The Role of Other Hemopoietic Growth Factors and the Marrow Microenvironment in Megakaryocytopoiesis

  • Ronald Hoffman

Abstract

The recent identification, purification, and cloning of thrombopoietin (TPO), a lineage-specific regulator of platelet production, is the culmination of several decades of research dealing with the regulation of megakaryocytopoiesis (1–5). Although endogenous TPO plays a pivotal role in promoting the proliferation and maturation of megakaryocytc progenitor cells and megakaryocytes, a considerable amount of data exists that indicates that other growth factors are also capable of altering this finely regulated biological process (6,7). These non-TPO regulatory factors are capable not only of promoting megakaryocytc proliferation and maturation, but also of downregulating these cellular processes (6,7). These growth factors might play an important role in the physiological regulation of megakaryocytopoiesis and may be instrumental in the pathogenesis of a number of clinical syndromes (8–12). In addition, recombinant forms of these growth factors have considerable potential in the treatment of clinical disorders of thrombopoiesis (7).

Keywords

Placebo Toxicity Doxorubicin Neutropenia Cyclophosphamide 

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References

  1. 1.
    Bartley TD, Bogenberger J, Hunt P, et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994; 77: 1117–1124.PubMedGoogle Scholar
  2. 2.
    Lok S, Kaushansky K, Holly RD, et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature. 1994; 369: 565–568.PubMedGoogle Scholar
  3. 3.
    Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci USA 1994; 91: 11,104–11,108.Google Scholar
  4. 4.
    Wendling F, Maraskovsky E, Debili N, et al. c-Mpl ligand is a humoral regulator of megakaryocytopoiesis. Nature. 1994; 369: 571–574.PubMedGoogle Scholar
  5. 5.
    DeSauvage F J, Hass PE, Spenser SD, et al. Stimulation of megakaryocytopoiesis and throm-bopoiesis by the c-Mpl ligand. Nature. 1994; 369: 533–538.Google Scholar
  6. 6.
    Hoffman R. Regulation of megakaryocytopoiesis. Blood. 1989; 74: 1196–1212.PubMedGoogle Scholar
  7. 7.
    Gordon MS, Hoffman R. Growth factors affecting human thrombocytopoiesis: Potential agents for the treatment of thrombocytopenia. Blood. 1992; 80: 302–307.PubMedGoogle Scholar
  8. 8.
    Hollen CW, Henthron J, Koziol JA, Burstein SA. Serum interleukin-6 levels in patients with thrombocytosis. Leukemia Lymphoma. 1992; 8: 235–241.PubMedGoogle Scholar
  9. 9.
    Straneva JE, Van Besien KW, Derigs G, Hoffman R. Is interleukin 6 the physiological regulator of thrombopoiesis? Exp Hematol . 1992; 20: 47–50.PubMedGoogle Scholar
  10. 10.
    Hollen CW, Henthorn J, Koziol JA, Burstein SA. Elevated serum interleukin-6 levels in patients with reactive thrombocytosis. Br J Haematol. 1991; 79: 286–290.PubMedGoogle Scholar
  11. 11.
    Beck JT, Hsu SM, Wijdenes J, et al. Brief report: alleviation of systemic manifestations of Castleman’s disease by monoclonal anti-interleukin-6 antibody therapy. N Engl J Med. 1994; 330: 602–605.PubMedGoogle Scholar
  12. 12.
    Hoffman R, Briddell RA, van Besien K, et al. Acquired cyclic amegakaryocytic thrombcytopenia associated with an immunoglobulin blocking the action of granulocyte-macrophage colony-stimulating factor. N Engl J Med. 1989; 321: 97–102.PubMedGoogle Scholar
  13. 13.
    Gurney AL, Carver-Moore K, de Sauvage FJ, Moore MW. Thrombocytopenia in c-mpl-deficientmice. Science. 1994: 265: 1445–1447.PubMedGoogle Scholar
  14. 14.
    deSauvage FJ, Luoh SM, Carver-Moore, et al. Deficiencies in early and late stages of megakaryocytopoiesis in TPO-KO mice. Blood. 1995; 86: 255a (abstract no 1007).Google Scholar
  15. 15.
