Skip to main content
SpringerLink
Log in
Book cover

Hematopoietic Growth Factors in Oncology pp 55–74Cite as

Erythropoiesis-Stimulating Agents

  • Chapter
  • First Online:

Part of the book series: Cancer Treatment and Research ((CTAR,volume 157))

Abstract

Erythropoiesis is the process whereby erythroid progenitor cells differentiate and divide, resulting in increased numbers of red blood cells (RBCs). RBCs contain hemoglobin, the main oxygen carrying component in blood. The large number of RBCs found in blood is required to support the prodigious consumption of oxygen by tissues as they undergo oxygen-dependent processes. Erythropoietin is a hormone that when it binds and activates Epo receptors resident on the surface of cells results in stimulation of erythropoiesis. Successful cloning of the EPO gene allowed for the first time production of recombinant human erythropoietin and other erythropoiesis stimulating agents (ESAs), which are used to treat anemia in patients. In this chapter, the control of Epo levels and erythropoiesis, the various forms of ESAs used commercially, and their physical and biological properties are discussed.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Lin FK, Suggs S, Lin CH, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA. 1985;82:7580–4.

    Article  PubMed  CAS  Google Scholar 

  2. Jacobs K, Shoemaker C, Rudersdorf R, et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature. 1985;313:806–10.

    Article  PubMed  CAS  Google Scholar 

  3. Smith JA. Exercise, training and red blood cell turnover. Sports Med. 1995;19:9–31.

    Article  PubMed  CAS  Google Scholar 

  4. Elliott S, Pham E, Macdougall IC. Erythropoietins: a common mechanism of action. Exp Hematol. 2008;36:1573–84.

    Article  PubMed  CAS  Google Scholar 

  5. Hebbel RP, Eaton JW. Pathobiology of heme interaction with the erythrocyte membrane. Semin Hematol. 1989;26:136–49.

    PubMed  CAS  Google Scholar 

  6. Ganz T. Iron homeostasis: fitting the puzzle pieces together. Cell Metab. 2008;7:288–90.

    Article  PubMed  CAS  Google Scholar 

  7. Elliott S. Erythropoiesis-stimulating agents and other methods to enhance oxygen transport. Br J Pharmacol. 2008;154:529–41.

    Article  PubMed  CAS  Google Scholar 

  8. Koury ST, Bondurant MC, Koury MJ. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood. 1988;71:524–7.

    PubMed  CAS  Google Scholar 

  9. Koury ST, Bondurant MC, Koury MJ, Semenza GL. Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood. 1991;77:2497–503.

    PubMed  CAS  Google Scholar 

  10. Koury ST, Koury MJ, Bondurant MC, Caro J, Graber SE. Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration. Blood. 1989;74:645–51.

    PubMed  CAS  Google Scholar 

  11. Lacombe C, Da Silva JL, Bruneval P, et al. Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. J Clin Invest. 1988;81:620–3.

    Article  PubMed  CAS  Google Scholar 

  12. Maxwell PH, Osmond MK, Pugh CW, et al. Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int. 1993;44:1149–62.

    Article  PubMed  CAS  Google Scholar 

  13. Lai PH, Everett R, Wang FF, Arakawa T, Goldwasser E. Structural characterization of human erythropoietin. J Biol Chem. 1986;261:3116–21.

    PubMed  CAS  Google Scholar 

  14. Browne JK, Cohen AM, Egrie JC, et al. Erythropoietin: gene cloning, protein structure, and biological properties. Cold Spring Harb Symp Quant Biol. 1986;51:693–702.

    PubMed  CAS  Google Scholar 

  15. Syed RS, Reid SW, Li C, et al. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature. 1998;395:511–16.

    Article  PubMed  CAS  Google Scholar 

  16. Cheetham JC, Smith DM, Aoki KH, et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation. Nat Struct Biol. 1998;5:861–6.

    Article  PubMed  CAS  Google Scholar 

  17. Mitjavila MT, Natazawa M, Brignaschi P, et al. Effects of five recombinant hematopoietic growth factors on enriched human erythroid progenitors in serum-replaced cultures. J Cell Physiol. 1989;138:617–23.

    Article  PubMed  CAS  Google Scholar 

  18. Uoshima N, Ozawa M, Kimura S, et al. Changes in c-Kit expression and effects of SCF during differentiation of human erythroid progenitor cells. Br J Haematol. 1995;91:30–6.

    Article  PubMed  CAS  Google Scholar 

  19. Broudy VC, Lin N, Zsebo KM, et al. Isolation and characterization of a monoclonal antibody that recognizes the human c-kit receptor. Blood. 1992;79:338–46.

