Summary
In an effort to overcome bone marrow failure in myelodysplastic syndrome (MDS), we have investigated recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in phase I–II clinical trials. Although these agents partially increased peripheral blood granulocyte counts, their effect on other hematopoietic lineages was generally sporadic. Since in vitro analysis and in vivo studies in primates indicate that GM-CSF and IL-3 synergistically enhance hematopoietic stem cell proliferation, we evaluated their combined effect on marrow progenitors obtained from ten MDS patients. When used singly, each growth factor stimulated replication of granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) colony-forming cells in a dose-dependent fashion. When colony-stimulating activity was compared at concentrations that maximally amplified individual MDS patients' colony numbers, IL-3 was a more potent stimulant in some patients and GM-CSF in others. When used in combination, IL-3 plus GM-CSF was more effective than each growth factor by itself in five of six patients. Our data indicate that the MDS hematopoietic progenitor stimulatory effect of these growth factors varies from patient to patient. However, the combination of GM-CSF and IL-3 appears to be more potent than the individual molecules in the majority of patients
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Antin JH, Smith BR, Holmes W, Rosenthal DS (1988) Phase I/II study of recombinant human granulocyte-macrophage colony-stimulating factor in aplastic anemia and myelodys-plastic syndrome. Blood 72: 705–713
Aye MT, Niho Y, Till JE, McCulloch EA (1974) Studies of leukemia cell populations in culture. Blood 44: 205–219
Bennet JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnik HR, Sultan C (1982) Proposal for the classification of the myelodysplastic syndromes. Br J Haematol 51: 189–199
Broxmeyer HE, Cooper S, Williams DE, Hangoc G, Gutterman JU, Vadhan-Raj S (1988) Growth characteristics of marrow hematopoietic progenitor/precursor cells from patients on a phase-I clinical trial with purified recombinant human granulocyte-macrophage colony-stimulating factor. Exp Hematol 16: 594–602
Budel LM, Elbaz O, Hoogerbrugge H, Deiwel R, Mahmoud LA, Löwenberg B, Touw IP (1990) Common binding structure for granulocyte macrophage colony-stimulating factor and interleukin-3 on human acute myeloid leukemia cells and monocytes. Blood 75: 1439–1445
Emerson SG, Yang Y-C, Clark SC, Long MW (1988) Human recombinant granulocyte-macrophage colony-stimulating factor and interleukin-3 have overlapping but distinct hematopoietic activites. J Clin Invest 82: 1282–1287
Estey E, Kurzrock R, Talpaz M, Deisseroth A, Gutterman J (1989) Treatment of myelodysplastic syndromes with GM-CSF ± ara-C. Blood 74: 236a (abstract)
Estrov Z, Grunberger T, Chan HSL, Freedman MH (1986) Juvenile chronic myelogenous leukemia: characterization of the disease using cell cultures. Blood 76: 1382–1387
Fauser AA, Messner HA (1978) Granuloerythropoietic colonies in human bone marrow, peripheral blood, and cord blood. Blood 52: 1243–1248
Ganser A, Seipelt G, Lindemann A, Ottmann OG, Falk S, Eder M, Herrmann F, Becher R, Höffken K, Büchner T, Klausmann M, Frisch J, Schulz G, Mertelsmann R, Hoelzer D (1989) Effects of recombinant human interleukin-3 in patients with myelodysplastic syndromes. Blood 76: 455–462
Ganser A, Volkers B, Greher J, Ottmann OG, Walther F, Becher R, Bergmann K, Schulz G, Hoelzer D (1989) Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes — a phase I/II trial. Blood 73: 31–37
Geissler K, Valent P, Mayer P, Liehl E, Hinterberger W, Lechner K, Bettelheim P (1989) Recombinant human interleukin-3 expands the pool of circulating hemopoietic progenitor cells in primates — synergism with recombinant human granulocyte/ macrophage colony-stimulating factor. Blood 75: 2305–2310
Jandl JH (1987) In: (ed) Blood, Textbook of Hematology. Little, Brown, Boston, pp 612–620
Kannourakis G, Johnson GR (1990) Proliferative properties of unfractionated, purified, and single-cell human progenitor populations stimulated by recombinant human interleukin-3. Blood 75: 370–377
Kessler SW, Clark SC, June CH (1989) Primary response of purified human hematopoietic progenitor cells to recombinant growth factors. Blood 74 [Suppl 1]: 148a (abstract)
Kurzrock R, Talpaz M, Estrov Z, Rosenblum M, Gutterman JU (1989) Phase-I study of recombinant human interleukin-3 in patients with bone marrow failure. J Clin Oncol 9: 1241–1250
McNiece IK, Stewart FM, Deacon DM, Quesenberry PJ (1988) Synergistic interactions between hematopoietic growth factors as detected by in vitro mouse bone marrow colony formation. Exp Hematol 16: 383–388
Messner HA, Fauser AA (1980) Culture studies of human pluripotent hemopoietic progenitors. Blut 41: 327–333
Negrin RS, Haeuber DH, Nagler A, Olds LC, Donlon T, Souza LM, Greenberg PL (1989) Treatment of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor. Ann Intern Med 110: 976–984
Park LS, Waldron PW, Friend D, Sassenfeld HM, Price V, Anderson D, Cosman D, Andrews RG, Berstein ID, Urdal DL (1989) Interleukin-3, GM-CSF, and G-CSF receptor expression on cell lines and primary leukemia cells: receptor heterogeneity and relationship to growth factor responsiveness. Blood 74: 56–65
Quesenberry PJ (1986) Synergistic hematopoietic growth factors. Int J Cell Clon 4: 3–15
Schipperus MR, Vink N, Sommeveld P, Lindemans J, Abels J (1989) Interleukin-2 enhances the granulocyte colonystimulating factor-induced proliferation of hematopoietic progenitor cells in myelodysplastic syndromes. Blood 74 [Suppl 1]: 202 (abstract)
Shaw GM, Levy PC, LoBuglio AF (1978) Human monocyte antibody-dependent cell-mediated cytotoxicity to tumor cells. J Clin Invest 62: 1172–1180
Sonoda Y, Yang Y-C, Wong GG, Clark SC, Ogawa M (1988) Analysis in serum-free culture of the targets of recombinant human hemopoietic growth factors: interleukin-3 and granulocyte/macrophage colony-stimulating factor are specific for early developmental stages. Proc Natl Acad Sci USA 85: 4360–4364
Thompson JA, Lee DJ, Kidd P, Rubin E, Kaufmann J, Bonnem EM (1989) Subcutaneous granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects. J Clin Oncol 7: 629–637
Vadhan-Raj S, Keating M, LeMaistre A, Hittelman WN, McCredie K, Trujillo JM, Broxmeyer HE, Henney C, Gutterman JU (1988) Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. N Engl J Med 31: 1545–1552
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Research conducted, in part, by the Clayton Foundation for Research; J.U.G. is a senior Clayton Foundation investigator
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Estrov, Z., Kurzrock, R., Talpaz, M. et al. Granulocyte-macrophage colony-stimulating factor and interleukin-3 in combination: A potent and consistent myelodysplastic syndrome bone marrow stimulant in vitro. Ann Hematol 63, 297–301 (1991). https://doi.org/10.1007/BF01709650
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DOI: https://doi.org/10.1007/BF01709650