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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of recombinant human G-CSF (rhG-CSF) and retinoic acid (RA) were studied on the proliferation and differentiation of HL-60 cells and human acute myeloid leukemic cells. Synergistic effect on granulocyte differentiation was observed when HL-60 cells and primary acute promyelocytic leukemic cells were cocultured with RA plus rhG-CSF. rhG-CSF combined with RA increased more significantly the percentage of mature cells than RA alone and greatly increased NBT reduction activity (P < 0.001). These results suggested that proliferated effect of rhG-CSF on leukemic cells may be important for inducing differentiation of myeloid leukemic cells. But this effect might expose the patients to the risk of acute myeloblastic leukemia if G-CSF was used alone. However, RA could not only rule out the latter situation but retain former merit as well. The authors suggest that the combined use of G-CSF with RA is probably a new approach to the treatment of leukemia.
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PMID:Recombinant human G-CSF and retinoic acid in synergistically inducing granulocyte differentiation of human promyelocytic leukemic cells. 128 43

A modified recombinant human granulocyte colony-stimulating factor (rhG-CSF), KW-2228, has some excellent properties such as high specific activity in stimulating granulocyte colony-formation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. Recently, the application of G-CSF against infectious diseases has been considered, and some animal experiments have been carried out to support its in clinical applications. Patients with underlying diseases such as leukemia or cancer often have recurrent infections because of reduced number and functions of neutrophils, which mediate an early stage of host defense. We investigated the prophylactic effect of KW-2228 against an experimental systemic infection with Pseudomonas aeruginosa in tumor-bearing mice (colon 26: BALB/c) treated with cyclophosphamide. KW-2228 (0.25-2.0 micrograms/mouse) was administered (s.c.) once a day for 4 days before the experimental bacterial infection. As a result of KW-2228 administration, the reduction in peripheral blood neutrophils usually caused by the injection with cyclophosphamide was prevented markedly. KW-2228 displayed excellent protective potency dose-dependently against the infection with P. aeruginosa in tumor-bearing mice. These data show the possibility that prophylactic therapy with KW-2228 may augment the host defense of immunocompromised patients to infections. It present, clinical efficacy studies on KW-2228 are under way.
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PMID:[Protective effect of KW-2228 in a systemic infection model of CPA-treated tumor-bearing mice]. 137 51

A modified recombinant human granulocyte colony-stimulating factor (rhG-CSF), KW-2228, has some excellent properties such as high specific activity in stimulating granulocyte colony-formation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. Recently, the application of G-CSF against infectious diseases has been considered, and some animal experiments have been carried out to support its clinical applications. Patients with underlying diseases such as leukemia and cancer often have recurrent infections because of reduced numbers or functions of neutrophils, which mediate an early stage of host defense. In out present study, we established a new method to evaluate in vivo potency of G-CSF in colon 26 tumor-bearing mice. By using the method, we examined combination effects of KW-2228 with aminoglycoside antibiotics against a systemic infection caused by Pseudomonas aeruginosa. KW-2228 (1 microgram/mouse/day) was administered (s.c.) once a day for 4 days before the bacterial infection was introduced in colon 26 tumor-bearing mice receiving cyclophosphamide 3 days after the transplantation of tumor. Antibiotics were administered (s.c.) 2 hours after the introduction of the bacterial infection. ED50 of gentamicin (GM) alone and that of the combination with KW-2228 were 40.7 mg/kg and 3.6 mg/kg, respectively. ED50 of astromicin (ASTM) alone and that of the combination with KW-2228 were 386 mg/kg and 17.8 mg/kg, respectively. Thus the combination therapy of KW-2228 with GM or ASTM exhibited excellent protective effects in comparison to the treatment with antibiotic alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Combination effect of KW-2228 and aminoglycoside antibiotics on systemic infection in cyclophosphamide-treated tumor-bearing mice]. 137 53

