Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Through direct synthetic efforts, we discovered a small molecule that is a nanomolar inhibitor of the human fibroblast growth factor-1 receptor (FGFR) tyrosine kinase. PD 166866, a member of a new structural class of tyrosine kinase inhibitors, the 6-aryl-pyrido[2,3-d]pyrimidines, was identified by screening a compound library with assays that measure protein tyrosine kinase activity. PD 166866 inhibited human full-length FGFR-1 tyrosine kinase with an IC50 value of 52.4 +/- 0.1 nM and was further characterized as an ATP competitive inhibitor of the FGFR-1. In contrast, PD 166866 had no effect on c-Src, platelet-derived growth factor receptor-beta, epidermal growth factor receptor or insulin receptor tyrosine kinases or on mitogen-activated protein kinase, protein kinase C and CDK4 at concentrations as high as 50 microM. PD 166866 was a potent inhibitor of basic fibroblast growth factor (bFGF)-mediated receptor autophosphorylation in NIH 3T3 cells expressing endogenous FGFR-1 and in L6 cells overexpressing the human FGFR-1 tyrosine kinase, confirming a tyrosine kinase-mediated mechanism. PD 166866 also inhibited bFGF-induced tyrosine phosphorylation of the 44- and 42-kDa (ERK 1/2) mitogen-activated protein kinase isoforms in L6 cells, presumably via inhibition of bFGF-stimulated FGFR-1 tyrosine kinase activation. PD 166866 did not inhibit platelet-derived growth factor, epidermal growth factor or insulin-stimulated receptor autophosphorylation in vascular smooth muscle, A431 or NIHIR cells, respectively, further supporting its specificity for the FGFR-1. In addition, daily exposure of PD 166866 to L6 cells at concentrations from 1 to 100 nM resulted in a concentration-related inhibition of bFGF-stimulated cell growth for 8 consecutive days with an IC50 value of 24 nM. In contrast, PD 166866 had little effect on platelet-derived growth factor-BB-stimulated growth of L6 cells or serum-stimulated vascular smooth muscle cell proliferation. Finally, PD 166866 was found to be a potent inhibitor of microvessel outgrowth (angiogenesis) from cultured artery fragments of human placenta. These results highlight the discovery of PD 166866, a new nanomolar potent and selective small molecule inhibitor of the FGFR-1 tyrosine kinase with potential use as antiproliferative/antiangiogenic agent for such therapeutic targets as tumor growth and neovascularization of atherosclerotic plaques.
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PMID:In vitro biological characterization and antiangiogenic effects of PD 166866, a selective inhibitor of the FGF-1 receptor tyrosine kinase. 965 4

We describe the development and optimization of an in vivo angiogenesis assay utilizing gelfoam sponges impregnated with 0.4% agarose and different proangiogenic factors, such as basic fibroblast growth factor (bFGF), vascular epidermal growth factor (VEGF), tumor growth factor-alpha (TGF-alpha), and endothelial growth factor (EGF). The sponges are implanted into the subcutis of mice and harvested after different times. The gelfoam sponges are fixed, sectioned, and stained with fluorescent antibodies against CD31. The median number of CD31+ cells is determined in 10 different 0.159-mm2 fields. Proangiogenic molecules induced significant migration and proliferation of endothelial cells. To demonstrate the utility of this assay for evaluation of an antiangiogenic agent, mice were implanted with gelfoam sponges containing different proangiogenic factors and treated orally with water or PTK 787, a novel tyrosine kinase inhibitor with specific activity against the VEGF-R. PTK 787 significantly inhibited angiogenesis in sponges containing agarose + VEGF but not other proangiogenic molecules. The data show that the implanted gelfoam sponges provide a reliable quantitative assay to study in vivo angiogenesis.
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PMID:Quantitative and qualitative in vivo angiogenesis assay. 1206 42

