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)

We assessed the safety, tolerability and efficacy of the immunomodulatory drug, CC-5013 (REVIMID trade mark ), in the treatment of patients with metastatic malignant melanoma and other advanced cancers. A total of 20 heavily pretreated patients received a dose-escalating regimen of oral CC-5013. Maximal tolerated dose, toxicity and clinical responses were evaluated and analysis of peripheral T-cell surface markers and serum for cytokines and proangiogenic factors were performed. CC-5013 was well tolerated. In all, 87% of adverse effects were classified as grade 1 or grade 2 according to Common Toxicity Criteria and there were no serious adverse events attributable to CC-5013 treatment. Six patients failed to complete the study, three because of disease progression, two withdrew consent and one was entered inappropriately and withdrawn from the study. The remaining 14 patients completed treatment without dose reduction, with one patient achieving partial remission. Evidence of T-cell activation was indicated by significantly increased serum levels of sIL-2 receptor, granulocyte-macrophage colony-stimulating factor, interleukin-12 (IL-12), tumour necrosis factor-alpha and IL-8 in nine patients from whom serum was available. However, levels of proangiogenic factors vascular endothelial growth factor and basic foetal growth factor were not consistently affected. This study demonstrates the safety, tolerability and suggests the clinical activity of CC-5013 in the treatment of refractory malignant melanoma. Furthermore, this is the first report demonstrating T-cell stimulatory activity of this class of compound in patients with advanced cancer.
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PMID:Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. 1499 89

Colony-stimulating factor (CSF)-1 is the primary regulator of tissue macrophage production. CSF-1 expression is correlated with poor prognosis in breast cancer and is believed to enhance mammary tumor progression and metastasis through the recruitment and regulation of tumor-associated macrophages. Macrophages produce matrix metalloproteases (MMPs) and vascular endothelial growth factor, which are crucial for tumor invasion and angiogenesis. Given the important role of CSF-1, we hypothesized that blockade of CSF-1 or the CSF-1 receptor (the product of the c-fms proto-oncogene) would suppress macrophage infiltration and mammary tumor growth. Human MCF-7 mammary carcinoma cell xenografts in mice were treated with either mouse CSF-1 antisense oligonucleotide for 2 weeks or five intratumoral injections of either CSF-1 small interfering RNAs or c-fms small interfering RNAs. These treatments suppressed mammary tumor growth by 50%, 45%, and 40%, respectively, and selectively down-regulated target protein expression in tumor lysates. Host macrophage infiltration; host MMP-12, MMP-2, and vascular endothelial growth factor A expression; and endothelial cell proliferation within tumors of treated mice were decreased compared with tumors in control mice. In addition, mouse survival significantly increased after CSF-1 blockade. These studies demonstrate that CSF-1 and CSF-1 receptor are potential therapeutic targets for the treatment of mammary cancer.
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PMID:Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice. 1528 45

It has been reported that vascular endothelial growth factor (VEGF), expressed by osteoblasts, can induce osteoclast recruitment and thus affects bone remodeling. The purpose of this study was to investigate the effects of cyclic tensile forces on the expression of VEGF and macrophage-colony-stimulating factor (M-CSF) in osteoblastic MC3T3-E1 cells. VEGF and M-CSF gene expression and protein concentration were determined by real-time PCR and enzyme-linked immunoassay. The expression of VEGF and M-CSF mRNA in the experimental group was higher than in the control group. The increase in the concentration of VEGF and M-CSF protein in the experimental group was time-dependent. Moreover, gadolinium (an S-A channel inhibitor), but not nifedipine (L-Type Ca2+ channel blocker), treatment reduced the concentration of VEGF and M-CSF mRNA and protein in the experimental groups. These findings suggest that cyclic tensile forces increase the expression of VEGF and M-CSF in osteoblastic MC3T3-E1 cells via a stretch-activated channel (S-A channel).
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PMID:Effects of cyclic tensile forces on the expression of vascular endothelial growth factor (VEGF) and macrophage-colony-stimulating factor (M-CSF) in murine osteoblastic MC3T3-E1 cells. 1584 Jul 77