    Harker LA, Finch CA. Thrombokinetics in man. J Clin Invest. 1969; 48: 963–974.PubMedGoogle Scholar
  16. 16.
    Bursteın SA, Adamson JW, Erb SK, Harker LA. Megakaryocytopoiesis in the mouse: response to varying platelet demand. J Cell Physiol. 1981; 109: 333–341.PubMedGoogle Scholar
  17. 17.
    Levin J, Levin FC, Metcalf D. The effects of acute thrombopenia on megakaryocyte-CFC and granulocyte-macrophage-CFC in mice: studies of bone marrow and spleen. Blood. 1980; 56: 274–283.PubMedGoogle Scholar
  18. 18.
    Ebbe S, Phalen E. Does autoregulation of megakaryocytopoiesis occur? Blood Cells. 1979; 5: 123–138.PubMedGoogle Scholar
  19. 19.
    Williams N, Eger RR, Jackson HM, Nelson DJ. Two factor requirement for murine megakaryocyte colony formation. J Cell Physiol. 1982; 110: 101–104.PubMedGoogle Scholar
  20. 20.
    Mazur EM. Megakaryocytopoiesis and platelet production: a review. Exp Hematol . 1987; 15: 340–350.PubMedGoogle Scholar
  21. 21.
    Debili N, Wendling F, Katz A, et al. The Mpl-ligand or thrombopoietin or megakaryocyte growth and differentiative factor has both proliferative and differentiative activities on human megakaryocyte progenitors. Blood. 1995; 86: 2516–2525.PubMedGoogle Scholar
  22. 22.
    Debili N, Wendliing F, Cosman D, et al. The Mpl receptor is expressed on the megakaryocyte lineage from late progenitors to platelets. Blood. 1995; 85: 391–401.PubMedGoogle Scholar
  23. 23.
    Hoffman R, Murray LJ, Young JS, Leuns KM, Bruno E. Hierarchical structure of human megakaryocyte progenitor cells. Stem Cells, (in press).Google Scholar
  24. 24.
    Kobayashi M, Laver JH, Kato T, Miyazaki H, Ogawa M. Recombinant human thrombopoietin (Mpl ligand) enhances proliferation of erythroid progenitors. Blood. 1995; 86: 2494–2496.PubMedGoogle Scholar
  25. 25.
    Zent CS, Hornkohl A, Arpeally G, et al. Cyclic thrombocytopenia: Thrombopoietin response to spontaneous changes in platelet counts. Blood. 1995; 86(suppl 1): 370a (abstract no 1470).Google Scholar
  26. 26.
    Quesenberry PJ, Ihle JN, McGrath E. The effect of interleukin-3 and GM-CSA-2 on megakaryocyte and myeloid clonal colony formation. Blood. 1995; 65: 214.Google Scholar
  27. 27.
    Robinson BE, McGrath HE, Quesenberry PJ. Recombinant murine granulocyte macrophage colony stimulating factor has megakaryocyte colony-stimulating activity and augments megakaryocyte colony stimulation by interleukin 3. J Clin Invest. 1987; 79: 1648–1652.PubMedGoogle Scholar
  28. 28.
    Kaushansky K, O ’Hara PJ, Berkner K. et al. Genomic cloning, characterization and multilineage growth-promoting activity of human granulocyte-macrophage colony-stimulating factor. Proc Natl Acad Sci USA. 1986; 83: 3101–3105.PubMedGoogle Scholar
  29. 29.
    Peschel C, Paul WE, Ohara J, Green I. Effects of B cell stimulatory factor-1/interleukin 4 on hematopoietic progenitor cells. Blood. 1987; 70: 254–263.PubMedGoogle Scholar
  30. 30.
    Williams N, Jackson H, Iscove NN, Dukes PP. The role of erythropoietin, thrombopoietic stimulating factor, and myeloid colony-stimulating factors on murine megakaryocyte colony formation. Exp Hematol . 1984; 12: 734–740.PubMedGoogle Scholar
  31. 31.
    Bruno E, Miller ME, Hoffman R. Interacting cytokines regulate in vitro human megakaryocytopoiesis. Blood. 1989; 73: 671–677.PubMedGoogle Scholar
  32. 32.
