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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction of colony-stimulating factors (CSF) and retinoic acid (RA) in the proliferation and differentiation of HL-60 cells was examined. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated the proliferation of HL-60 cells in a dose-dependent manner at concentrations of 0.01-100 ng/ml; however, the proliferation due to GM-CSF was suppressed by 100 nM RA. Granulocyte colony-stimulating factor (G-CSF) slightly stimulated the proliferation of HL-60 cells at concentrations above 10 ng/ml. Neither G-CSF nor GM-CSF alone induced 12-o-tetra-decanoyl-phorbol-13-acetate (TPA)- or N-formyl-methionyl-phenylalanine (FMLP)-stimulated nitro-blue tetrazolium (NBT) reduction at concentrations of 0.01-100 ng/ml. G-CSF induced TPA- and FMLP-stimulated NBT reduction in the presence of 100 nM RA, but GM-CSF induced only TPA-stimulated NBT reduction. RA in addition to G-CSF synergistically increased FMLP binding to HL-60 cells, accompanied by increased NBT reduction in response to FMLP. RA in addition to GM-CSF markedly increased FMLP binding to HL-60 cells more than that induced by RA alone, but the combined treatment with RA and GM-CSF did not increase FMLP-stimulated NBT reduction more than that induced by RA alone. The results suggest that G-CSF stimulates RA-induced morphological and functional differentiation of HL-60 cells, but the differentiation-enhancing effects of GM-CSF are limited, whereas the growth-stimulating effect of GM-CSF on HL-60 cells is greater than that of G-CSF.
Leukemia 1991 Jan
PMID:Granulocyte colony-stimulating factor, not granulocyte-macrophage colony-stimulating factor, co-operates with retinoic acid on the induction of functional N-formyl-methionyl-phenylalanine receptors in HL-60 cells. 170 36

The regulation of haemopoiesis in myelodysplastic syndromes (MDS) was evaluated by measuring and comparing the in vitro response of marrow progenitors from 18 MDS patients to stimulation with recombinant haemopoietic growth factors (HGFs), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF) and interleukin-3 (IL-3). A similar pattern of colony growth was detected with all three HGFs in most MDS patients, exhibiting subnormal growth of GM-CFU and markedly poor to absent growth of BFU-E and CFU-GEMM. A common severe impairment in the growth of all colony types with all three HGFs was observed in five patients, four of whom presented with pancytopenia. The stimulation of MDS marrow progenitors with a five-fold higher than control saturating dose of HGFs induced a significant increase in the frequency of one, two, or all three colony types in cultures of 14 patients, whereas colony numbers in control (n = 8) marrow cell cultures were not significantly changed. All four of the non-responders were pancytopenic and three exhibited markedly impaired colony growth. Supersaturating GM-CSF, G-CSF and IL-3 increased GM-CFU numbers in six, three, and three patients, respectively. The values for BFU-E were three, six, and seven and for CFU-GEMM two, one, and five. The enhancement of MDS marrow colony numbers by supersaturating HGFs which exert their effects directly or via the action of marrow accessory cells, suggests that the progenitor cell growth abnormalities in these disorders may involve a defect in the capacity of accessory and/or progenitor cells to respond to stimulation with specific haemopoietic growth regulators.
Leukemia 1991 Apr
PMID:Impaired response of myelodysplastic marrow progenitors to stimulation with recombinant haemopoietic growth factors. 170 45