An important development in the treatment of cancer is the recognition that the tumour's microenvironment, notably its vasculature, may be an attractive target for therapy. In the eighties of the last century, the concept of angiogenesis (the formation of new blood vessels from existing vasculature) was developed. Angiogenesis is the driving force behind tumour growth and metastasis. Recent angiogenesis research has elucidated the role of growth factors (vascular endothelial growth factor (VEGF), epidermal growth factor), metalloproteinases and endogenous proteins such as angiostatin and endostatin. This new knowledge has led to the rapid development of several angiogenesis inhibiting strategies. Although these new strategies showed very promising results in preclinical animal studies, early clinical studies with individual angiogenesis inhibitors have shown no antitumour effect so far. However, in recent studies blocking VEGF in addition to conventional chemotherapy has led to an increase in disease-free survival time and in response rate to chemotherapy. Angiogenesis research has contributed to the knowledge of the biology of cancer, the design of modified clinical studies and the development of surrogate markers that can be used as pharmacodynamic end points in future studies.
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PMID:[The clinical perspective of angiogenesis inhibitors]. 1451 38

Targeting cell-signalling pathways that confer survival advantage to cancer cells has become a major focus of investigation for the treatment of various malignancies. Non-small cell lung cancer (NSCLC), a disease with wide molecular heterogeneity, has become a main testing ground for the evaluation of various targeted agents. Inhibition of the epidermal growth factor pathway with erlotinib results in improved survival and symptom control for patients with advanced NSCLC who progressed following one or two prior chemotherapy regimens. Gefitinib, the first epidermal growth factor receptor (EGFR) inhibitor to be approved by the FDA, failed to demonstrate survival advantage over placebo in a large Phase III trial for patients with advanced NSCLC. The results of this study have raised several important clinical and biological issues that may be relevant for the development of other targeted agents. Recent identification of mutations in the ATP-binding pocket of the EGFR is the first step towards proper patient selection for therapy with an EGFR tyrosine kinase inhibitor. In addition, predictive potential has also been seen with EGFR gene amplification. It is unclear whether monoclonal antibodies against the EGFR may be active independent of the EGFR mutation, as the site of action is different from tyrosine kinase inhibitors. A recent randomised clinical trial that combined the antiangiogenic agent bevacizumab with chemotherapy has demonstrated survival advantage over chemotherapy alone for certain subsets of patients with advanced NSCLC. The exciting results of this study represent an important advance in the treatment of patients with advanced NSCLC.
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PMID:Molecularly-targeted therapies for non-small cell lung cancer. 1631 5

There is much evidence that rheumatoid arthritis is closely linked to angiogenesis. Important angiogenic mediators have been demonstrated in synovium and tenosynovium of rheumatoid joints. VEGF (Vascular Endothelial Growth Factor), expressed in response to soluble mediators such as cytokines and growth factors and its receptors are the best characterized system in the angiogenesis regulation of rheumatoid joints. Moreover, other angiogenic mediators such as platelet-derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2), epidermal growth factor (EGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, IL-8, IL-13, IL-15, IL-18, angiogenin, platelet activating factor (PAF), angiopoietin, soluble adhesion molecules, endothelial mediator (endoglin) play an important role in angiogenesis in rheumatoid arthritis. On the other hand, endostatin, thrombospondin-1 and -2 are angiogenic inhibitors in rheumatoid arthritis. The persistence of inflammation in rheumatoid joints is a consequence of an imbalance between these inducers and inhibitors of angiogenesis.
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PMID:Angiogenesis in rheumatoid arthritis. 1649 85

The kringle domain is a triple loop structure present in angiostatin and endostatin. The disulfide bond-linked kringle architectures have been known to be essential for anti-angiogenic activity. Plasma hyaluronan binding protein (PHBP) is a novel serine protease which consists of three epidermal growth factor (EGF) domains, a kringle domain, and a serine protease domain. PHBP can be cleaved autocatalytically to generate activity and is highly expressed in the human blood and liver. To determine the anti-angiogenic activities of PHBP, we purified recombinant mouse PHBP from stable cell line overexpressing PHBP and used protein in vivo and in vitro angiogenesis assays. We found that recombinant PHBP inhibits not only angiogenesis in vivo in chorioallantoic membrane (CAM) assay but also the basic fibroblast growth factor (bFGF)-induced proliferation, invasion and tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependant manner. Moreover, we found that the kringle domain of PHBP was essential for the anti-angiogenic action of PHBP by the deletion mutants. These findings unravel a new function of PHBP as an inhibitor of the proangiogenic phenotype of vascular endothelial cells and demonstrate that the kringle domain of PHBP might be a potent novel inhibitor of activated endothelial cells in vitro and in vivo.
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PMID:Anti-angiogenic action of plasma hyaluronan binding protein in human umbilical vein endothelial cells. 1677 2