    Emerson SG, Yang YC, Clark SC, Long MW. Human recombinant granulocyte-macrophage colony stimulating factor and interleukini 3 have overlapping but distinict hematopoietic activities. J Clin Invest. 1988; 82: 1282–1287.PubMedGoogle Scholar
  33. 33.
    Bruno E, Cooper RJ, Briddell RA, Hoffman R. Further examination of the effects of recombinant cytokines on the proliferation of human megakaryocyte progenitor cells. Blood. 1991; 77: 2339–2346.PubMedGoogle Scholar
  34. 34.
    Quesenberry PJ, McGrath HE, Williams ME, et al. Multifactor stimulation of megakaryocytopoiesis: effects of interleuken 6. Exp Hemato L 1991; 19: 35–41.Google Scholar
  35. 35.
    Williams N, Jackson H, Walker F, Oon SH. Multiple levels of regulation of megakaryocytopoiesis. Blood Cells. 1989; 15: 123–133.PubMedGoogle Scholar
  36. 36.
    Ishibashi T, Kimura H, Uchida T, et al. Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci USA. 1989; 86: 5953–5957.PubMedGoogle Scholar
  37. 37.
    Burstein SA. Interleukin 3 promotes maturation of murine megakaryocytes in vitro. Blood. 1986; 67: 1512.PubMedGoogle Scholar
  38. 38.
    Ishibashi T, Burstein SA. Interleukin 3 promotes the differentiation of isolated single megakaryocytes. Blood. 1986; 67: 1512–1514.PubMedGoogle Scholar
  39. 39.
    Ishibashi T, Koziol JA, Burstein SA. Human recombinant erythropoietin promotes differentiation of murine megakaryocytes in vitro. J Clin Invest. 1987; 79: 286–289.PubMedGoogle Scholar
  40. 40.
    Teramura M, Kobayashi S, Hoshino S, Oshimi K, Mizoguchi H. Interleukin-11 enhances human megakaryocytopoiesis in vitro. Blood. 1992; 79: 327–331.PubMedGoogle Scholar
  41. 41.
    Burstein SA, Henthorn J, Mei R, Williams DE. Mast cell growth factor (MGF) promotes human and murine megakaryocytc (MK) differentiation in vitro. Blood 1991; 78 (suppl 1): 160a (abstract no 629).Google Scholar
  42. 42.
    Goldman SJ, Lobelenz J, McCarthy K, et al. Recombinant human interleukin-11 (rhIL-11) stimulates megakaryocyte maturation and increases in peripheral platelet numbers in vivo. Blood. 1991; 78 (suppl 1): 132a (abstract no 518).Google Scholar
  43. 43.
    Metcalf D, Hilton D, Nicola NA. Leaukemia inhibitory factor can potentiate murine megakaryocyte production in vitro. Blood. 1991; 77: 2150–2153.PubMedGoogle Scholar
  44. 44.
    Ishibashi T, Miller SL, Burstein SA. Type beta transforming growth factor is a potent inhibitor of murine megakaryocytopoiesis in vitro. Blood. 1987; 69: 1737–1741.PubMedGoogle Scholar
  45. 45.
    Dessypris EN, Gleaton JH, Sawyer ST, Armstrong OL. Suppression of maturation of megakaryocyte colony forming unit in vitro by a platelet released glycoprotein. J Cell Physiol 1987; 130: 361–368.PubMedGoogle Scholar
  46. 46.
    Mitjavila MT, Vinci G, Villeval JL, et al. Human platelet alpha granules contain a nonspecific inhibitor of megakaryocyte colony formation: its relationship to type beta transforming growth factor (TGF-beta). J Cell Physiol. 1988; 139: 93–100.Google Scholar
  47. 47.
    Gewirtz AM, Calabretta B, Rucinski B, et al. Inhibition of human megakaryocytopoiesis in vitro by platelet factor 4 (PF4) and a synthetic COOH-terminal PF4 peptide. J Clin Invest. 1989; 83: 1477–1486.PubMedGoogle Scholar
  48. 48.
