full Text]
  71. Fraser JK, Tan AS, Lin FK et al. Expression of specific high-affinity binding sites for erythropoietin on rat and mouse megakaryocytes. Exp Hematol 1989;17:10–16.[Medline]
  72. Westenfelder C, Biddle DL, Baranowski RL. Human, rat, and mouse kidney cells express functional erythropoietin receptors. Kidney Int 1999;55:808–820.[CrossRef][Medline]
  73. Feldman L, Wang Y, Rhim JS et al. Human prostate epithelial and prostate cancer cells express both erythropoietin and functional erythropoietin receptors [abstract]. Proc Am Soc Hematol 2002;100:171b.
  74. Arcasoy MO, Amin K, Haroon ZA. Erythropoietin (EPO) receptor expression in macrophages is associated with EPO-mediated stimulation of wound healing response, angiogenesis and transforming growth factor ß-1 production [abstract]. Proc Am Soc Hematol 2002;100:681a.
  75. Wang H, Pastore Y, Pool L et al. Gain-of-function mutation of human erythropoietin receptor in mice decreases neointimal formation [abstract]. Blood 2002;100:680a–681a.
  76. Marti HH, Wenger RH, Rivas LA et al. Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci 1996;8:666–676.[CrossRef][Medline]
  77. Juul SE, Anderson DK, Li Y et al. Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatr Res 1998;43:40–49.[Medline]
  78. Sirén AL, Knerlich F, Poser W et al. Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol (Berl) 2001;101:271–276.[Medline]
  79. Celik M, Gokmen N, Erbayraktar S et al. Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci USA 2002;99:2258–2263.[Abstract/Free Full Text]
  80. Bocker-Meffert S, Rosenstiel P, Rohl C et al. Erythropoietin and VEGF promote neural outgrowth from retinal explants in postnatal rats. Invest Ophthalmol Vis Sci 2002;43:2021–2026.[Abstract/Free Full Text]
  81. Grimm C, Wenzel A, Groszer M et al. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 2002;8:718–724.[CrossRef][Medline]
  82. Brines M. What evidence supports use of erythropoietin as a novel neurotherapeutic? Oncology (Huntingt) 2002;16(suppl 10):79–89.
  83. Xenocostas A, Cheung WK, Farrell FX et al. Recombinant human erythropoietin crosses the blood brain barrier: the pharmacokinetics of rhEPO in the cerebrospinal fluid after intravenous administration [abstract]. Proc Am Soc Clin Oncol 2003;22:230.
  84. Morishita E, Masuda S, Nagao M et al. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 1997;76:105–116.[Medline]
  85. Agnello D, Bigini P, Villa P et al. Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis. Brain Res 2002;952:128–134.[CrossRef][Medline]
  86. Gorio A, Gokmen N, Erbayraktar S et al. Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci USA 2002;99:9450–9455.[Abstract/Free Full Text]
  87. Brines ML, Ghezzi P, Keenan S et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000;97:10526–10531.[Abstract/Free Full Text]
  88. Ehrenreich H, Hasselblatt M, Dembowski C et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 2002;8:495–505.[Medline]
  89. Junk AK, Mammis A, Savitz SI et al. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci USA 2002;99:10659–10664.[Abstract/Free Full Text]
  90. Yu X, Shacka JJ, Eells JB et al. Erythropoietin receptor signalling is required for normal brain development. Development 2002;129:505–516.
  91. Suzuki N, Ohneda O, Takahashi S et al. Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality. Blood 2002;100:2279–2288.[Abstract/Free Full Text]
  92. Sadamoto Y, Igase K, Sakanaka M et al. Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun 1998;253:26–32.[CrossRef][Medline]
  93. Bernaudin M, Marti HH, Roussel S et al. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 1999;19:643–651.[Medline]
  94. Springborg JB, Ma X, Rochat P et al. A single subcutaneous bolus of erythropoietin normalizes cerebral blood flow autoregulation after subarachnoid haemorrhage in rats. Br J Pharmacol 2002;135:823–829.[CrossRef][Medline]
  95. Renzi MJ, Thirumalai N, Jolliffe LK et al. Erythropoietin down regulates SHP1 and induces a sustained activation of ERK1/ERK2 in primary cortical neurons [abstract]. Proc Am Soc Hematol 2001;100:77a.