    PubMed  CAS  Google Scholar 

  20. Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell. 1995;83:59–67.

    Article  PubMed  CAS  Google Scholar 

  21. Winkelmann JC, Penny LA, Deaven LL, Forget BG, Jenkins RB. The gene for the human erythropoietin receptor: analysis of the coding sequence and assignment to chromosome 19p. Blood. 1990;76:24–30.

    PubMed  CAS  Google Scholar 

  22. Jones SS, D’Andrea AD, Haines LL, Wong GG. Human erythropoietin receptor: cloning, expression, and biologic characterization. Blood. 1990;76:31–5.

    PubMed  CAS  Google Scholar 

  23. Elliott S, Busse L, Bass MB, et al. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood. 2006;107:1892–5.

    Article  PubMed  CAS  Google Scholar 

  24. Liu ZY, Chin K, Noguchi CT. Tissue specific expression of human erythropoietin receptor in transgenic mice. Dev Biol. 1994;166:159–69.

    Article  PubMed  CAS  Google Scholar 

  25. Wognum AW, Lansdorp PM, Humphries RK, Krystal G. Detection and isolation of the erythropoietin receptor using biotinylated erythropoietin. Blood. 1990;76:697–705.

    PubMed  CAS  Google Scholar 

  26. McArthur GA, Longmore GD, Klingler K, Johnson GR. Lineage-restricted recruitment of immature hematopoietic progenitor cells in response to Epo after normal hematopoietic cell transfection with EpoR. Exp Hematol. 1995;23:645–54.

    PubMed  CAS  Google Scholar 

  27. Ashihara E, Vannucchi AM, Migliaccio G, Migliaccio AR. Growth factor receptor expression during in vitro differentiation of partially purified populations containing murine stem cells. J Cell Physiol. 1997;171:343–56.

    Article  PubMed  CAS  Google Scholar 

  28. Billia F, Barbara M, McEwen J, Trevisan M, Iscove NN. Resolution of pluripotential intermediates in murine hematopoietic differentiation by global complementary DNA amplification from single cells: confirmation of assignments by expression profiling of cytokine receptor transcripts. Blood. 2001;97:2257–68.

    Article  PubMed  CAS  Google Scholar 

  29. Broudy VC, Lin N, Brice M, Nakamoto B, Papayannopoulou T. Erythropoietin receptor characteristics on primary human erythroid cells. Blood. 1991;77:2583–90.

    PubMed  CAS  Google Scholar 

  30. Sawada K, Krantz SB, Kans JS, et al. Purification of human erythroid colony-forming units and demonstration of specific binding of erythropoietin. J Clin Invest. 1987;80:357–66.

    Article  PubMed  CAS  Google Scholar 

  31. Fraser JK, Lin FK, Berridge MV. Expression of high affinity receptors for erythropoietin on human bone marrow cells and on the human erythroleukemic cell line, HEL. Exp Hematol. 1988;16:836–42.

    PubMed  CAS  Google Scholar 

  32. Wojchowski DM, Gregory RC, Miller CP, Pandit AK, Pircher TJ. Signal transduction in the erythropoietin receptor system. Exp Cell Res. 1999;253:143–56.

    Article  PubMed  CAS  Google Scholar 

  33. Jegalian AG, Wu H. Differential roles of SOCS family members in EpoR signal transduction. J Interferon Cytokine Res. 2002;22:853–60.

    Article  PubMed  CAS  Google Scholar 

  34. Minoo P, Zadeh MM, Rottapel R, Lebrun JJ, Ali S. A novel SHP-1/Grb2-dependent mechanism of negative regulation of cytokine-receptor signaling: contribution of SHP-1 C-terminal tyrosines in cytokine signaling. Blood. 2004;103:1398–407.

    Article  PubMed  CAS  Google Scholar 

  35. Koury MJ, Bondurant MC. Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science. 1990;248:378–81.

    Article  PubMed  CAS  Google Scholar 

  36. Mayeux P, Billat C, Jacquot R. The erythropoietin receptor of rat erythroid progenitor cells – characterization and affinity cross-linkage. J Biol Chem. 1987;262:13985–90.

    PubMed  CAS  Google Scholar 

  37. Jegalian AG, Acurio A, Dranoff G, Wu H. Erythropoietin receptor haploinsufficiency and in vivo interplay with granulocyte–macrophage colony-stimulating factor and interleukin 3. Blood. 2002;99:2603–5.

    Article  PubMed  CAS  Google Scholar 

  38. Migliaccio AR, Jiang Y, Migliaccio G, et al. Transcriptional and posttranscriptional regulation of the expression of the erythropoietin receptor gene in human erythropoietin-responsive cell lines. Blood. 1993;82:3760–9.

    PubMed  CAS  Google Scholar 

  39. Migliaccio G, Migliaccio AR, Visser JW. Synergism between erythropoietin and interleukin-3 in the induction of hematopoietic stem cell proliferation and erythroid burst colony formation. Blood. 1988;72:944–51.

    PubMed  CAS  Google Scholar 

  40. Migliaccio AR, Migliaccio G, D’Andrea A, et al. Response to erythropoietin in erythroid subclones of the factor-dependent cell line 32D is determined by translocation of the erythropoietin receptor to the cell surface. Proc Natl Acad Sci USA. 1991;88:11086–90.

    Article  PubMed  CAS  Google Scholar 

  41. Santucci MA, Pierce JH, Zannini S, et al. Erythropoietin increases the radioresistance of a clonal hematopoietic progenitor cell line expressing a transgene for the erythropoietin receptor. Stem Cells. 1994;12:506–13.

    Article  PubMed  CAS  Google Scholar 

  42. Wang Y, Kayman SC, Li JP, Pinter A. Erythropoietin receptor (EpoR)-dependent mitogenicity of spleen focus-forming virus correlates with viral pathogenicity and processing of env protein but not with formation of gp52–EpoR complexes in the endoplasmic reticulum. J Virol. 1993;67:1322–7.

    PubMed  CAS  Google Scholar 

  43. Gobert S, Chretien S, Gouilleux F, et al. Identification of tyrosine residues within the intracellular domain of the erythropoietin receptor crucial for STAT5 activation. EMBO J. 1996;15:2434–41.

    PubMed  CAS  Google Scholar 

  44. Binder C, Lafayette A, Archibeque I, et al. Optimization and utilization of the SureFire phospho-STAT5 assay for a cell-based screening campaign. Assay Drug Dev Technol. 2008;6:27–37.

    Article  PubMed  CAS  Google Scholar 

  45. Broudy VC, Lin N, Egrie J, et al. Identification of the receptor for erythropoietin on human and murine erythroleukemia cells and modulation by phorbol ester and dimethyl sulfoxide. Proc Natl Acad Sci USA. 1988;85:6513–17.

    Article  PubMed  CAS  Google Scholar 

  46. Longmore GD, Lodish HF. An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: a cytokine receptor superfamily oncogene. Cell. 1991;67:1089–102.

    Article  PubMed  CAS  Google Scholar 

  47. Sakamoto H, Kitamura T, Yoshimura A. Mitogen-activated protein kinase plays an essential role in the erythropoietin-dependent proliferation of CTLL-2 cells. J Biol Chem. 2000;275:35857–62.

    Article  PubMed  CAS  Google Scholar 

  48. Yamamura Y, Noda M, Ikawa Y. Erythropoietin receptor and interleukin-2 receptor use different downstream signaling pathways for proliferation and apoptosis-block. Leukemia. 1994;8:s107–10.

    PubMed  Google Scholar 

  49. Wakao H, Harada N, Kitamura T, Mui AL, Miyajima A. Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways. EMBO J. 1995;14:2527–35.

    PubMed  CAS  Google Scholar 

  50. Yamamura Y, Kageyama Y, Matuzaki T, Noda M, Ikawa Y. Distinct downstream signaling mechanism between erythropoietin receptor and interleukin-2 receptor. EMBO J. 1992;11:4909–15.

    PubMed  CAS  Google Scholar 

  51. Minamoto S, Treisman J, Hankins WD, Sugamura K, Rosenberg SA. Acquired erythropoietin responsiveness of interleukin-2-dependent T lymphocytes retrovirally transduced with genes encoding chimeric erythropoietin/interleukin-2 receptors. Blood. 1995;86:2281–7.

    PubMed  CAS  Google Scholar 

  52. Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW. Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med. 1989;321:158–63.

    Article  PubMed  CAS  Google Scholar 

  53. Guthrie M, Cardenas D, Eschbach JW, et al. Effects of erythropoietin on strength and functional status of patients on hemodialysis. Clin Nephrol. 1993;39:97–102.

    PubMed  CAS  Google Scholar 

  54. Locatelli F, Baldamus CA, Villa G, Ganea A, Martin de Francisco AL. Once-weekly compared with three-times-weekly subcutaneous epoetin beta: results from a randomized, multicenter, therapeutic-equivalence study. Am J Kidney Dis. 2002;40:119–25.