    Ganser A, Carlo-Stella C, Greher J, Volkers B, Hoelzer D. Effect of recombinant interferons alpha and gamma on human bone marrow derived megakaryocyte progenitor cells. Blood. 1987;70:1173–1179.PubMedGoogle Scholar
  49. 49.
    Williams DE, Park LS, Broxmeyer HE, Lu L. Hybrid cytokines as hematopoietic growth factors. Int J Cell Cloning. 1991; 9: 542–547.PubMedGoogle Scholar
  50. 50.
    Bruno E, Briddel RA, Cooper RJ, Brandt JE, Hoffman R. Recombinant GM-CSF/IL-3 fusion protein. Its effects on in vitro human megakaryocytopoiesis. Exp Hematol . 1992; 20: 494–499.PubMedGoogle Scholar
  51. 51.
    Broudy VC, Lin NL, Kaushansky K. Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor and interleukin-11 to enhance murine megakaryocyte colony growth and increase megakaryocyte ploidy in vitro. Blood. 1995; 85: 1719–1726.PubMedGoogle Scholar
  52. 52.
    Briddell RA, Hoffman R. Cytokine regulation of the human burst-forming unit-megakaryo-cyte. Blood. 1990; 76: 516–522.PubMedGoogle Scholar
  53. 53.
    Briddell RA, Bruno E, Cooper RJ, Brandt JE, Hoffman R. Effect of c-kit ligand on in vitro human megakaryocytopoiesis. Blood. 1991; 78: 2854–2859.PubMedGoogle Scholar
  54. 54.
    Warren MK, Conroy LB, Rose JS. The role of interleukin 6 and interleukin 1 in megakaryocytic development. Exp Hematol . 1989; 17: 1095–1099.PubMedGoogle Scholar
  55. 55.
    Bruno E, Cooper RJ, Briddell RA, Hoffman R. Effects of recombinant interleukin 11 on human megakaryocyte progenitor cells. Exp Hematol . 1991; 19: 378–381.PubMedGoogle Scholar
  56. 56.
    Wallace PM, MacMaster JF, Rillena JR, et al. Thrombocytopoietic properties of oncostatin M. Blood. 1995; 86: 1310–1315.PubMedGoogle Scholar
  57. 57.
    Poloni A, Kobari I, Firat H, et al. Ex vivo expansion of megakaryocytic progenitor cells (CFU-MK) in serum-free conditions: the effect of Flt3 ligand, MGDF and G-CSF. Blood. 1995; 86: 702a (abstract no 2796).Google Scholar
  58. 58.
    Bruno E, Hoffman R. Effect of interleukin 6 on in vitro human megakaryocytopoiesis: its interaction with other cytokines. Exp Hematol . 1989; 17: 1038–1043.PubMedGoogle Scholar
  59. 59.
    Burstein SA, Meir J, Friese P, Turner K. Recombinant human leukemia inhibitory factor (LIF) and interleukin 11 (IL-11) promote murine and human megakaryocytopoiesis in vitro. Blood. 1990; 86 (suppl. 1): 450a (abstract no 1789).Google Scholar
  60. 60.
    Liu J, Modrell B, Aruffo A, et al. Interleukin-6 signal transducer gp 130 mediates oncostatin M signaling. J Biol Chem. 1992; 267: 16,763–16,766.Google Scholar
  61. 61.
    Bikfalvi A, Han C, Fuhrmann G. Interaction of fibroblast growth factor (FGF) with megakaryocytopoiesis and demonstration of FGF receptor expression in megakaryocytes and megakaryocyte-like cells. Blood. 1992; 80: 1905–1913.PubMedGoogle Scholar
  62. 62.
    Brunner G, Nguyen H, Gabrilove JR, Rifkin DB, Wilson EL. Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells. Blood. 1993; 81: 631–638.PubMedGoogle Scholar
  63. 63.
    Oliver LJ, Rifkin DB, Gabrilove J, Hannocks MJ, Wilson EL. Long-term culture of human bone marrow stromal cells in the presence of basic fibroblast growth factor. Growth Factors. 1990;3:231–236.PubMedGoogle Scholar
  64. 64.