  96. Sirén AL, Fratelli M, Brines M et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 2001;98:4044–4049.[Abstract/Free Full Text]
  97. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-{kappa}B signalling cascades. Nature 2001;412:641–647.[CrossRef][Medline]
  98. Wen TC, Sadamoto Y, Tanaka J et al. Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-xL expression. J Neurosci Res 2002;67:795–803.[CrossRef][Medline]
  99. Yamamoto Y, Gaynor RB. Role of the NF-kB pathway in the pathogenesis of human disease states. Curr Mol Med 2001;1:287–296.[CrossRef][Medline]
  100. Martin LJ, Al-Abdulla NA, Brambrink AM et al. Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of apoptosis and necrosis. Brain Res Bull 1998;46:281–309.[CrossRef][Medline]
  101. Becerra SP, Amaral J. Erythropoietin: an endogenous retinal survival factor. N Engl J Med 2002;347:1968–1970.[Free Full Text]
  102. Acs G, Acs P, Beckwith SM et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 2001;61:3561–3565.[Abstract/Free Full Text]
  103. Arcasoy MO, Amin K, Karayal AF et al. Functional significance of erythropoietin receptor expression in breast cancer. Lab Invest 2002;82:911–918.[Medline]
  104. Westenfelder C, Baranowski RL. Erythropoietin stimulates proliferation of human renal carcinoma cells. Kidney Int 2000;58:647–657.[CrossRef][Medline]
  105. Batra S, Perelman N, Luck LR et al. Pediatric tumor cells express erythropoietin and a functional erythropoietin receptor that promote angiogenesis and tumor cell survival [abstract]. Proc Am Soc Hematol 2002;100:736a.
  106. Yasuda Y, Musha T, Tanaka H et al. Inhibition of erythropoietin signalling destroys xenografts of ovarian and uterine cancers in nude mice. Br J Cancer 2001;84:836–843.[CrossRef][Medline]
  107. Yasuda Y, Fujita Y, Masuda S et al. Erythropoietin is involved in growth and angiogenesis in malignant tumours of female reproductive organs. Carcinogenesis 2002;23:1797–1805.[Abstract/Free Full Text]
  108. Olujohungbe A, Handa S, Holmes J. Does erythropoietin accelerate malignant transformation in multiple myeloma? Postgrad Med J 1997;73:163–164.[Abstract/Free Full Text]
  109. Falcioni M, Taibah A, De Donato G et al. Fast-growing vestibular schwannoma. Skull Base Surg 2000;2:95–100.
  110. Sigounas G, Collins M, Sallah S et al. Erythropoietin enhances antineoplastic activity of chemotherapeutic agents [abstract]. Proc Am Soc Hematol 2002;100:210b.
  111. Mittelman M, Zeidman A, Fradin Z et al. Erythropoietin has an anti-myeloma effect: a clinical observation supported by animal studies [abstract]. Proc Am Soc Hematol 2002;100:391b.
  112. Mittelman M, Neumann D, Peled A et al. Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models. Proc Natl Acad Sci USA 2001;98:5181–5186.[Abstract/Free Full Text]
  113. Silver DF, Piver MS. Effects of recombinant human erythropoietin on the antitumor effect of cisplatin in SCID mice bearing human ovarian cancer: a possible oxygen effect. Gynecol Oncol 1999;73:280–284.[CrossRef][Medline]
  114. Golab J, Olszewska D, Mróz P et al. Erythropoietin restores the antitumor effectiveness of photodynamic therapy in mice with chemotherapy-induced anemia. Clin Cancer Res 2002;8:1265–1270.[Abstract/Free Full Text]
  115. Thews O, Kelleher DK, Vaupel P. Erythropoietin restores the anemia-induced reduction in cyclophosphamide cytotoxicity in rat tumors. Cancer Res 2001;61:1358–1361.[Abstract/Free Full Text]
  116. Itri LM. The use of epoetin alfa in chemotherapy patients: a consistent profile of efficacy and safety. Semin Oncol 2002;29(suppl 8):81–87.
  117. Meyers CA. Neurocognitive dysfunction in cancer patients. Oncology (Huntingt) 2000;14:75–79; discussion 79, 81–82, 85.
  118. Ahles TA, Saykin AJ, Furstenberg CT et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol 2002;20:485–493.[Abstract/Free Full Text]
  119. Brezden CB, Phillips KA, Abdolell M et al. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2000;18:2695–2701.[Abstract/Free Full Text]
  120. O’Shaughnessy JA. Effects of epoetin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy. Clin Breast Cancer 2002;3(suppl 3):S116–S120.
  121. Schagen SB, van Dam FS, Muller MJ et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999;85:640–650.[CrossRef][Medline]
  122. Schagen SB, Muller MJ, Boogerd W et al. Cognitive dysfunction and chemotherapy: neuropsychological findings in perspective. Clin Breast Cancer 2002;3(suppl 3):S100–S108.
  123. van Dam FS, Schagen SB, Muller MJ et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 1998;90:210–218.[Abstract/Free Full Text]
  124. Wieneke MH, Dienst ER. Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psychooncology 1995;4:61–66.
Received August 29, 2003; accepted for publication October 3, 2003.




This article has been cited by other articles:


Home page
 Cancer Res.Home page
W. D Stein, T. Litman, T. Fojo, and S. E Bates
A Serial Analysis of Gene Expression (SAGE) Database Analysis of Chemosensitivity: Comparing Solid Tumors with Cell Lines and Comparing Solid Tumors from Different Tissue Origins
Cancer Res., April 15, 2004; 64(8): 2805 - 2816.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. P. Singh, N. Moniaux, S. C. Chauhan, J. L. Meza, and S. K. Batra
Inhibition of MUC4 Expression Suppresses Pancreatic Tumor Cell Growth and Metastasis
Cancer Res., January 15, 2004; 64(2): 622 - 630.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Weiss, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Weiss, M. J.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS