Gene/Protein Disease Symptom Drug Enzyme Compound
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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 present study was undertaken to determine the identities and characteristics of proteins with molecular masses between 40 and 44 kDa whose tyrosine phosphorylation increases in human neutrophils following stimulation of these cells with tumour necrosis factor alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Immunoblotting results demonstrate that addition of GM-CSF to human neutrophils increases the tyrosine phosphorylation of two proteins with molecular masses of 42 and 44 kDa. However, the addition of TNF-alpha to neutrophils induces a time- and dose-dependent increase in tyrosine phosphorylation of a 40 kDa protein. Immunoprecipitation using specific mitogen-activated protein kinase (MAPK) isoform antibodies and an antibody which recognizes phosphotyrosine-containing proteins demonstrated that the 42 and 44 kDa proteins are isoforms of MAPKs. Utilizing an in situ gel kinase activity assay, GM-CSF increases the kinase activity of the 42 and 44 kDa proteins. Moreover, using immunoprecipitated p42 and p44 MAPK isoforms in this gel assay revealed activity associated with the p42 and p44 MAPK isoforms. Using the same in situ assay, TNF-alpha induces an increase in kinase activity of a 40-42 kDa protein. However, the 40 kDa protein whose phosphorylation on tyrosine residues increased in human neutrophils following stimulation with TNF-alpha is not a member of the known MAPK family, demonstrating the divergences in pathways utilized by GM-CSF and TNF-alpha. This 40 kDa protein may be related to the recently identified protein that becomes phosphorylated on tyrosine residues upon stimulation of the human epidermal carcinoma cell line KB by interleukin-1. In these cells the p40 protein is part of a protein kinase cascade which results in the phosphorylation of the small heat shock protein, hsp27.
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PMID:Effects of granulocyte-macrophage colony-stimulating factor and tumour necrosis factor-alpha on tyrosine phosphorylation and activation of mitogen-activated protein kinases in human neutrophils. 771 91

This review is a brief overview of recent advances in biology as well as in potential clinical application of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Biologically active rhGM-CSF is a recombinant human protein expressed in Escherichia coli. GM-CSF is produced by nontransformed (T-lymphocytes, trophoblasts, keratinocytes, osteoblasts, tracheal epithelial cells, renal mesangial cells, endothelial cells, macrophages, fibroblasts, smooth muscle cells) and transformed (murine plasmocytoma, bladder carcinoma HIBY cell line, anaplastic carcinoma of the gall bladder, Yoshida sarcoma cell line, HC3T3-osteoblast cell line) cells. RhGM-CSF increases the number of circulating neutrophils, monocytes and eosinophils and increases chemotactic, microcidal killing and cytotoxic activity of monocytes and granulocytes. The present clinically relevant uses of rhGM-CSF two general areas: restoration of haematopoietic dysfunction by raising cell counts from suppressed to normal levels, and augmentation of host defence against infection. Thus, rhGM-CSF reduces risk of infections. In addition, rhGM-CSF may increase tumour cell destruction in some malignant diseases. RhGM-CSF produces dose-dependent toxicity consisting of myalgic fever, fluid retention and serosal effusions.
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PMID:[Biologic effects and possible therapeutic use of the granulocyte-macrophage colony-stimulating factor. Modern treatment of leukopenia]. 772 60

The pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), induction of anti-GM-CSF antibodies, and clinical effects related to the induction of the antibodies were analyzed in patients with metastatic colorectal carcinoma (CRC) who were not on chemotherapy (n = 20, nonimmunocompromised patients). rhGM-CSF (250 micrograms/m2/d; Escherichia coli-derived) was administered subcutaneously for 10 days every month for 4 months. Eight patients with multiple myeloma (MM) on intensive chemotherapy followed by rhGM-CSF treatment were also included (immunocompromised patients). After a single injection of GM-CSF at the first cycle in CRC patients, the maximum calculated concentration (Cmax) was 5.24 +/- 0.56 ng/mL; the half life (T1/2) was 2.91 +/- 0.8 hours; and the area under the concentration curve (AUC) was 30.86 +/- 6.03 hours x ng/mL (mean +/- SE). No anti-GM-CSF antibodies were detected. During the subsequent cycles, 95% of the CRC patients developed anti-GM-CSF IgG antibodies, which significantly altered the pharmacokinetics of rhGM-CSF at the third and fourth cycles with decreased Cmax (2.87 +/- 0.57 ng/mL; P < .05), T1/2 (1.57 +/- 0.2 hours; P < .05), and AUC (14.90 +/- 4.10 hours x ng/mL; P < .005). The presence of anti-GM-CSF antibodies significantly reduced the GM-CSF-induced enhancement of granulocytes, and there was a clear tendency for a decreased increment of monocytes. Antibodies diminished systemic side effects of rhGM-CSF. Only 1 of 8 MM patients showed a very low anti-GM-CSF antibody titer after GM-CSF therapy, as shown by enzyme-linked immunosorbent assay and Western blot. Therefore, in nonimmunocompromised patients, exogenous nonglycosylated GM-CSF induced an anti-GM-CSF IgG antibody response in practically all patients, which seemed to be of clinical significance. In immunocompromised patients, virtually no significant antibody response was shown.
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PMID:Induction of anti-recombinant human granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived) antibodies and clinical effects in nonimmunocompromised patients. 799 26

Secretion of several cytokines by colorectal carcinoma cells has been substantiated. These do not include granulocyte-macrophage colony-stimulating factor (GM-CSF) thus far. We show that the supernatant of two human colorectal carcinoma cell lines, LS1034 and SW480, stimulates proliferation of GM-CSF-dependent M07e cells. The activity was constitutively secreted by LS1034 cells and could be induced by serum-free culture conditions in SW480 cells. Addition of a neutralizing anti-GM-CSF antibody completely inhibited this activity. Preabsorption with anti-GM-CSF antibody removed all M07e growth-stimulating activity from LS1034 and SW480 supernatant. Western blot analysis revealed the presence of GM-CSF in LS1034 supernatant. Our results indicate that human colorectal carcinoma cells secrete indeed biologically active GM-CSF.
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PMID:Secretion of bioactive granulocyte-macrophage colony-stimulating factor by human colorectal carcinoma cells. 803 86

The potential efficacy and clinical feasibility of gene therapy for prostate cancer were tested. Efficacy was tested using the Dunning rat prostate carcinoma model. Rats with anaplastic, hormone refractory prostate cancer treated with irradiated prostate cancer cells genetically engineered to secrete human granulocyte-macrophage colony-stimulating factor (GM-CSF) showed longer disease-free survival compared to either untreated control rats or rats receiving prostate cancer cell vaccine mixed with soluble human GM-CSF. A gene modified prostate cancer cell vaccine thus provided effective therapy for anaplastic, hormone refractory prostate cancer in this animal model. An evaluation of the clinical feasibility of gene therapy for human prostate cancer based on these findings was then undertaken. Prostate cancer cells from patients with stage T2 prostate cancer undergoing radical prostatectomy were first transduced with MFG-lacZ, a retroviral vector carrying the beta-galactosidase reporter gene. Efficient gene transfer was achieved in each of 16 consecutive cases (median transduction efficiency 35%, range 12 to 65%). Cotransduction with a drug-selectable gene was not required to achieve high yield of genetically modified cells. Histopathology confirmed malignant origin of these cells and immunofluorescence analysis of cytokeratin 18 expression confirmed prostatic luminal-epithelial phenotype in each case tested. Cell yields (2.5 x 10(8) cells per gram of prostate cancer) were sufficient for potential entry into clinical trials. Autologous human prostate cancer vaccine cells were then transduced with MFG-GM-CSF, and significant human GM-CSF secretion was achieved in each of 10 consecutive cases. Sequential transductions increased GM-CSF secretion in each of 3 cases tested, demonstrating that increased gene dose can be used to escalate desired gene expression in individual patients. These studies show a preclinical basis for proceeding with clinical trials of gene therapy for human prostate cancer.
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PMID:Demonstration of a rational strategy for human prostate cancer gene therapy. 830 72

Results from in vitro investigations and recent data obtained in patients with drug-induced cytopenia or myelodysplasia suggest that leukotrienes may be involved in mediating some of the actions of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, the possible role of leukotrienes was further characterized in 21 healthy individuals to avoid modification of response to GM-CSF by disease-specific variables. The effects of two different preparations of human recombinant GM-CSF, ie, glycosylated GM-CSF as expressed in a Chinese hamster ovary carcinoma (CHO) cell line and nonglycosylated GM-CSF obtained from Escherichia coli, were compared. GM-CSF was administered subcutaneously at a single dose of 0.7 nmol/kg body weight. Pharmacokinetic parameters and hematopoietic and adverse effects were monitored by blood analyses or physical examination, respectively. Leukotriene generation in vivo was evaluated by determination of leukotriene E4 and N-acetyl-leukotriene E4 in urine. After the injection of GM-CSF from E coli, serum concentrations increased and decreased more rapidly and reached a 2.3-fold higher maximum compared with GM-CSF from CHO. GM-CSF induced a biphasic change in leukocyte counts that proceeded considerably faster after the E coli preparation than after GM-CSF from CHO. The urinary leukotriene concentration increased 1.3- to 14-fold or 2.1- to 44-fold after the administration of GM-CSF from CHO or E coli, respectively. Urinary leukotriene concentrations correlated significantly with the maximum of basophil counts and correlated with the occurrence of some adverse reactions, ie, flu-like symptoms, bone pain, or dyspnoea. Our data confirm the conception that leukotrienes may play a significant role in GM-CSF action in vivo. They especially direct attention to the possible relevance of leukotrienes to untoward effects of GM-CSF treatment.
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PMID:Differential activation of the endogenous leukotriene biosynthesis by two different preparations of granulocyte-macrophage colony-stimulating factor in healthy volunteers. 838 25

Antibody-dependent cellular cytotoxicity (ADCC) is considered to be one of the effector functions of unconjugated monoclonal antibodies (MAbs) in tumor therapy. The antitumor activity of MAbs might therefore be augmented if the cytotoxic capability of the effector cells could be increased. In an in vitro system, the killing capacity of MAb was significantly enhanced by pre-treatment of the effector cells with granulocyte-macrophage colony-stimulating factor (GM-CSF). Based on these findings, the therapeutic effect of the combination of mouse MAb 17-1A (IgG2a) and GM-CSF was evaluated in 20 patients with metastatic colorectal carcinoma (CRC). The patients received GM-CSF for 10 days and a single i.v. infusion of MAb 17-1A on day 3 of the cycle. Four cycles were given at 1-monthly intervals. There was a continuous increase in blood monocytes and lymphocytes during all 4 GM-CSF cycles. Neutrophils and eosinophils were also significantly augmented but in a biphasic manner and the cell counts on day 10 of cycle IV were significantly lower than in cycles I and II. GM-CSF-related side-effects were of no major clinical importance. During the third cycle, an immediate-type allergic reaction (ITAR) against MAb 17-1A occurred in most patients, necessitating reduction of the MAb dose as well as of the infusion rate. Two patients achieved complete remission. One patient had a minor response, and 3 other patients were considered to have stable disease > 3 months.
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PMID:Effect of monoclonal antibody 17-1A and GM-CSF in patients with advanced colorectal carcinoma--long-lasting, complete remissions can be induced. 844 98