    Article  PubMed  CAS  Google Scholar 

  55. Macdougall IC. An overview of the efficacy and safety of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant. 2001;16:14–21.

    Article  PubMed  CAS  Google Scholar 

  56. Glaspy JA. Hematopoietic management in oncology practice. Part 2: Erythropoietic factors. Oncology (Huntington). 2003;17:1724–30.

    Google Scholar 

  57. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–98.

    Article  PubMed  CAS  Google Scholar 

  58. Nowrousian MR, Dunst J, Vaupel P. Erythropoiesis-stimulating agents: favorable safety profile when used as indicated. Strahlenther Onkol. 2008;184:121–36.

    Article  PubMed  Google Scholar 

  59. Rush RS, Derby PL, Smith DM, et al. Microheterogeneity of erythropoietin carbohydrate structure. Anal Chem. 1995;67:1442–52.

    Article  PubMed  CAS  Google Scholar 

  60. Sasaki H, Bothner B, Dell A, Fukuda M. Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. J Biol Chem. 1987;262:12059–76.

    PubMed  CAS  Google Scholar 

  61. Takeuchi M, Kobata A. Structures and functional roles of the sugar chains of human erythropoietins. Glycobiology. 1991;1:337–46.

    Article  PubMed  CAS  Google Scholar 

  62. Wide L, Bengtsson C. Molecular charge heterogeneity of human serum erythropoietin. Br J Haematol. 1990;76:121–7.

    Article  PubMed  CAS  Google Scholar 

  63. Lasne F, Martin L, Crepin N, De Ceaurriz J. Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones. Anal Biochem. 2002;311:119–26.

    Article  PubMed  CAS  Google Scholar 

  64. Takeuchi M, Takasaki S, Miyazaki H, et al. Comparative study of the asparagine-linked sugar chains of human erythropoietins purified from urine and the culture medium of recombinant Chinese hamster ovary cells. J Biol Chem. 1988;263:3657–63.

    PubMed  CAS  Google Scholar 

  65. Noguchi A, Mukuria CJ, Suzuki E, Naiki M. Failure of human immunoresponse to N-glycolylneuraminic acid epitope contained in recombinant human erythropoietin. Nephron. 1996;72:599–603.

    Article  PubMed  CAS  Google Scholar 

  66. Hokke CH, Bergwerff AA, Van Dedem GW, Kamerling JP, Vliegenthart JF. Structural analysis of the sialylated N- and O-linked carbohydrate chains of recombinant human erythropoietin expressed in Chinese hamster ovary cells. Sialylation patterns and branch location of dimeric N-acetyllactosamine units. Eur J Biochem. 1995;228:981–1008.

    Article  PubMed  CAS  Google Scholar 

  67. Kawasaki N, Haishima Y, Ohta M, et al. Structural analysis of sulfated N-linked oligosaccharides in erythropoietin. Glycobiology. 2001;11:1043–9.

    Article  PubMed  CAS  Google Scholar 

  68. Strickland T, Adler B, Aoki K, et al. Occurrence of sulfate on the N-linked oligosaccharides of human erythropoietin. J Cell Biochem. 1992;Suppl 16D:167.

    Google Scholar 

  69. Elliott S, Egrie J, Browne J, et al. Control of rHuEPO biological activity: the role of carbohydrate. Exp Hematol. 2004;32:1146–55.

    Article  PubMed  CAS  Google Scholar 

  70. Sinclair AM, Elliott S. Glycoengineering: the effect of glycosylation on the properties of therapeutic proteins. J Pharm Sci. 2005;94:1626–35.

    Article  PubMed  CAS  Google Scholar 

  71. Bernard BA, Yamada KM, Olden K. Carbohydrates selectively protect a specific domain of fibronectin against proteases. J Biol Chem. 1982;257:8549–54.

    PubMed  CAS  Google Scholar 

  72. Runkel L, Meier W, Pepinsky RB, et al. Structural and functional differences between glycosylated and non-glycosylated forms of human interferon-beta (IFN-beta). Pharm Res. 1998;15:641–9.

    Article  PubMed  CAS  Google Scholar 

  73. Sola RJ, Griebenow K. Effects of glycosylation on the stability of protein pharmaceuticals. J Pharm Sci. 2009;98:1223–45.

    Article  PubMed  CAS  Google Scholar 

  74. Cleland JL, Powell MF, Shire SJ. The development of stable protein formulations: a close look at protein aggregation, deamidation, and oxidation. Crit Rev Ther Drug Carrier Syst. 1993;10:307–77.