The effects of human recombinant colony-stimulating factors (r-CSFs), interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on inducing the growth of colonies derived from patients with acute myeloid leukemia (AML) (CFU-L) were investigated and compared to the proliferative response of CFU-GM derived from highly enriched normal blast cell populations. The effects of GM-CSF and IL-3 alone were similar. Both only minimally stimulated normal colonies derived from CFU-GM when compared to stimulation with MoCM (a mean of 28% of the total colonies and 17% of the colonies greater than 100 cells obtained with MoCM). Similarly, the number of leukemic colonies was substantially less than with MoCM (less than 30% of MoCM) in all but 3/10 AML patients and both were only able to significantly stimulate CFU-L derived colonies greater than 50 cells from 2/10 patients. G-CSF alone stimulated some CFU-L derived colony growth in 9/10 patients but the number stimulated was minimal relative to MoCM in five of the patients and significant stimulation of colonies greater than 50 cells occurred in only one patient. The mean number of normal CFU-GM derived colonies stimulated by G-CSF was 41% of the total colonies and 34% of the colonies greater than 100 cells generated by MoCM. The combination of G-CSF with GM-CSF and G-CSF with IL-3 resulted in a synergistic or additive increase in the number of CFU-L in 5/10 and 7/10 patients, respectively, and a synergistic increase in the size of CFU-L in 5/10. The same combinations resulted in a significant synergistic effect on size of normal CFU-GM derived colonies. There was no evidence of a synergistic increase in the number or size of CFU-L and CFU-GM derived colonies stimulated with GM-CSF in combination with IL-3. In addition, a combination of all three (G-CSF + GM-CSF + IL-3) did not enhance the effect of G-CSF + GM-CSF or G-CSF + IL-3. These results suggest that there is significant heterogeneity among AML patients in the pattern of responsiveness of the leukemic cells to the recombinant growth factors. In addition, their responsiveness does not significantly differ from that of normal progenitors. In view of the current clinical trials with r-CSFs and cytotoxic drugs in AML patients, this issue is important and worthy of further investigation.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1991 May
PMID:Proliferative response of human acute myeloid leukemia cells and normal marrow enriched progenitor cells to human recombinant growth factors IL-3, GM-CSF and G-CSF alone and in combination. 170 11

The effects of the inhibitor for protein kinase A or C, or tyrosine kinase (H-8, staurosporine, or genistein, respectively) on the proliferation of leukemic and normal bone marrow cells stimulated by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interleukin-3 (IL-3) were studied using the MTT assay. These inhibitors suppressed the proliferation of leukemic and normal bone marrow cells in a dose-dependent manner. Although the suppressive effect of each inhibitor on cell proliferation was varied in each instance, the effects were almost similar whichever CSF was added. A significant difference was not recognized between leukemic and normal bone marrow cells in terms of sensitivity to these inhibitors. The data indicate that protein kinase inhibitors have an inhibitory effect on leukemic and normal hematopoietic cell proliferation and that further studies are required to determine if this effect is due to the inhibition of protein kinases acting as the second messenger of CSFs.
Leukemia 1991 Sep
PMID:Effect of protein kinase inhibitors on the proliferation of leukemic cells stimulated by granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor or interleukin-3. 171 9

The treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with high dose cytosine arabinoside (ara-C) results in short-lived complete response rates of 30-50%. We have previously shown that entry of myeloid leukemic cells into S phase can be accelerated in vitro through the use of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), resulting in enhancement of ara-C-mediated cytotoxicity. In order to evaluate the in vivo biological and clinical effects of this strategy in patients with high risk AML, we treated three patients with either refractory or relapsed disease with a continuous infusion of rhGM-CSF (0.45 micrograms/kg/h aglycoprotein) for 18 h, followed by the institution of high dose ara-C and continuation of rhGM-CSF throughout the 4 day duration of ara-C treatment. Prior to therapy, no patient had detectable levels of circulating rhGM-CSF, and there was no evidence of GM-CSF receptor occupancy in leukemic myeloblasts. After 18 h of rhGM-CSF therapy, all patients had biologically active levels of circulating rhGM-CSF (7.9-12.0 ng/ml), and two patients showed a significant degree of leukemic GM-CSF receptor occupancy without evidence of GM-CSF receptor down-regulation. A significant rise in the S phase fraction of leukemic myeloblasts was observed at 18 h of rhGM-CSF treatment in all three patients (29-56% increment). The toxicity of combined rhGM-CSF/ara-C therapy included pericarditis and cerebellar degeneration in one patient, fever and mild renal dysfunction in two patients, and mild hepatic dysfunction in all three patients. Each patient showed a transient rise in the absolute neutrophil and blast count during rhGM-CSF/ara-C administration, followed by profound, but clinically tolerable, myelosuppression. No patient developed clinical evidence of leukostasis. There was one death related to pericardial tamponade, one death related to refractory disease, and one clinical and cytogenetic remission. These results suggest that exogenously administered rhGM-CSF is capable of rapidly mobilizing leukemic cells into S phase in vivo and theoretically should be useful in overcoming kinetic resistance to ara-C. Clinical trials of this regimen in patients with high risk AML who are not already pharmacologically resistant to ara-C are warranted.
Leukemia 1991 Mar
PMID:Simultaneous administration of granulocyte-macrophage colony-stimulating factor and cytosine arabinoside for the treatment of relapsed acute myeloid leukemia. 182 36