    Wilson EL, Rifkin DB, Kelley F, Hannocks MJ, Gabrilove JL. Basic fibroblast growth factor stimulates myelopoiesis in long-term human bone marrow cultures. Blood. 1991; 77: 954–960.PubMedGoogle Scholar
  65. 65.
    Bruno E, Cooper RJ, Wilson EL, Gabrilove JL, Hoffman R. Basic fibroblast growth factor promotes the proliferation of human megakaryocyte progenitor cells. Blood. 1993; 82: 430–435.PubMedGoogle Scholar
  66. 66.
    Hill RJ, Warren MK, Levin J, Gauldie J. Evidence that interleukin-6 does not play a role in the stimulation of platelet production after induction of acute thrombocytopenia. Blood. 1992; 80: 346–351.PubMedGoogle Scholar
  67. 67.
    Navarro S, Debili N, LeCoudic JR et al. Interleukin-6 and its receptor are expressed by human megakaryocytes: in vitro effect on proliferation and endoreplication. Blood. 1991; 77: 461–471.PubMedGoogle Scholar
  68. 68.
    Wickenhauser C, Lorenzen J, Thiele J, et al. Secretion of cytokines (interleukins-1 alpha, -3, and -6 and granulocyte-macrophage colony-stimulating factor) by normal human bone marrow megakaryocytes. Blood. 1995; 85: 685–691.PubMedGoogle Scholar
  69. 69.
    Vainchenker W, Chapman J, Deschamps JF, et al. Normal human serum contains a factor(s) capable of inhibiting megakaryocyte colony formation. Exp Hematol . 1982; 10: 650–660.PubMedGoogle Scholar
  70. 70.
    Han ZC, Sensebe L, Abgrall JF, Briere J. Platelet factor 4 inhibits human megakaryocytopoiesis in vitro. Blood. 1990; 75: 1234–1239.PubMedGoogle Scholar
  71. 71.
    Griffin CG, Grant BW. Effects of recombinant interferons on human megakaryocyte growth. Exp Hematol . 1990; 18: 1013–1018.PubMedGoogle Scholar
  72. 72.
    Gewirtz AM, Zhang J, Ratajczak M, et al. Chemokine regulation of human megakaryocytopoiesis. Blood. 1995; 86: 2559–2567.PubMedGoogle Scholar
  73. 73.
    Montovani A, Sozzani S. Chemokines. Lancet. 1994; 343: 923.Google Scholar
  74. 74.
    Walz A, Baggiolini M. A novel cleavage product of beta-thromboglobulin formed in cultures of stimulated mononuclear cells activates human neutrophils. Biochem BiophyRes Commun. 1989; 159: 969–975.Google Scholar
  75. 75.
    Springer TA. Adhesion receptors of the immune system. Nature. 1990; 346: 425–434.PubMedGoogle Scholar
  76. 76.
    Long MW. Blood cell cytoadhesion molecules. Exp Hematol 1992; 20: 288–301.PubMedGoogle Scholar
  77. 77.
    Anderson DM, Lyman SD, Baird A, et al. Molecular cloning of mast cell growth factor, ahematopoietin that is active in both membrane bound and soluble forms. Cell. 1990; 63: 235–243.PubMedGoogle Scholar
  78. 78.
    Gordon MY, Riley GP, Watt SM, Greaves MF. Compartmentalization of a haematopoietic growth factor (GM-CSF) by glycosaminoglycans in the bone marrow microenvironment. Nature. 1987; 326: 403–405.PubMedGoogle Scholar
  79. 79.
    Gospodarowicz D, Ill C. Extracellular matrix and control proliferation of vascular endothelial cells. J Clin Invest. 1980; 65: 1351–1364.PubMedGoogle Scholar
  80. 80.
    Gospodarowicz D, Delagado D, Vlodavsky I. Permissive effect of the extracellular matrix on cell proliferation in vitro. Proc Natl Acad Sci USA. 1980; 77: 4094–4098.PubMedGoogle Scholar
  81. 81.
    Zucker-Franklin D, Petursson SR. Thrombocytopoiesis—analysis by membrane tracer and freeze-fracture studies on fresh human and cultured mouse megakaryocytes. J Cell Biol. 1984; 99: 390–402.PubMedGoogle Scholar
  82. 82.