    PubMed  CAS  Google Scholar 

  75. Covic A, Kuhlmann MK. Biosimilars: recent developments. Int Urol Nephrol. 2007;39:261–6.

    Article  PubMed  CAS  Google Scholar 

  76. Roger SD, Goldsmith D. Biosimilars: it’s not as simple as cost alone. J Clin Pharm Ther. 2008;33:459–64.

    Article  PubMed  CAS  Google Scholar 

  77. Bouchet JL, Brunet P, Canaud B, et al. Position statements regarding usage of biosimilars of Epoetins. Position paper of the Societe de nephrologie, Societe francophone de dialyse, and Societe de nephrologie pediatrique. Nephrol Ther. 2009;5:61–6.

    PubMed  Google Scholar 

  78. Antonetti F, Finocchiaro O, Mascia M, Terlizzese MG, Jaber A. A comparison of the biologic activity of two recombinant IFN-beta preparations used in the treatment of relapsing–remitting multiple sclerosis. J Interferon Cytokine Res. 2002;22:1181–4.

    Article  PubMed  CAS  Google Scholar 

  79. Crommelin DJ, Storm G, Verrijk R, et al. Shifting paradigms: biopharmaceuticals versus low molecular weight drugs. Int J Pharm. 2003;266:3–16.

    Article  PubMed  CAS  Google Scholar 

  80. Rosenberg AS. Immunogenicity of biological therapeutics: a hierarchy of concerns. Dev Biol. 2003;112:15–21.

    CAS  Google Scholar 

  81. Schellekens H. Recombinant human erythropoietins, biosimilars and immunogenicity. J Nephrol. 2008;21:497–502.

    PubMed  CAS  Google Scholar 

  82. Smalling R, Foote M, Molineux G, Swanson SJ, Elliott S. Drug-induced and antibody-mediated pure red cell aplasia: a review of literature and current knowledge. Biotechnol Annu Rev. 2004;10:237–49.

    Article  PubMed  CAS  Google Scholar 

  83. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346:469–75.

    Article  PubMed  CAS  Google Scholar 

  84. Verhelst D, Rossert J, Casadevall N, et al. Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study. Lancet. 2004;363:1768–71.

    Article  PubMed  CAS  Google Scholar 

  85. Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov. 2002;1:457–62.

    Article  PubMed  CAS  Google Scholar 

  86. Schellekens H. Follow-on biologics: challenges of the ‘next generation’. Nephrol Dial Transplant. 2005;20:iv31–36.

    Article  PubMed  Google Scholar 

  87. Park SS, Park J, Ko J, et al. Biochemical assessment of erythropoietin products from Asia versus US Epoetin alfa manufactured by Amgen. J Pharm Sci. 2009;98:1688–99.

    Article  PubMed  CAS  Google Scholar 

  88. Keithi-Reddy SR, Kandasamy S, Singh AK. Pure red cell aplasia due to follow-on epoetin. Kidney Int. 2008;74:1617–22.

    Article  PubMed  Google Scholar 

  89. Belalcazar V, Ventura R, Segura J, Pascual JA. Clarification on the detection of epoetin delta and epoetin omega using isoelectric focusing. Am J Hematol. 2008;83:754–5.

    Article  PubMed  Google Scholar 

  90. Elliott S, Lorenzini T, Asher S, et al. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat Biotechnol. 2003;21:414–21.

    Article  PubMed  CAS  Google Scholar 

  91. Egrie JC, Dwyer E, Browne JK, Hitz A, Lykos MA. Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Exp Hematol. 2003;31:290–9.

    Article  PubMed  CAS  Google Scholar 

  92. Macdougall IC, Gray SJ, Elston O, et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999;10:2392–5.

    PubMed  CAS  Google Scholar 

  93. Jarsch M, Brandt M, Lanzendorfer M, Haselbeck A. Comparative erythropoietin receptor binding kinetics of C.E.R.A. and epoetin-beta determined by surface plasmon resonance and competition binding assay. Pharmacology. 2008;81:63–9.

    Article  PubMed  CAS  Google Scholar 

  94. Macdougall IC, et al. Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous continuous erythropoietin receptor activator (C.E.R.A.) in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:1211–15.

    Article  PubMed  CAS  Google Scholar 

  95. Fan Q, Leuther KK, Holmes CP, et al. Preclinical evaluation of hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol. 2006;34:1303–11.