Using specific ELISA kits, we investigated the secretion of cytokines in five human prostate carcinoma cell lines: ALVA 31, DU145, LNCaP, ND1 and PC3. Three of the five cell lines investigated secreted granulocyte-macrophage colony-stimulating factor (GM-CSF); GM-CSF was not identified in ALVA31 or LNCaP. In addition, we have shown that conditioned media of DU145, ND1 and PC3 stimulated proliferation of the GM-CSF-dependent cell line MO7e indicating that these cells secrete biologically active GM-CSF. By flow cytometric analysis we determined that all five cell lines expressed the alpha-subunit of the GM-CSF receptor on the cell surface but only ALVA31 expressed both the alpha- and beta-subunits of the GM-CSF receptor. Varying concentrations of GM-CSF did not stimulate the proliferation rate of any of the prostate carcinoma cell lines. Thus, there does not appear to be autocrine loop of GM-CSF-induced proliferation. However, the expression of E-cadherin and endoglin (CD105) was modulated under GM-CSF treatment in ALVA31. In addition, GM-CSF decreased the level of soluble CD44 in ND1. These results suggest that the GM-CSF receptor alpha-subunit may play a role in metabolic activity of prostate cancer.
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PMID:Human prostate carcinoma cell lines secrete GM-CSF and express GM-CSF-receptor on their cell surface. 868 98

The level of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA is fourfold lower in phorbol myristate acetate (PMA) + phytohemagglutinin (PHA)-activated mononuclear cells (MNC) from newborns compared with adults. The GM-CSF transcription rate is similar in umbilical cord and adult MNC, but transcript half-life is threefold lower in cord activated MNC. Interaction of RNA binding proteins, such as the cloned adenosine + uridine-rich element, binding factor, AUF1, with eight AUUUA motifs in the human GM-CSF mRNA 3'-untranslated region (GM-3'-UTR) has been implicated in regulating transcript stability. Translational inhibition by cycloheximide (CHX) significantly increased GM-CSF mRNA accumulation and half-life by three-fold in activated cord MNC, but had a minimal effect in activated adult MNC as compared with PMA + PHA alone. Electrophoretic mobility-shift assays with a 32P-labeled, 305-nucleotide RNA comprising the GM-3'-UTR revealed two RNaseT1-resistant, bound complexes that were almost twice as abundant in cord than in adult MNC extracts. Mobility-shift competition assays and RNaseT1 mapping localized the binding site of both complexes to a 52-nucleotide region containing seven of eight AUUUA motifs. Inclusion of AUF1 antiserum produced a supershifted complex at 35-fold higher levels in cord than in adult MNC extracts. Extracts from the carcinoma cell line 5637, with extended GM-CSF mRNA half-life, also had very low levels of anti-AUF1 supershifted complex. Anti-AUF1 immunoblotting showed significantly higher levels of two AUF1 protein isoforms and lower levels of one in cord than in adult MNC or 5637 extracts. These results suggest that destabilization of GM-CSF mRNA in cord MNC is translation-dependent and that increased levels of specific AUF1 isoforms in cord MNC may target transcripts for increased degradation, which could account in part for dysregulation of neonatal phagocytic immunity.
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PMID:Increased granulocyte-macrophage colony-stimulating factor mRNA instability in cord versus adult mononuclear cells is translation-dependent and associated with increased levels of A + U-rich element binding factor. 887 85

Cancers producing colony-stimulating factors and associated with marked leukocytosis are relatively rare. We report here a case of a thyroid cancer producing both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). A 72-year-old woman had a thyroid carcinoma with significant neutrophilia and eosinophilia without any evidence of infection. The serum concentrations of both G-CSF and GM-CSF were elevated significantly in this patient, which might have induced the leukocytosis. Furthermore, the G-CSF concentrations in thyroid tumor tissue and metastatic lesions in the lung and skin examined at autopsy also were extremely high.
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PMID:The production of colony-stimulating factors by thyroid carcinoma is associated with marked neutrophilia and eosinophilia. 893 94


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