Tumor necrosis factor alpha (TNF-alpha) has been previously shown to modulate the expression of hematopoietic growth factor genes in monocytes and other mesenchymal cells. As acute myeloblastic leukemia (AML) blasts can express and produce hematopoietic growth factors, the influence of TNF-alpha on the accumulation of mRNAs for c-myc, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, IL-6 and IL-1 beta was evaluated in fresh blasts from 13 patients with AML. Total cellular RNA was extracted from blast cells cultured for 24 hours with or without TNF-alpha (500 U/ml). The c-myc transcript level was decreased by TNF-alpha treatment in 9/13 cases, and increased in only one case. Among the growth factor genes, the GM-CSF gene was more often and consistently influenced by TNF-alpha, increased levels of its transcript being observed in 6/13 cases following treatment with the cytokine; in no case was there a reduction of GM-CSF mRNA. G-CSF and IL-6 transcripts were more heterogeneously influenced, whereas the IL-3 transcript was never detected in our AML samples. The IL-1 beta message was present in 8/13 untreated and in 13/13 TNF-alpha treated samples. Moreover, in untreated cells, GM-CSF, G-CSF and IL-6 expression was always associated with IL-beta expression. These findings indicate that TNF-alpha can modulate the levels of growth factor transcripts in AML blasts, and raise questions about the effects of TNF-alpha on leukemic hematopoiesis, considering that TNF-alpha, IL-1 and GM-CSF can synergistically stimulate the growth of AML clonogenic cells.
Leukemia 1991 Oct
PMID:Tumor necrosis factor alpha modulates the messenger RNA expression of hematopoietic growth factor genes in fresh blast cells from patients with acute myeloblastic leukemia. 196 Oct 22

Granulocyte-macrophage colony-stimulating factor, (GM-CSF) was given at 8 micrograms/kg daily by continuous i.v. infusion for 72 h to six patients with acute myeloid leukemia (AML) in expansion and one with chronic myeloid leukemia in blastic crisis to determine whether it was possible to augment the proliferative activity of the neoplastic population. The percentage of marrow blasts in S phase (labeling index, LI) was increased in five patients (1.3-, 1.5-, 1.9-, 2.3- and 3.2-fold change). The increase in LI was similar 24 and 48 h after beginning GM-CSF. The RNA Index also increased in patients who showed an increased LI, suggesting that GM-CSF had recruited quiescent neoplastic cells into the cell cycle. Forty eight hours after beginning GM-CSF, chemotherapy was started. The fate of S phase cells, labeled in vivo with bromodeoxyuridine (BrdU) immediately before cytostatic treatment, was monitored. BrdU positive cells were identified by fluorescent antibody for up to 28 days. A preferential killing of BrdU (S phase) cells was observed in 5/7 patients who obtained a complete remission, whereas this was not apparent in the two patients who achieved only a partial remission. Chemotherapy induced a rapid and profound aplasia; its duration, however, was not significantly different from that observed in historical controls. GM-CSF may have a potential role in the treatment of AML, as this study shows that it recruits leukemic cells into the cell cycle without adversely prolonging aplasia after cycle-specific therapy.
Leukemia 1991 Nov
PMID:In vivo effect of granulocyte-macrophage colony-stimulating factor on the kinetics of human acute myeloid leukemia cells. 196 Oct 40

Bryostatin 1 is a macrocyclic lactone which activates protein kinase C (PKC), and is able to induce maturation in cells from some cases of acute myelogenous leukemia. This paper reports that bryostatin inhibits the spontaneous in vitro proliferation of chronic myelomonocytic leukemia cells (CMMoL) in semi-solid medium at concentrations between 10(-8) and 10(-10) M. Growth inhibition was equivalent to or greater than that seen with phorbol-12-myristate-13-acetate. Bryostatin acted primarily as a cytotoxic agent, rather than as a cytostatic agent. The spontaneous in vitro proliferation of CMMoL cells is due to autocrine or paracrine secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF). Bryostatin 1 actually increased GM-CSF secretion by CMMoL cells while inhibiting their proliferation. Bryostatin 1 also increased tumor necrosis factor alpha (TNF alpha) secretion by CMMoL cells, and in 2/5 cases the cytotoxic effect of bryostatin 1 on fresh CMMoL cells could be substantially reversed by the addition of antibody to TNF alpha to the culture medium. Bryostatin 1 may produce a cytotoxic effect on CMMoL cells in part by increasing the secretion of, or sensitivity to, TNF alpha, and may have therapeutic potential in CMMoL.
Leukemia 1991 Apr
PMID:Bryostatin 1: a potential anti-leukemic agent for chronic myelomonocytic leukemia. 202 97