    Eldor A, Fuks Z, Levine RF, Vlodavsky I. Measurement of platelet and megakaryocyte interaction with the subendothelial extracellular matrix. Methods Enzymol. 1989; 169: 76–91.PubMedGoogle Scholar
  83. 83.
    Tablin F, Castro M, Levin RM. Blood platelet formation in vitro. The role of the cytoskeleton in megakaryocyte fragmentation. J Cell Sci. 1990; 97: 59–70.PubMedGoogle Scholar
  84. 84.
    Long MW, Briddell R, Walter AW, Bruno E, Hoffman R. Human hematopoietic stem cell adherence to cytokines and matrix molecules. J Clin Invest. 1992; 90: 251–255.PubMedGoogle Scholar
  85. 85.
    McDonald TP, Cottrell MB, Clift RE, Cullin MC, Lin FK. High doses of recombinant erythropoietin stimulate platelet production in mice. Exp Hematol . 1987; 15: 719–721.PubMedGoogle Scholar
  86. 86.
    Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multi-center clinical trial. Ann Intern Med. 1989; 111: 992–1000.PubMedGoogle Scholar
  87. 87.
    Ganser A, Volkers B, Greher J, et al. Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes: A phasel/II trial. Blood. 1989; 73: 31–37.PubMedGoogle Scholar
  88. 88.
    Vadhan-Raj S, Keating M, Hittelman WN, et al. Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. N Engl J Med. 1987; 317: 1545–1552.PubMedGoogle Scholar
  89. 89.
    Neumanitis J, Rabinowe S, Singer J, et al. Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer. N Engl J Med. 1991; 324: 1773–.PubMedGoogle Scholar
  90. 90.
    Levine JD, Allan JD, Tessitore JH, et al. Recombinant human granulocyte-macrophage colony-stimulating factor ameliorates zidovudine-induced neutropenia in patients with acquired immune deficiency syndrome (AIDS)/AIDS related complex. Blood. 1991; 78: 3148–3154.PubMedGoogle Scholar
  91. 91.
    Lieschke GJ, Maher D, Cebon J, et al. Effects of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy. Ann Intern Med. 1989; 110: 357–364.PubMedGoogle Scholar
  92. 92.
    Bunn PA Jr, Browly J, Hazaka M, et al. The role of GM-CSF in limited stage SCLC: a randomized phase III study of the Southwest Oncology Group (SWOG). Proc Am Soc Clin Oncol. 1992; 11: 292 (abstract no 974).Google Scholar
  93. 93.
    Anasetti C, Anderson G, Applebaum FR, et al. Phase III study of rhGM-CSF in allogeneic marrow transplantation from unrelated donors. Blood. 1993; 82 (suppl 1): 454a (abstract no 1799).Google Scholar
  94. 94.
    Nash RA, Burstein SA, Storb R, et al. Thrombocytopenia in dogs induced by granulocyte-macrophage colony-stimulating factor: increased destruction of circulating platelets. Blood. 1995; 86: 1765–1775.PubMedGoogle Scholar
  95. 95.
    Smith J II, Longo D, Alvord W, et al. Thrombopoietic effects of IL-1 alpha in combination with high dose carboplatin. Proc Am Soc Clin Oncol. 1992; 11: 252 (abstract no 820a).Google Scholar
  96. 96.
    Tewari A, Buhles W Jr, Starnes HF Jr. Preliminary report: effects of interleukin-1 on platelet counts. Lancet. 1990; 336: 712–714.PubMedGoogle Scholar
  97. 97.
    Crown J, Jakubowski A, Kemeny N, et al. Phase I trial of recombinant human interleukin-1 beta alone and in combination with myeluppressive doses of 5-fluorouracil in patients with gastrointestinal cancer. Blood. 1991; 78: 1420–1427.PubMedGoogle Scholar
  98. 98.
    Tong J, Gordon MS, Srour EF, et al. In vivo administration of recombinant methionyl stem cell factor expands the number of human marrow hematopoietic stem cells. Blood. 1993; 82: 785–789.Google Scholar
  99. 99.