Fibulins are a family of five extracellular matrix proteins characterized by tandem arrays of epidermal growth factor-like domains and a C-terminal fibulin-type module. They are widely distributed and often associated with vasculature and elastic tissues. In this study, we expressed the three more recently identified family members, fibulin-3, fibulin-4, and fibulin-5, as recombinant proteins in mammalian cells. The purified proteins showed short rod structures of approximately 20 nm with a globule at one end, after rotary shadowing and electron microscopy. Two forms of mouse fibulin-3 were purified, and the O-glycan profiles of the larger form were characterized. Polyclonal antibodies raised against the purified proteins did not show any cross-reactivity with other family members and were used to assess the levels and localization of the fibulins in mouse tissues. Their binding interactions, cell adhesive properties, and tissue localization were analyzed in parallel with the previously characterized fibulin-1 and -2. Binding to tropoelastin was strong for fibulin-2 and -5, moderate for fibulin-4 and -1, and relatively weak for fibulin-3. Fibulin-4, but not fibulin-3 and -5, exhibited distinct interactions with collagen IV and nidogen-2 and moderate binding to the endostatin domain from collagen XV. Cell adhesive activities were not observed for all fibulins, except mouse fibulin-2, with various cell lines tested. All five fibulins were found in perichondrium and various regions of the lungs. Immunoelectron microscopy localized fibulin-4 and -5 to fibrillin microfibrils at distinct locations. Our studies suggest there are unique and redundant functions shared by these structurally related proteins.
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PMID:A comparative analysis of the fibulin protein family. Biochemical characterization, binding interactions, and tissue localization. 1732 35

Hepatocellular carcinoma (HCC) is a hypervascular tumor, and tumor progression and prognosis is associated with angiogenesis. Extracellular matrix remodeling and inflammation play important roles in hepatocarcinogenesis. Some ingredients of extracellular matrix such as endostatin and sulfated polysaccharide, some immunomodulatory agents and cox-2 inhibitor suppress the angiogenesis of HCC. Because vasculogenic mimicry is associated with high tumor grade, some differentiation agents are used to inhibit antiagiogenesis. Besides suppressing the proliferation directly, somatostatin inhibits angiogenesis to suppress growth indirectly. Copper chelator prevents copper from functioning as a cofactor in angiogenesis. The renin-angiotensin system is frequently activated in patients with chronic liver diseases. Perindopril, an angiotensin converting enzyme inhibitor, inhibits angiogenesis by reducing vascular endothelial growth factor (VEGF) production. Kinase inhibitors of VEGF and epidermal growth factor receptors are expected to be of benefit for some patients. Following transarterial embolisation and/or resection, antiangiogenic therapy could prevent the recurring and metastasis. Hypoxia enhances the proliferation, suppresses the differentiation and apoptosis, and induces multidrug resistance of HCC. Because antiangiogenic therapies induce hypoxia, it should be borne in mind the side affects of antiangiogenic therapy. Because long-acting antiangiogenent are needed to control cancer, it needs more clinical studies to confirm the drug resistance of antiangiogenetic therapy.
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PMID:New strategy of antiangiogenic therapy for hepatocellular carcinoma. 1899 74

Endostatin is a C-terminal proteolytic fragment of collagen XVIII that is localized in vascular basement membrane zones in various organs. It binds to heparin/heparan sulfate and to a number of proteins, but its molecular mechanisms of action are not fully elucidated. We have used surface plasmon resonance (SPR) arrays to identify new partners of endostatin, and to give further insights on its molecular mechanism of action. New partners of endostatin include glycosaminoglycans (chondroitin and dermatan sulfate), matricellular proteins (thrombospondin-1 and SPARC), collagens (I, IV, and VI), the amyloid peptide Abeta-(1-42), and transglutaminase-2. The biological functions of the endostatin network involve a number of extracellular proteins containing epidermal growth factor and epidermal growth factor-like domains, and able to bind calcium. Depending on the trigger event, and on the availability of its members in a given tissue at a given time, the endostatin network might be involved either in the control of angiogenesis, and tumor growth, or in neurogenesis and neurodegenerative diseases.
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PMID:The first draft of the endostatin interaction network. 1954 24