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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hemolymphopoietic growth factors, including the colony-stimulating factors (CSF) and interleukins (IL), are described and categorized on the basis of their biological features in laboratory systems. Although these agents are varied and exceptions exist, in general they lack lineage specificity although they may express lineage-predominant activity. They act at multiple levels of hemolymphopoietic cell differentiation, demonstrate additive or synergistic effects when combined in vitro, require surface receptors on target cells to directly express their activity, and may be produced by a variety of cells. This framework of behavioral generalizations, completed by the specifics of each factor's activity, despite the artifactual and simplified nature of in vivo systems, forms the basis for concepts of in vitro activity and for clinical applications. Hemolymphopoietic growth factors studied in the clinic have demonstrated impressive and important activity, validating much of the in vitro data. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have clearly reduced neutropenia and infection rates when administered following conventional chemotherapy and high-dose chemotherapy followed by autologous bone marrow transplantation. To a varying degree, similar results with G-CSF and/or GM-CSF have been described in other diseases including acute myelogenous leukemia (AML) treated following induction chemotherapy, myelodysplastic syndrome, hairy cell leukemia, aplastic anemia, and chronic neutropenias. In preliminary studies IL-3 has been shown to have similar qualitative activities. However, these agents have not demonstrated a reproducible salutary impact on platelet or red cell lineages. Adverse effects on platelet counts and/or platelet recovery have been noted. Additionally, hemolymphopoietic growth factor receptors have been identified on malignant cells, suggesting that these factors could stimulate neoplastic growth. Studies with GM-CSF and IL-3 have demonstrated blast proliferation in some cases of AML and myelodysplasia, underscoring the capacity of these agents to stimulate the growth of myeloid leukemia. No clinically evident impact of these factors upon the growth of solid tumors has been identified but this issue has not been adequately studied. The toxicity of these agents has been surprisingly limited and appears to be related to their biologic activities. Hemolymphopoietic growth factors as single agents have broad clinical applications in cytopenias. Several methods for enhancing the clinical activity of these agents are under study, including the use of combinations of growth factors synergistic in vitro.
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PMID:Recombinant human hematopoietic growth factors in the treatment of cytopenias. 172 85

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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PMID:Granulocyte-macrophage colony-stimulating factor and interleukin-3 in combination: a potent and consistent myelodysplastic syndrome bone marrow stimulant in vitro. 175 90

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor that stimulates myeloid cell proliferation and maturation and enhances the function of terminally differentiated effector cells. Phase I and II clinical trials have demonstrated mild to moderate toxicities at doses of less than 30 micrograms/kg/day. These studies suggest a potential role for this growth factor to stimulate myelopoiesis in patients with aplastic anemia, myelodysplastic syndromes, AIDS, chemotherapy-induced myelosuppression, chronic neutropenia, and following bone marrow transplantation. The potential clinical uses of GM-CSF will depend on results of studies designed to optimize its therapeutic efficacy.
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PMID:Clinical applications of human granulocyte-macrophage colony-stimulating factor. 177 Feb 27

We have established a new nonlymphoid leukemic cell ine from a patient with myelodysplastic syndrome (MDS), which progressed to overt leukemia. The parental cell line and a subline derived from this line have absolute dependency on several cytokines for their long-term survival and growth. The parental line designated F-36P requires granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) for continuous growth, while a subline designated F-36E can be maintained in the presence of erythropoietin (Epo) alone. When these cytokines are depleted, both the parental and the subline cells die within several days, even in medium supplemented with fetal calf serum (FCS). F-36E, maintained in the presence of Epo, constitutively synthesizes hemoglobin at a significant level. F-36P, which is usually maintained in the presence of GM-CSF or IL-3, can be induced to synthesize hemoglobin when GM-CSF or IL-3 is substituted by Epo. The surface marker profile shows that the F-36P cells are positive for the leukocyte common antigen (CD45) and some common multilineage markers such as CD13, CD33, and CD34, and negative for T- and B-cell antigens and mature myelomonocytic antigens. However, some monoclonal antibodies recognizing erythroid and platelet glycoproteins react with these cells. Thus, this cell line has a multilineage phenotype, suggesting that the transformation event occurred in a multipotent stem cell. It is also evident that the F-36 cells can be induced to differentiate into the erythroid lineage in the presence of Epo. This, to our knowledge, is the first description of a human leukemic cell line that can be stimulated to synthesize hemoglobin by Epo.
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PMID:Establishment and erythroid differentiation of a cytokine-dependent human leukemic cell line F-36: a parental line requiring granulocyte-macrophage colony-stimulating factor or interleukin-3, and a subline requiring erythropoietin. 183 51