Bryostatin 1 is a macrocyclic lactone activator of protein kinase C which has displayed promising antileukemic potential in pre-clinical studies. We have assessed the effect of bryostatin 1 on the in vitro clonogenic response of leukemic myeloblasts obtained from 12 patients with acute non-lymphocytic leukemia to recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), and have compared these responses to those of normal human hematopoietic progenitors. Although leukemic blast progenitors responded in a heterogenous manner to bryostatin 1 as a single agent, co-administration of 12.5 or 100 nM bryostatin 1 in conjunction with 1.25 ng/ml rGM-CSF resulted in a significant reduction in colony formation (compared to rGM-CSF alone) in 8/12 specimens, and sub-additive stimulatory effects in all samples. In addition, the exposure of cells to 12.5 nM bryostatin 1, either alone or in conjunction with 1.25 ng/ml rGM-CSF, substantially reduced or eliminated leukemic cell self-renewal capacity in all samples assayed. In contrast to the effects observed in leukemic cells, exposure of adherent and T-cell depleted normal bone marrow mononuclear cells to equivalent concentrations of bryostatin 1 and rGM-CSF consistently produced supra-additive effects on the growth of normal committed myeloid progenitors (day 14 CFU-GM). When normal marrow cells were further enriched for progenitors (MY-10+), concentrations of bryostatin 1 that were unable to support growth when administered alone significantly potentiated the number of GM colonies formed in response to rGM-CSF. These studies suggest that bryostatin 1 may modulate the in vitro response of certain normal and leukemic progenitor cells to rGM-CSF, and that the nature of this response differs between the two cell types. They also indicate that bryostatin 1 may be particularly effective in limiting the self-renewal capacity of leukemic myeloblasts, an in vitro characteristic with potentially important in vivo significance.
Leukemia 1991 May
PMID:Effect of the protein kinase C activating agent bryostatin 1 on the clonogenic response of leukemic blast progenitors to recombinant granulocyte-macrophage colony-stimulating factor. 203 60

The receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF) on the surfaces of normal and leukemic myeloid cells were characterized using 125I-labeled bacterially synthesized GM-CSF. The binding was rapid, specific, time dependent, and saturable. Scatchard analysis of the 125I-GM-CSF binding to peripheral blood neutrophils indicated the presence of a single class of binding site (Kd = 99 +/- 21 pM; 2,304 +/- 953 sites/cell). However, for peripheral blood monocytes and two GM-CSF-responsive myeloid cell lines (U-937 and TF-1), the Scatchard plots were biphasic curvilinear, which were best fit by curves derived from two binding site model: one with high affinity (Kd1 = 10-40 pM) and the other with low affinity (Kd2 = 0.9-2.0 nM). For U-937 cells, the number of high-affinity receptors was 1,058 +/- 402 sites/cell and that of low-affinity receptors was estimated to be 10,834 +/- 2,396 sites/cell. Cross-linking studies yielded three major bands with molecular masses of 150 kDa, 115 kDa, and 95 kDa, which were displaced by an excess amount of unlabeled GM-CSF, suggesting 135-kDa, 100-kDa, and 80-kDa species for the individual components of the human GM-CSF receptor. These bands comigrated for different cell types including peripheral blood neutrophils, U-937 cells and TF-1 cells. In experiments using U-937 cells, only the latter two bands appeared to be labeled in a dose-dependent manner in a low-affinity state. These results suggest that the human GM-CSF receptor possibly forms a multichain complex.
Leukemia 1990 Jan
PMID:Characterization and molecular features of the cell surface receptor for human granulocyte-macrophage colony-stimulating factor. 215 63


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