    Article  PubMed  CAS  Google Scholar 

  96. Connolly PJ, Wetter SK, Murray WV, et al. Synthesis and erythropoietin receptor binding affinities of N, N-disubstituted amino acids. Bioorg Med Chem Lett. 2000;10:1995–9.

    Article  PubMed  CAS  Google Scholar 

  97. Suzuki N, Obara N, Yamamoto M. Use of gene-manipulated mice in the study of erythropoietin gene expression. Methods Enzymol. 2007;435:157–77.

    Article  PubMed  CAS  Google Scholar 

  98. Erslev AJ. Clinical erythrokinetics: a critical review. Blood Rev. 1997;11:160–7.

    Article  PubMed  CAS  Google Scholar 

  99. Schuster SJ, Badiavas EV, Costa-Giomi P, et al. Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. Blood. 1989;73:13–16.

    PubMed  CAS  Google Scholar 

  100. Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem. 1996;271:17771–8.

    Article  PubMed  CAS  Google Scholar 

  101. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 1995;92:5510–14.

    Article  PubMed  CAS  Google Scholar 

  102. Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402.

    Article  PubMed  CAS  Google Scholar 

  103. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107:43–54.

    Article  PubMed  CAS  Google Scholar 

  104. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 2001;20:5197–206.

    Article  PubMed  CAS  Google Scholar 

  105. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337–40.

    Article  PubMed  CAS  Google Scholar 

  106. Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.

    Article  PubMed  CAS  Google Scholar 

  107. Hon WC, Wilson MI, Harlos K, et al. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature. 2002;417:975–8.

    Article  PubMed  CAS  Google Scholar 

  108. Maxwell PH, Pugh CW, Ratcliffe PJ. Insights into the role of the von Hippel–Lindau gene product. A key player in hypoxic regulation. Exp Nephrol. 2001;9:235–40.

    Article  PubMed  CAS  Google Scholar 

  109. Heatherington AC. Clinical pharmacokinetic properties of rHuEpo: a review. In: Molineux G, Foot MA, Elliott SG, editors. Erythropoietins and erythropoiesis: molecular, cellular, preclinical and clinical biology. Basel: Birkhauser; 2003. pp. 87–112.

    Google Scholar 

  110. Eckardt KU, Boutellier U, Kurtz A, et al. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia. J Appl Physiol. 1989; 66: 1785–8.

    PubMed  CAS  Google Scholar 

  111. Cheung WK, Goon BL, Guilfoyle MC, Wacholtz MC. Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects. Clin Pharmacol Ther. 1998;64:412–23.

    Article  PubMed  CAS  Google Scholar 

  112. McMahon FG, Vargas R, Ryan M, et al. Pharmacokinetics and effects of recombinant human erythropoietin after intravenous and subcutaneous injections in healthy volunteers. Blood. 1990;76:1718–22.

    PubMed  CAS  Google Scholar 

  113. Boxenbaum H. Pharmacokinetics tricks and traps: flip–flop models. J Pharm Pharm Sci. 1998;1:90–1.

    PubMed  CAS  Google Scholar 

  114. Padhi D, Ni L, Cooke B, Marino R, Jang G. An extended terminal half-life for darbepoetin alfa: results from a single-dose pharmacokinetic study in patients with chronic kidney disease not receiving dialysis. Clin Pharmacokinet. 2006;45:503–10.

    Article  PubMed  CAS  Google Scholar 

  115. Glaspy J, Henry D, Patel R, et al. Effects of chemotherapy on endogenous erythropoietin levels and the pharmacokinetics and erythropoietic response of darbepoetin alfa: a randomised clinical trial of synchronous versus asynchronous dosing of darbepoetin alfa. Eur J Cancer. 2005;41:1140–9.

    Article  PubMed  CAS  Google Scholar 

  116. Blumer J, Berg S, Adamson PC, et al. Pharmacokinetic evaluation of darbepoetin alfa for the treatment of pediatric patients with chemotherapy-induced anemia. Pediatr Blood Cancer. 2007;49:687–93.

    Article  PubMed  Google Scholar 

  117. Fukuda MN, Sasaki H, Lopez L, Fukuda M. Survival of recombinant erythropoietin in the circulation: the role of carbohydrates. Blood. 1989;73:84–9.

    PubMed  CAS  Google Scholar 

  118. Spivak JL, Hogans BB. The in vivo metabolism of recombinant human erythropoietin in the rat. Blood. 1989;73:90–9.

    PubMed  CAS  Google Scholar 

  119. Fu J-S, Lertora JJL, Brookins J, Rice JC, Fisher JW. Pharmacokinetics of erythropoietin in intact and anephric dogs. J Lab Clin Med. 1988;111:669–76.