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifunctional haematopoietin which can promote production of several blood cell lineages, though the predominant target cells are neutrophils, monocytes, and their precursors. Occasional undesirable clinical effects include eosinophilia, an increase in blasts, or thrombocytopenia. Here, we describe four patients who were treated with GM-CSF, at subcutaneous doses significantly lower than are conventional, and experienced an unusual response pattern. Three patients had severe pancytopenia associated with chronic lymphocytic leukaemia (CLL) or myelodysplastic syndrome (MDS) and exhibited an unexpected switch in the responsive lineage on high- versus very low-dose therapy. The two CLL patients developed marked eosinophilia (up to 10.0 x 10(9) cells/l) without an increase in neutrophils on 125-300 micrograms/m2/d of GM-CSF. In contrast, when the dose was lowered to 10 micrograms/m2/d, the neutrophils rose to physiological levels, without significant eosinophilia. The MDS patient showed a rapid rise in peripheral blasts (baseline level = 0; post-therapy level = 5.0 x 10(9)/l), without a change in other cell types, when receiving 60 micrograms/m2/d of GM-CSF. After GM-CSF was held, blasts returned to baseline levels; reinstituting therapy at the very low dose of 6 micrograms/m2/d was followed by an increase in platelet counts from 50 to 185 x 10(9)/l with only a minor increase in blasts. The fourth patient, who suffered from severe aplastic anaemia complicated by recurrent gastrointestinal haemorrhage, was only treated with the low-dose regimen. He showed a predominant platelet effect with counts rising from 9 to 169 x 10(9)/l. Very low-dose GM-CSF therapy was devoid of constitutional side effects. The biological implications of these GM-CSF responses are discussed. Our results indicate that, in some patients, GM-CSF may stimulate different target cells depending on the dose. Therefore, in contrast to the results of administration of many classical drugs, there may not always be a direct relationship between the amount of GM-CSF given and the optimal effect.
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PMID:Differential dose-related haematological effects of GM-CSF in pancytopenia: evidence supporting the advantage of low- over high-dose administration in selected patients. 187 20

Interleukin-1 (Il-1) and Interleukin-6 (Il-6) have been reported to enhance the growth factor dependent colony formation of normal primitive haematopoietic progenitor cells as well as of leukaemic blast-cell progenitors. We investigated the effects of Il-1 beta and Il-6 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) on the in vitro colony formation of myeloid progenitors from 23 patients with a myelodysplastic syndrome (MDS). Neither Il-1 beta nor Il-6 were found to have colony stimulating activity on their own. In normal bone marrow cultures, either stimulated with optimal or suboptimal doses of GM-CSF, no enhancing or antagonistic effect of Il-6 or Il-1 beta was detected. In a majority of the MDS cases, however, an enhancing effect of Il-6 and Il-1 beta in combination with GM-CSF was observed (20/23 and 10/21 cases respectively). In three cases of the Il-6 and GM-CSF combination an antagonistic effect was observed as well as in four cases of the Il-1 beta and GM-CSF combination. A delayed addition of Il-6 to the cultures did not result in an abrogation of the effect, indicating that Il-6 is not required immediately at the initiation of the culture. These results indicate that costimulation with Il-6 or Il-1 beta is able to augment the GM-CSF activity on MDS myeloid progenitor cells.
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PMID:Interleukin-6 and interleukin-1 enhancement of GM-CSF-dependent proliferation of haematopoietic progenitor cells in myelodysplastic syndromes. 202 77