    Ganser A, Lindemann A, Seipelt G, et al. Effects of recombinant interleukin-3 in normal hemtopoiesis and in patients with bone marrow failure. Blood. 1990; 76: 1666–1667.Google Scholar
  100. 100.
    Ganser A, Seipert G, Lindemann A, et al. Effects of recombinant human interleukin-3 in patients with myelodysplastic syndromes. Blood. 1990; 76: 455–462.PubMedGoogle Scholar
  101. 101.
    Ottmann OG, Ganser A, Seipert G, et al. Effects of recombinant interleukin-3 on human hematopoietic progenitor and precursor cells in vivo. Blood. 1990; 76: 1494–1502.PubMedGoogle Scholar
  102. 102.
    Kurzrock R, Talpaz M, Estrov Z, Rosenblum MG, Gutterman JD. Phase I study of recombinant human interleukin-3 in patients with bone marrow failure. J Clin Oncol. 1991; 9: 1241–1250.PubMedGoogle Scholar
  103. 103.
    Postmus PE, Gietma JA, Damsma O, et al. Effects of recombinant interleukin-3 in patients with relapsed small cell lung cancer treatment with chemotherapy: a dose finding study. J Clin Oncol. 1992; 10: 1131–1140.PubMedGoogle Scholar
  104. 104.
    Biesma B, Willemse PH, Mulder NH, et al. Effects of interleukin-3 after chemotherapy for advanced ovarian cancer. Blood. 1992; 80: 1141–1148.PubMedGoogle Scholar
  105. 105.
    D’Hondt V, Weynants P, Humblet Y, et al. Dose-dependent interleukin-3 stimulation of throm-bopoiesis and neutropoiesis in patients with small-cell lung carcinoma before and following chemotherapy: a placebo-controlled randomized phase lb study. J Clin Oncol. 1993; 11:2063–2071.PubMedGoogle Scholar
  106. 106.
    Weber J, Yang JC, Topalian SL, et al. Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies. J Clin Oncol. 1993; 11: 499–506.PubMedGoogle Scholar
  107. 107.
    Gordon MS, Nemunaitis J, Hoffman R, et al. A phase I trial of recombinant human interleukin-6 on patients with myelodysplastic syndromes and thrombocytopenia. Blood. 1995; 85: 3066–3075.PubMedGoogle Scholar
  108. 108.
    Van Gameren MM, Willemse PH, Mulder NH. Effects of recombinant human interleukin-6 in cancer patients: a phase I-II study. Blood. 1994; 84: 1434–1444.PubMedGoogle Scholar
  109. 109.
    Veldhuis GJ, Willemse PH, Sleijfer DT, et al. Toxicity and efficacy of escalating dosages of recombinant human interleukin-6 after chemotherapy in patients with breast cancer or non-small cell lung cancer. J Clin Oncol. 1995; 13: 2585–2593.PubMedGoogle Scholar
  110. 110.
    D’Hondt V, Humblet Y, Guillaume T, et al. Thrombopoietic effects and toxicity of interleukin-6 in patients with ovarian cancer before and after chemotherapy: a multicentric placebo-controlled, randomized phase Ib study. Blood. 1995; 85: 2347–2353.PubMedGoogle Scholar
  111. 111.
    Gorden MS, Hoffman R, Battiato L, et al. Recombinant human interleukin-11 (NEUMEGA™ rhIL-11 growth factor, rhIL-11) prevents severe thrombocytopenia in breast cancer patients receiving multiple cycles of cyclophosphamide and doxorubicin chemotherapy. Proc Am Soc Clin Oncol. 1994; 13: 133, 1994 (abstract no 326a).Google Scholar
  112. 112.
    Orazi A, Cooper RJ, Tong J, et al. Effects of recombinant human interleukin eleven (NEUMEGA™rhIL-l 1 growth factor) on megakaryocytopoiesis in human bone marrow. Exp Hematol . 1996 (in press).Google Scholar
  113. 113.
    Elias L, Tepler I, Smith JW, et al. Randomized trial of recombinant human interleukin eleven (NEUMEGA™rhIL-11 growth Factor) in patients with severe chemotherapy-induced thrombocytopenia. Blood. 1995; 86: 1979 (abstract no 498a).Google Scholar

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  • Ronald Hoffman

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