Non-adherent cord blood and bone marrow mononuclear cells were analyzed by multiparameter flow cytometry before and at day 2, 4, 7, and 11 of culture in recombinant interleukin 3 (IL-3) and granulocyte colony-stimulating factor (G-CSF, cord blood) or stem cell factor (SCF), IL3 and granulocyte-macrophage colony-stimulating factor (GM-CSF, BM) to assess the differentiation and maturational pathway of myeloid cells. Before cell culture cord blood contained progenitor cells (CD34+) in various differentiation stages (CD38(-)----CD38bright), mature lymphocytes, monocytes, and neutrophils, but no immature neutrophils and immature monocytes. During cell culture, all CD34+ cells acquired the CD38 antigen between day 2 and 5 of cell culture, the CD34 antigen was lost between day 5 and 11 of cell culture. Differentiation of cells into the myeloid cell lineage was characterized by the acquisition of both CD33 and CD71. The latter is indicative for the active proliferation of these cells. Maturation of the cells into the neutrophilic pathway was indicated by the acquisition of first the CD15 antigen followed by CD11b and CD16 respectively. Whereas maturation of the cells into the monocytic pathway was indicated by the acquisition of first CD11b followed by CD14 and a dim expression of both CD15 and CD16. In normal bone marrow, cells of various maturational stages are already present before cell culture. During cell culture differentiation of cells into the myeloid lineage and maturation of the cells along the monocyte and neutrophilic lineage followed identical pathways as was observed before cell culture. Differentiation and maturational pathways of cord blood and adult bone marrow were identical. The results confirm the surface-antigen-defined pathways of myeloid cell differentiation described previously for non-cultured normal bone marrow aspirates. The detailed assessment of cell maturation and differentiation of cultured cells by multidimensional flow cytometry permits the determination of the specific effects of various recombinant human growth factors on myeloid cells.
Leukemia 1992 Oct
PMID:Differentiation and maturation of growth factor expanded human hematopoietic progenitors assessed by multidimensional flow cytometry. 140 53

Studies on the structure of haemopoiesis in acute myeloblastic leukaemia (AML) has shown the presence of a small population of malignant cells with extensive proliferative and self-renewal properties which are features of stem cells. The requirements of these cells for proliferation have been studied both in clonogenic assays in semi-solid media and in liquid suspension culture. These have demonstrated that AML clonogenic cells from the majority of patients, can be stimulated to proliferate by colony-stimulating factors (GM-CSF, G-CSF and IL-3) as well as other cytokines including interleukin-1 and interleukin-6, all of which are known to stimulate normal haemopoietic progenitors. Unlike normal haemopoietic cells, leukaemic blasts from many patients with AML express transcripts for haemopoietic growth factors including GM-CSF, G-CSF and IL-1 but not IL-3, and secrete growth factor protein. When leukaemic cells are cultured at sufficiently high density to permit cell-cell interactions, autonomous growth of clonogenic cells can be seen. Autonomous growth is related to the autocrine secretion of haemopoietic growth factors including GM-CSF, G-CSF and IL-6. The degree of autonomous colony growth is variable but approximately 70% of AML samples exhibit either partial or totally autonomous growth; the remaining cells being absolutely dependent on exogenous CSF or fail to grow in the culture systems employed. Similar patterns of growth have been found in murine haemopoietic cells lines which have been transformed as the result of the retroviral insertion of genes for GM-CSF or IL-3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autocrine growth factors and leukaemic haemopoiesis. 142 83

Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) can have pleiotropic effects on different cell types. M1 myeloid leukaemic cells respond to IL-6 with activation of a terminal differentiation programme which includes activation of genes for certain haemopoietic regulatory proteins (IL-6, IL-1 alpha, IL-1 beta, granulocyte-macrophage colony-stimulating factor [GM-CSF], M-CSF, tumour necrosis factor and transforming growth factor [TGF] beta 1) and for receptors for some of these proteins, thus establishing a network of positive and negative regulatory cytokines. IL-6 and some other cytokines also induce during differentiation sustained levels of transcription factors that can regulate and maintain gene expression in the differentiation programme. M1 leukaemic cells induced to differentiate with IL-6 undergo programmed cell death (apoptosis) on withdrawal of IL-6, and can be rescued from apoptosis by IL-6, IL-3, M-CSF, G-CSF or IL-1, but not by GM-CSF. These differentiating leukaemic cells can also be rescued from apoptosis by the tumour promoter TPA (12-O-tetradecanoylphorbol-13-acetate) but not by the non-tumour-promoting isomer 4-alpha-TPA, and rescue from apoptosis can be achieved by different pathways. Apoptosis can also be induced in undifferentiated M1 leukaemic cells by expression of the wild-type form of the tumour suppressor p53 protein and IL-6 can rescue the cells from this wild-type p53-mediated apoptosis. There are clones of M1 cells that differentiate with IL-6 but not with LIF and another M1 clone that differentiates with either IL-6 or LIF. Differentiation induced by IL-6 or LIF is inhibited by TGF-beta 1. The pleiotropic effects of LIF, like those of IL-6, are presumably also in a network of interacting regulatory proteins.
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PMID:Regulation of leukaemic cells by interleukin 6 and leukaemia inhibitory factor. 142 20

Myeloid leukemia development requires the acquisition by a cell of two abnormalities: an abnormal capacity for self-replication; and a capacity for autocrine stimulation, usually involving the known growth factors for granulocyte-macrophage cells. Curiously, in human leukemia, this does not usually result in autonomous growth when assessed in clonal in vitro cultures. Depending on gene programming, in particular in human or murine myeloid leukemias, the hemopoietic growth factors can also suppress the leukemic population by inhibiting the capacity of the leukemic stem cells for self-generation. The regulator showing the highest suppressive activity varies from leukemia to leukemia, with G-CSF. GM-CSF, IL-6, or leukemia-inhibitory factor (LIF) all having high activity on appropriate target cells. Combinations of these regulators are more effective than single agents alone. Analyses of human HL60, U937 and murine M1 leukemic models indicate that the development of morphological maturation in the leukemic cells is not a necessary feature of stem-cell suppression. LIF has an anomalous action on stem-cell self-generation, being highly effective in the suppression of certain myeloid leukemic cell lines, but being necessary to maintain self-generation in normal embryonic cells. This suggests the existence of a common control medium governing self-generation decisions in cells of different lineages, but that the outcome of the decision is determined by the differentiation program operating in different cells. The colony-stimulating factors are being used in combination with chemotherapy in the treatment of patients with acute myeloid leukemia, but the above principles require caution in certain situations.
Leukemia 1992
PMID:Role of hemopoietic growth factors in the development and suppression of myeloid leukemia. 160 21

Thuja polysaccharide g fraction (TPSg) was shown to be an inducer of the CD4+ fraction of the human peripheral blood T-cell subset (1,2). Furthermore, it could be demonstrated that TPSg is a potent inhibitor of the expression of HIV-1-specific antigens and of the HIV-1-specific reverse transcriptase (3). This report deals with the cytokine pattern induced by TPSg in human peripheral blood lymphocyte (PBL) and purified monocyte/macrophage cultures. In addition, a further characterization of the CD4+ T-cell fraction stimulated by TPSg was performed by FACS analysis. TPSg is induces IL-1 beta, IL-2, IL-3, IL-6, gamma-IFN, G-CSF, GM-CSF, and TNF-beta production in PBL cultures; and IL-1 beta and IL-6 in monocyte/macrophage cultures. Enzyme-linked immunosorbent assays (ELISAs) demonstrated that no IL-4 was produced by PBL cultures under TPSg influence.
Leukemia 1992
PMID:Mitogenic activity of high molecular polysaccharide fractions isolated from the cuppressaceae Thuja occidentalis L. enhanced cytokine-production by thyapolysaccharide, g-fraction (TPSg). 160 22