    PubMed  CAS  Google Scholar 

  120. Widness JA, Veng-Pedersen P, Schmidt RL, et al. In vivo 125I-erythropoietin pharmacokinetics are unchanged after anesthesia, nephrectomy and hepatectomy in sheep. J Pharmacol Exp Ther. 1996;279:1205–10.

    PubMed  CAS  Google Scholar 

  121. Kindler J, Eckardt KU, Ehmer B, et al. Single-dose pharmacokinetics of recombinant human erythropoietin in patients with various degrees of renal failure. Nephrol Dial Transplant. 1989;4:345–9.

    PubMed  CAS  Google Scholar 

  122. Macdougall IC, Roberts DE, Coles GA, Williams JD. Clinical pharmacokinetics of epoetin (recombinant human erythropoietin). Clin Pharmacokinet. 1991;20:99–113.

    Article  PubMed  CAS  Google Scholar 

  123. Sawyer ST, Krantz SB, Goldwasser E. Binding and receptor-mediated endocytosis of erythropoietin in Friend virus-infected erythroid cells. J Biol Chem. 1987;262:5554–62.

    PubMed  CAS  Google Scholar 

  124. Gross AW, Lodish HF. Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem. 2006;281:2024–32.

    Article  PubMed  CAS  Google Scholar 

  125. Agoram B, Aoki K, Doshi S, et al. Investigation of the effects of altered receptor binding activity on the clearance of erythropoiesis-stimulating proteins: Nonerythropoietin receptor-mediated pathways may play a major role. J Pharm Sci. 2009;98(6):2198–211.

    Google Scholar 

  126. Porter CJ, Charman SA. Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci. 2000;89:297–310.

    Article  PubMed  CAS  Google Scholar 

  127. Yoshioka E, Kato K, Shindo H, et al. Pharmacokinetic study of darbepoetin alfa: absorption, distribution, and excretion after a single intravenous and subcutaneous administration to rats. Xenobiotica. 2007;37:74–90.

    Article  PubMed  CAS  Google Scholar 

  128. Agoram B, Sutjandra L, Molineux G, Jang G, Elliott S. Tissue distribution and excretion of 125I darbepoetin alfa in Sprague Dawley rats following a single subcutaneous or IV administration [abstract]. Nephrol Dial Transplant. 2006;21:304.

    Google Scholar 

  129. Erslev AJ. Erythropoietin titers in health and disease. Semin Hematol. 1991;28:2–7.

    PubMed  CAS  Google Scholar 

  130. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 1987;316:73–8.

    Article  PubMed  CAS  Google Scholar 

  131. Egrie JC, Strickland TW, Lane J, et al. Characterization and biological effects of recombinant human erythropoietin. Immunobiology. 1986;172:213–24.

    PubMed  CAS  Google Scholar 

  132. Hodges VM, Rainey S, Lappin TR, Maxwell AP. Pathophysiology of anemia and erythrocytosis. Crit Rev Oncol Hematol. 2007;64:139–58.

    Article  PubMed  Google Scholar 

  133. Bokemeyer C, Oechsle K, Hartmann JT. Anaemia in cancer patients: pathophysiology, incidence and treatment. Eur J Clin Invest. 2005;35:26–31.

    PubMed  Google Scholar 

  134. Finch CA, Harker LA, Cook JD. Kinetics of the formed elements of human blood. Blood. 1977;50:699–707.

    PubMed  CAS  Google Scholar 

  135. Hillman RS, Finch CA. Erythropoiesis: normal and abnormal. Semin Hematol. 1967;4:327–36.

    PubMed  CAS  Google Scholar 

  136. Brines M, Cerami A. Discovering erythropoietin’s extra-hematopoietic functions: biology and clinical promise. Kidney Int. 2006;70:246–50.

    Article  PubMed  CAS  Google Scholar 

  137. Hardee ME, Arcasoy MO, Blackwell KL, Kirkpatrick JP, Dewhirst MW. Erythropoietin biology in cancer. Clin Cancer Res. 2006;12:332–9.

    Article  PubMed  CAS  Google Scholar 

  138. Laugsch M, Metzen E, Svensson T, Depping R, Jelkmann W. Lack of functional erythropoietin receptors of cancer cell lines. Int J Cancer. 2008;122:1005–11.

    Article  PubMed  CAS  Google Scholar 

  139. Sinclair AM, Rogers N, Busse L, et al. Erythropoietin receptor transcription is neither elevated nor predictive of surface expression in human tumour cells. Br J Cancer. 2008;98:1059–67.