Tumor-associated and tumor-infiltrating neutrophils (TAN) and macrophages (TAM) can account for as much as 50% of the total tumor mass in invasive breast carcinomas. It is thought that tumors secrete factors that elicit a wound-repair response from TAMs and TANs and that this response inadvertently stimulates tumor progression. Oncostatin M is a pleiotropic cytokine belonging to the interleukin-6 family that is expressed by several cell types including activated human T lymphocytes, macrophages, and neutrophils. Whereas oncostatin M can inhibit the proliferation of breast cancer cells in vitro, recent studies suggest that oncostatin M may promote tumor progression by enhancing angiogenesis and metastasis. In addition, neutrophils can be stimulated to synthesize and rapidly release large quantities of oncostatin M. In this article, we show that human neutrophils secrete oncostatin M when cocultured with MDA-MB-231 and T47D human breast cancer cells. Neutrophils isolated from whole blood or breast cancer cells alone express little oncostatin M by immunocytochemistry and ELISA, but neutrophils express and release high levels of oncostatin M when they are cocultured with breast cancer cells. In addition, we show that granulocyte-macrophage colony-stimulating factor produced by breast cancer cells and cell-cell contact are both necessary for the release of oncostatin M from neutrophils. Importantly, neutrophil-derived oncostatin M induces vascular endothelial growth factor from breast cancer cells in coculture and increases breast cancer cell detachment and invasive capacity, suggesting that neutrophils and oncostatin M may promote tumor progression in vivo.
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PMID:Breast cancer cells stimulate neutrophils to produce oncostatin M: potential implications for tumor progression. 1620 61

The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4+ VEGFR1+ hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4+ VEGFR1+ hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2-/- Csf3-/-), profound impairment in neovascularization was detected in sKitL-deficient Mmp9-/- as well as thrombocytopenic Thpo-/- and TPO receptor-deficient (Mpl-/-) mice. SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo-/-, Mpl-/- and Mmp9-/- mice. Transplantation of CXCR4+ VEGFR1+ hemangiocytes into Mmp9-/- mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A-mediated mobilization of CXCR4+ VEGFR1+ cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4+ VEGFR1+ hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF-1 may be effective in restoring angiogenesis in individuals with vasculopathies.
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PMID:Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. 1664 59

Dermal papilla cells (DPC) control the growth character of the hair follicle through their elaboration of mitogenic factors and extracellular matrix components. Further, the dermal papilla is a primary site of androgen action in the hair follicle. Interleukin-1alpha (IL-1alpha) is prominent in skin wounding and inflammatory responses although regarded as a negative hair growth regulator. We studied the effect of IL-1alpha and the potent androgen 5alpha-dihydrotestosterone (DHT) on the expression of the androgen receptor (AR) and various factors secreted by cultured human temporal scalp DPC. IL-1alpha triggered cellular changes consistent with nuclear factor-kappaB pathway activation as well as reduced AR mRNA and protein expression levels for DHT-stimulated DPC. This cytokine also increased DPC supernatant keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations. IL-1alpha did not influence DPC supernatant levels of transforming growth factor-beta1, a negative hair growth regulator. The stimulatory effect of IL-1alpha on DPC VEGF, GM-CSF, KGF, and IL-8 expression was also evident at the mRNA level for these cytokines. IL-1alpha also increased mRNA transcript levels of protease-nexin-1, a secreted serine protease inhibitor expressed in the dermal papilla of anagen-stage hair follicles. Although DHT did not affect supernatant cytokine concentrations, the androgen altered mRNA transcript levels of several factors for DPC co-stimulated with IL-1alpha. In consideration of its in vitro activity profile, IL-1alpha may be an important modifier of dermal papilla activity as well as potentially influence androgen-regulated gene expression in DPC.
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PMID:Influence of interleukin-1alpha on androgen receptor expression and cytokine secretion by cultured human dermal papilla cells. 1698 60