The binding of haemopoietic growth factors and cytokines to specific receptors triggers a cascade of intracellular events which results in cell proliferation and differentiation. The knowledge of ligand-receptor-signal pathways is not only important in understanding the pathophysiology of malignant disease but also essential for devising future therapeutic strategies. The advent of recombinant technology has made it possible to test the efficacy of selective differentiation therapy, and haemopoietic growth factors are undergoing clinical trials for a number of indications. In addition, increasingly the receptors for haemopoietic growth factors and cytokines have come under scientific scrutiny. Recently receptors for IL-2 alpha, IL-2 beta, IL-3, IL-4, IL-5, IL-6, IL-7, erythropoietin, G-CSF and GM-CSF have been isolated and cloned. It has become apparent that they have structural homology that is shared by receptors for growth hormone and prolactin, and this receptor group makes up the new cytokine receptor superfamily. The finding of sequence homology within these receptors suggests their evolutionary relationship. These receptors are transmembrane proteins 257-856 amino acids and their extracellular ligand-binding domain contains four conserved cysteine residues and a Trp-Ser-X-Trp-Ser motif. The secondary structure of the extracellular domain is made up of alpha-helices. High and low affinity binding forms exist for all these receptors. Binding affinity may depend on the formation of receptor heterodimers or multimers, association with other membrane proteins or differential glycosylation. Soluble receptor forms have been described for IL-2 alpha, IL-4, IL-5, IL-6 and IL-7. It is not known whether they are actively secreted or represent the degradation products of cell turnover. Their function may be to mop up excess cytokines and thereby confine the cytokine response. There is no sequence homology of the intracytoplasmic domains although several are rich in proline and serine residues, which may be important in mechanisms of signal transduction. No receptor in this superfamily functions as a receptor tyrosine kinase or has intrinsic protein tyrosine kinase activity. Detailed study of individual receptors holds clues to the regulation of receptor expression, ligand-receptor interactions and mechanisms involved in signal transduction. Such knowledge might explain the pleotropic effects cytokines may have on different cell types and their overlap in biological functions. Elevated levels of soluble IL-2 alpha receptor (Tac) are detected in hairy cell leukaemia, lymphomas and adult T-cell leukaemia (TL), and levels reflect tumour burden.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The cytokine receptor superfamily. 166 10

In this study we demonstrate that tumor necrosis factors (TNF alpha and TNF beta) are potent modulators of the in vitro proliferation of human AML cells. Blast cells from 11 cases of acute myeloblastic leukemia (AML) were incubated with recombinant TNF alpha or TNF beta in serum-free 3H-TdR uptake and colony culture systems in the presence or absence of recombinant interleukin-3 (IL-3), granulocyte macrophage colony-stimulating factor (GM-CSF), G-CSF, or M-CSF. Depending on the supplemented CSF, TNF could upregulate or suppress AML blast proliferation. Enhancement of AML growth by TNF was observed in the presence of IL-3 (in 9 of 11 cases in 3H-TdR assay; 6 of 9 cases in colony assay) and GM-CSF (in 8 of 11 cases in 3H-TdR assay; 4 of 9 cases in colony assay). In certain cases in which IL-3 or GM-CSF alone was unable to induce proliferative responses of AML cells, the simultaneous addition of TNF elicited colony growth and DNA synthesis suggesting a synergistic action between TNF and IL-3 or GM-CSF. In contrast, TNF suppressed G-CSF-induced growth (9 of 10 cases in 3H-TdR assay; 5 of 6 cases in colony assay). TNF could also stimulate DNA synthesis (in 2 of 11 cases) or colony formation (in 2 of 9 cases) in AML cultures without the addition of other growth factors. Experiments with neutralizing antibodies and specific radioimmunoassays for individual CSFs showed that the synergistic and antagonistic effects of TNF on AML growth could not be attributed to a release of one of these CSFs by the AML cells. The opposing consequence of exposure of AML blasts to TNF are of interest in view of our understanding of the pathophysiology of AML growth and the in vivo application of recombinant cytokines in AML patients.
Leukemia 1990 Jan
PMID:Modulation of colony stimulating factor-(CSF) dependent growth of acute myeloid leukemia by tumor necrosis factor. 168 38


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