Recombinant technology has been harnessed to produce sufficient quantities of colony-stimulating factors (CSFs)--also known as hematopoietic growth factors--to make clinical trials with these agents possible. Endogenous CSFs are hormone-like glycoproteins that bind to receptors on target cells and stimulate processes within these cells that mediate their proliferation, maturation, differentiation, and functional activation. Several such CSFs cloned by recombinant DNA technology now are being tested clinically. Some are multilineage growth factors, such as interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which tend to affect cells early in the hematopoietic hierarchy. Others, such as granulocyte colony-stimulating factor (G-CSF), primarily stimulate the formation of neutrophilic granulocytes. Macrophage CSF predominantly affects monocytes/macrophages. These are late-stage, single-lineage growth factors. Numerous clinical trials with all of these agents are under way. The granulopoietic agents, including GM-CSF and G-CSF, are being tested for their potential use in preventing or ameliorating myelosuppression related to AIDS, antineoplastic chemotherapy, bone marrow transplantation, myelodysplastic syndromes, and aplastic anemia. Clinical trial results on G-CSF and GM-CSF are encouraging thus far. However, it is too early to characterize the effects of IL-3, which is just entering clinical trials.
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PMID:Future strategies in the control of myelosuppression: the use of colony-stimulating factors. 204 96

The primary objective of this study was to compare the toxicity and hemopoietic effects of s.c. and i.v. recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in patients with primary myelodysplasia. Twenty patients were treated in this phase I crossover-designed study. In three groups of patients, the dose of rhGM-CSF was escalated from 60 to 250 micrograms/m2/day. Each patient was to receive 2 weeks of i.v. (daily 2-h infusion) and s.c. (twice daily) rhGM-CSF separated by a 2-week rest period. The decision to start with i.v. or s.c. administration was by random selection. Toxicity was comparable between i.v. and s.c. administration. At the highest dose level, 63% (five of eight) of the patients developed moderate to severe toxicity. Increases in the absolute neutrophil count showed a dose-response relationship and were more pronounced with s.c. than i.v. administration. Failure to grow in vitro granulocyte-macrophage colonies or a hypocellular marrow (less than or equal to 30%) predicted for a poor response to therapy. No patient had a platelet or a reticulocyte response. No patient progressed to acute leukemia. Compared to a 2-h infusion of i.v. rhGM-CSF, s.c. administration is more myelostimulatory without an increase in toxicity.
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PMID:Comparison of intravenous versus subcutaneous recombinant human granulocyte-macrophage colony-stimulating factor in patients with primary myelodysplasia. 205 92

The colony-stimulating factors (CSF) are a class of glycoprotein hormones that regulate the production and function of blood cells. Human sequences encoding four of the factors active on myeloid cells--granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-3 (IL-3)--have been molecularly cloned and the biosynthetic (recombinant) products introduced into clinical trials. Sufficient clinical data have accumulated regarding G-CSF and GM-CSF to allow insight into their potential use in clinical practice. Both molecules have shown some impact in the prevention of chemotherapy-induced neutropenia and in the treatment of cytopenias associated with myelodysplastic syndromes and aplastic anemia. G-CSF has shown promise in the treatment of congenital and idiopathic neutropenias.
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PMID:The colony-stimulating factors: biology and clinical use. 214 19

An increasing amount of data provides strong evidence for the complex multifactorial control of primary hemopoietic functions. Here we present a new multicellular functional unit, the Hematon, isolated from the light-density floating fraction of normal human bone marrow (BM) aspirates. The Hematon is organized in a compact, three-dimensional spheroid complex from central adipocytes, fibroblastoid cells, and resident macrophages that compartmentalize myeloid, erythroid, and megakaryocyte progenitor cells and their progenies. The Hematon fraction is more than twofold more abundant in progenitor cells when compared to the mononuclear cell (MNC) fraction as gauged by cytological techniques and by analysis of granulocyte-macrophage colony-forming unit (GM-CFU) populations. Individual Hematons may produce, within 2-3 weeks, up to 50,000 hemopoietic cells of different cell lineages in organotypic microcultures. Recombinant human hematopoietic growth factors interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF) significantly stimulated the endogenous cell production of some but not all of the individually treated Hematons, indicating the heterogeneity of factor-responsive cells within the Hematon population. Comparative observations of 184 BM aspirates support the hypothesis that the presence of Hematons in a BM aspirate correlates positively with homeostatic blood cell production, because the Hematon was present in normal BM (31/40) and it was rare among patients with myelodysplastic syndromes (15/53), acute myeloblastic leukemia (7/39), and chronic myelocytic leukemia (5/52). We suggest that the Hematon represents a unifying model around which the variability of fundamental BM functions and dysfunctions can be explored.
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PMID:Hematon, a multicellular functional unit in normal human bone marrow: structural organization, hemopoietic activity, and its relationship to myelodysplasia and myeloid leukemias. 218 30


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