In vivo vascularization of implanted (bio)artificial constructs is essential for their proper function. Vascularization may rely on sprouting angiogenesis, vascular incorporation of bone marrow-derived endothelial cells (BMDECs), or both. Here we investigated the relative contribution of these 2 mechanisms to neovascularization in a mouse model of a foreign body reaction (FBR) to subcutaneously implanted Dacron and in hind limb ischemia (HLI) in relation to the molecular microenvironment at these neovascularization sites. Neovascularization was studied in C57Bl/6 mice reconstituted with enhanced green fluorescent protein (EGFP) transgenic bone marrow. Sprouting angiogenesis, detected using nuclear incorporation of bromodeoxyuridine in endothelial cells was present in both models, whereas vascular incorporation of EGFP(+) BMDECs was restricted to HLI. In HLI, the presence of a pro-angiogenic molecular microenvironment comprising vascular endothelial growth factor, fibroblast growth factor 2, and granulocyte colony-stimulating factor corroborated the importance of these factors for vascular BMDEC incorporation, whereas this microenvironment was absent in FBR. Enhanced mobilization of BMDECs by granulocyte-macrophage colony-stimulating factor administration or by combining HLI and FBR with Dacron did not induce incorporation of BMDECs in FBR neovessels. We conclude that the efficacy of BMDEC-based therapy is not generally warranted, but it depends on the molecular microenvironment in the targeted tissue.
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PMID:Dependence of neovascularization mechanisms on the molecular microenvironment. 1803 45

It has been reported that both vascular endothelial growth factor (VEGF) and macrophage colonystimulating factor (M-CSF) can induce osteoclast recruitment. Thus, VEGF and M-CSF are considered to be closely involved in the bone remodeling process. The purpose of this study was to evaluate changes in VEGF and M-CSF expression during orthodontic treatment. The expression of VEGF and M-CSF mRNA in osteoblasts and fibroblasts was detected by in situ hybridization during experimental tooth movement in mice. Furthermore, the canine retraction side and the control side of orthodontic patients were compared, revealing a statistically significant increase in both VEGF and M-CSF concentrations in gingival crevicular fluid. These results suggest that orthodontic tooth movement causes an increase in VEGF and M-CSF levels. These factors may induce bone remodeling via osteoclastic bone resorption.
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PMID:VEGF and M-CSF levels in periodontal tissue during tooth movement. 1872 5

The aim of this study was to determine influence of prenatal granulocyte-macrophage colony-stimulating factor (GM-CSF) administration on lung growth, maturation, and vascular endothelial growth factor (VEGF) expression. Twenty Wistar rats received sterile saline (1 mL) or recombinant human GM-CSF (50 micro g/kg) on day 16 of pregnancy. Rats were sacrificed on days 18 and 20 of gestation. H-score for VEGF was calculated immunohistochemically. Alveolar VEGF expression on days 18 and 20 of gestation was significantly higher in the GM-CSF group (P < .01). Increase in VEGF with prenatal GM-CSF administration indicates that GM-CSF may stimulate lung growth and maturation and may be protective against lung disease due to prematurity.
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PMID:Prenatal administration of granulocyte-macrophage colony-stimulating factor increases mesenchymal vascular endothelial growth factor expression and maturation in fetal rat lung. 1900 20

Biomarkers for treatment response would facilitate the testing of urgently needed new anti-tuberculous drugs. The present study investigated the profiles of 30 proinflammatory, anti-inflammatory and angiogenic factors [epidermal growth factor, eotaxin, fractalkine, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin (IL)-1alpha, IL-1beta, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, interferon-gamma, interferon-inducible protein-10, Krebs von den Lungen-6, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, sCD40L, transforming growth factor-alpha, tumour necrosis factor-alpha and vascular endothelial growth factor] in the plasma of 12 healthy tuberculin skin test-positive community controls and 20 human immunodeficiency virus-negative patients with active tuberculosis (TB) and identified potential biomarkers for early treatment response. We showed differences in the level of circulating cytokines between healthy controls and TB patients, but also between fast responders and slow responders to anti-tuberculosis treatment. The general discriminant analysis based on pre-treatment and week 1 measurements identified 10 sets of three-variable models that could classify fast and slow responders with up to 83% accuracy. Overall, this study shows the potential of cytokines as indicators of anti-tuberculosis treatment response.
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PMID:Differential cytokine secretion and early treatment response in patients with pulmonary tuberculosis. 1919 52


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