    Article  PubMed  CAS  Google Scholar 

  140. Keller MA, Addya S, Vadigepalli R, et al. Transcriptional regulatory network analysis of developing human erythroid progenitors reveals patterns of coregulation and potential transcriptional regulators. Physiol Genomics. 2006;28:114–28.

    Article  PubMed  CAS  Google Scholar 

  141. Jeong JY, Feldman L, Solar P, Szenajch J, Sytkowski AJ. Characterization of erythropoietin receptor and erythropoietin expression and function in human ovarian cancer cells. Int J Cancer. 2008;122:274–80.

    Article  PubMed  CAS  Google Scholar 

  142. Brown WM, Maxwell P, Graham AN, et al. Erythropoietin receptor expression in non-small cell lung carcinoma: a question of antibody specificity. Stem Cells. 2007;25:718–22.

    Article  PubMed  CAS  Google Scholar 

  143. Della Ragione F, Cucciolla V, Borriello A, Oliva A, Perrotta S. Erythropoietin receptors on cancer cells: a still open question. J Clin Oncol. 2007;25:1812–13.

    Article  PubMed  Google Scholar 

  144. Kirkeby A, van Beek J, Nielsen J, Leist M, Helboe L. Functional and immunochemical characterisation of different antibodies against the erythropoietin receptor. J Neurosci Methods. 2007;164:50–8.

    Article  PubMed  CAS  Google Scholar 

  145. Ulich TR, del Castillo J, Yin SM, Egrie JC. The erythropoietic effects of interleukin 6 and erythropoietin in vivo. Exp Hematol. 1991;19:29–34.

    PubMed  CAS  Google Scholar 

  146. Grossi A, Vannucchi AM, Rafanelli D, Rossi FP. Recombinant human erythropoietin has little influence on megakaryocytopoiesis in mice. Br J Haematol. 1989;71:463–8.

    Article  PubMed  CAS  Google Scholar 

  147. Suzuki N, Ohneda O, Takahashi S, et al. Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality. Blood. 2002;100:2279–88.

    Article  PubMed  CAS  Google Scholar 

  148. Banks WA, Jumbe NL, Farrell CL, Niehoff ML, Heatherington AC. Passage of erythropoietic agents across the blood–brain barrier: a comparison of human and murine erythropoietin and the analog darbepoetin alfa. Eur J Pharmacol. 2004;505:93–101.

    Article  PubMed  CAS  Google Scholar 

  149. Buemi M, Allegra A, Corica F, et al. Intravenous recombinant erythropoietin does not lead to an increase in cerebrospinal fluid erythropoietin concentration. Nephrol Dial Transplant. 2000;15:422–3.

    Article  PubMed  CAS  Google Scholar 

  150. Hardee ME, Kirkpatrick JP, Shan S, et al. Human recombinant erythropoietin (rEpo) has no effect on tumour growth or angiogenesis. Br J Cancer. 2005;93:1350–5.

    Article  PubMed  CAS  Google Scholar 

  151. Sinclair AM, Todd MD, Forsythe K, et al. Expression and function of erythropoietin receptors in tumors: implications for the use of erythropoiesis-stimulating agents in cancer patients. Cancer. 2007;110:477–88.

    Article  PubMed  CAS  Google Scholar 

  152. Katavetin P, Tungsanga K, Eiam-Ong S, Nangaku M. Antioxidative effects of erythropoietin. Kidney Int. 2007;72:S10–S15.

    Article  CAS  Google Scholar 

  153. Yazihan N, Uzuner K, Salman B, et al. Erythropoietin improves oxidative stress following spinal cord trauma in rats. Injury. 2008;39:1408–13.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Amgen, Inc., Thousand Oaks, CA, 91320, USA

    Steve Elliott

Authors
  1. Steve Elliott
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steve Elliott .

Editor information

Editors and Affiliations

  1. Department of Medicine, Duke University and the Duke Comprehensi, Durham, 27705, North Carolina, USA

    Gary H. Lyman

  2. Health Sciences Center, Department of Medicine, University of Washington, Seattle, 98195, Washington, USA

    David C. Dale

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Elliott, S. (2010). Erythropoiesis-Stimulating Agents. In: Lyman, G., Dale, D. (eds) Hematopoietic Growth Factors in Oncology. Cancer Treatment and Research, vol 157. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7073-2_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-7073-2_4

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4419-7072-5

  • Online ISBN: 978-1-4419-7073-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation