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

Cytogenin (8-hydroxy-3-hydroxymethyl-6-methoxyisocoumarin) is a new microbial product with antitumor and antirheumatoid arthritis effects in vivo when administered orally, although its mechanism(s) of action is not known well. Both neoplasia and rheumatoid arthritis are referred to as angiogenesis-dependent diseases. The aim of the present study was to investigate the effects of cytogenin on both physiological and pathological angiogenesis, using the growing chick embryo chorioallantoic membrane and mouse dorsal air sac assay systems, respectively. The microbial product at doses up to 100 micrograms/egg did not significantly affect embryonic angiogenesis when topically placed on the surface of the chorioallantoic membrane, suggesting that it has no effect on the physiological (or normal) angiogenic response. By contrast, systemic administration of cytogenin (100 mg/kg p.o., for 5 consecutive days) significantly suppressed angiogenesis induced by malignant tumor cells (S-180), one of pathological neovascularization, in a mouse dorsal air sac assay system. Pharmacokinetic studies in mice revealed that the maximal concentration of cytogenin in plasma after a single 100 mg/kg oral dose of the compound was 32 microM. In vitro experiments involving cultured vascular endothelial cells showed that cytogenin at concentrations determined by pharmacokinetic study, had little effect on plasminogen activator secretion, tube formation and the proliferation of endothelial cells. These results suggest that cytogenin is a novel oral antiangiogenic agent, that the mechanism of its antiangiogenic action contributes to its suppressive effects on both tumor growth and rheumatoid arthritis that we previously found, and that it could be developed as a potential therapeutic agent for cancer, rheumatoid arthritis and other angiogenesis-dependent disorders such as diabetic retinopathy.
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PMID:Effects of cytogenin, a novel microbial product, on embryonic and tumor cell-induced angiogenic responses in vivo. 921 39

There is growing evidence that anti-angiogenic drugs will improve future therapies of diseases like cancer, rheumatoid arthritis and ocular neovascularisation. However, it is still uncertain which kind of substance, out of the large number of angiogenesis inhibitors, will prove to be a suitable agent to treat these human diseases. There are currently more than 30 angiogenesis inhibitors in clinical trials and a multitude of promising new candidates are under investigation in vitro and in animal models. Important therapeutic strategies are: suppression of activity of the major angiogenic regulators like vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF); inhibition of function of alphav-integrins and matrix metalloproteinases (MMPs); the exploitation of endogenous anti-angiogenic molecules like angiostatin, endostatin or thrombospondin. Given the wide spectrum of diseases which could be treated by anti-angiogenic compounds, it is important for today's clinicians to understand their essential mode of action at a cellular and molecular level. Here we give an in-depth overview of the basic pathophysiological mechanisms underlying the different anti-angiogenic approaches used to date based on the most recent fundamental and clinical research data. The angiogenesis inhibitors in clinical trials are presented and promising future drug candidates are discussed.
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PMID:Target molecules for anti-angiogenic therapy: from basic research to clinical trials. 1079 35

Rheumatoid arthritis is a prevalent example of an inflammatory angiogenic disease, which is mediated by pro-inflammatory and pro-angiogenic cytokines such as tumor necrosis factor (TNF). To evaluate the effect of the potent anti-angiogenic factor endostatin on TNF-induced inflammatory arthritis, we injected an endostatin-expressing lentiviral vector directly into the joints of human TNF-transgenic mice before the onset of disease. Histological analysis of the injected joints 8 weeks later revealed that endostatin reduced blood vessel density within the synovial tissues and an overall mean arthritis index. In vitro and in vivo examination of the potential mechanism by which endostatin inhibited the arthritis revealed that endostatin blocks TNF-induced activation of JNK and JNK-dependent pro-angiogenic gene expression. These data suggest a novel mechanism by which endostatin inhibits angiogenesis, and demonstrates the potential utility of anti-angiogenic gene therapy for treatment of inflammatory arthritis.
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PMID:Endostatin gene transfer inhibits joint angiogenesis and pannus formation in inflammatory arthritis. 1199 45

The integrin receptor alphavbeta3 has been shown to play a critical role in several distinct processes, such as angiogenesis, osteoclast-mediated bone resorption and tumor metastasis. Its expression is upregulated in newly synthesized blood vessels produced in response to a variety of tumors and purified angiogenic factors. Studies show that alphavbeta3 is a critical target downstream from perhaps all angiogcnic factors. Proof-of-principle that alphavbeta3 antagonists such as monoclonal antibodies and small molecules block angiogenesis and tumor growth has been obtained in several animal models. Many endogenous inhibitors of angiogenesis such as angiostatin, endostatin and tumstatin seem to work through the alphavbeta3 receptor further emphasizing the critical role of this receptor in angiogenesis. In addition, the alphavbeta3 receptor has been clearly implicated in several pathological processes such as rheumatoid arthritis, osteoporosis, and metastasis of prostate cancer to bone. Thus alphavbeta3 may prove to be an important target for pharmacological intervention in more than one clinical setting.
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PMID:Integrin alpha v beta 3 as a therapeutic target for blocking tumor-induced angiogenesis. 1255 65

The aim of the present research was to study the relationship between chemical structure and antiangiogenic activity of endostatin. Four peptides, containing about 40 amino acid residues, designed to cover nearly the whole sequence of endostatin, were synthesized by the solid-phase method. They were termed Fragment I (sequence 6-49), II (sequence 50-92), III (sequence 93-133), and IV (sequence 134-178), with the latter bearing the original disulfide bond Cys135-Cys165. These peptides were tested for their ability to inhibit endothelial cell proliferation, migration, and both in vitro and in vivo angiogenesis assays in matrigel. Fragments I and IV inhibited cell proliferation and cell migration with a potency and an efficacy higher than that of the full length endostatin. Fragment I was also active in inhibiting in vitro the formation of tubules and in vivo the vascularization of the matrigel. Fragments II and III were devoid of antiangiogenic activity. We propose to use the peptides 6-49 and 134-178 as angiogenesis inhibitors in substitution of full length endostatin, in therapeutic applications for cancer, rheumatoid arthritis, and retinopathies.
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PMID:Studies on the structure-activity relationship of endostatin: synthesis of human endostatin peptides exhibiting potent antiangiogenic activities. 1295 68

Angiogenesis, the growth of new capillaries from pre-existing vessels, contributes to the development and progression of a variety of physio-pathological conditions. There is growing evidence that anti-angiogenic drugs will improve future therapies of diseases like cancer, rheumatoid arthritis and ocular neovascularisation. Conversely, therapeutic angiogenesis is an important homeostatic response contributing to limit the damage to ischemic tissues. Molecular processes involved in angiogenesis include stimulation of endothelial growth by cytokine production (i.e. vascular endothelial growth factor, VEGF; fibroblast growth factor-2, FGF-2), degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs), and migration of endothelial cells mediated by integrins (cell membrane adhesion molecules). Drugs targeting pathologic angiogenesis have been designed to interfere with any of these steps and are currently undergoing evaluation in early clinical studies. Important therapeutic strategies are: suppression of activity and signaling pathways activated by the major angiogenic regulators like VEGF and FGF-2; inhibition of function of alphav-integrins and MMPs; exploitation of endogenous anti-angiogenic molecules like angiostatin and endostatin. The strategy to "silence" endothelium with antiangiogenic drugs to starve tumors, provides a novel approach for cancer treatment. The unique targets of these drugs (endothelium) make them distinct from traditional cytotoxic chemotherapeutic agents. Conversely, gene transfer of angiogenesis inducers is the new approach for therapeutic neovascularization, which is under investigation using a variety of growth factors and a wide array of potential delivery systems, including the application of the gene as naked DNA or by viral vector. The status of pro- and anti-angiogenic therapies is here presented and discussed.
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PMID:Development of new drugs in angiogenesis. 1521 14

Angiogenesis is characterized by the development of new vasculature from pre-existing vessels and plays a central role in physiological processes such as embryogenesis, wound healing and female reproductive function, as well as pathophysiologic events including cancer, rheumatoid arthritis and diabetic retinopathy. The growth and metastasis of tumors is critically dependent upon angiogenesis. Although targeting angiogenesis as a therapeutic strategy has to date met with limited success in the clinic, the recent FDA approval of the anti-VEGF antibody Avastin has validated the use of anti-angiogenic therapeutic strategies for cancer treatment. We have recently identified several plasma proteins having anti-angiogenic properties, including Histidine-Proline-Rich Glycoprotein (HPRG) and activated high-molecular-weight kininogen (HKa). Both of these proteins are able to induce apoptosis in endothelial cells in vitro and can inhibit angiogenesis in vivo. Recent studies from our laboratories have also identified a novel cell-surface binding protein for HKa that mediates its anti-angiogenic activity. This protein, tropomyosin, is normally found inside the cell and is associated with the actin cytoskeleton, where it plays a critical role in stabilizing actin filaments in a variety of cell types. However, in angiogenic endothelial cells, tropomyosin appears to have extracellular localization. Previous studies have also suggested the involvement of tropomyosin in the anti-angiogenic activity of endostatin, and our recent work indicates that tropomyosin may mediate the antiangiogenic activity of HPRG as well. In this review, we summarize data describing extracellular tropomyosin as a novel receptor for multiple anti-angiogenic proteins. Extracellular tropomyosin may therefore represent a previously undescribed central target for the development of anti-angiogenic therapy.
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PMID:Extracellular tropomyosin: a novel common pathway target for anti-angiogenic therapy. 1557 12

Angiogenesis inhibition, which has been extensively studied for the treatment of various malignancies, is beginning to emerge as a new potential therapy for proliferative synovitis, particularly rheumatoid arthritis (RA). The rheumatoid pannus, the site of inflammation and joint destruction in the rheumatoid synovium, relies on the development of new vasculature to sustain its growth. A host of mediators have been shown to induce angiogenesis at the site of the inflamed synovium; these include vascular endothelial growth factor, fibroblast growth factor, integrin alpha(V)beta3, angiopoietin, prosta-glandin E1 and prostaglandin E2, and matrix metalloproteinases. In addition, hypoxia at the site of synovial inflammation contributes to angiogenesis stimulation. Several naturally-occurring inhibitors exist, such angiostatin and endostatin. There are a number of drugs undergoing study in the treatment of proliferative synovitis, which capitalise on the correlation between angiogenesis inhibition and the reduction of signs and symptoms of RA. Paclitaxel and an anti-integrin alpha(V)beta3 antibody, LM-609, are currently in clinical trials. Other drugs that may inhibit angiogenesis in RA include TNP-470 (formerly called AGM-1470), PPI-2458, PTK-787, bevacizumab and thalidomide. Many of these drugs have shown promise for the treatment of oncologic disorders, and are now being evaluated for the treatment of proliferative synovitis.
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PMID:New antiangiogenic strategies for the treatment of proliferative synovitis. 1570 17

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 formation of new blood vessels permits a supply of nutrients and oxygen to the proliferating synovial cells and augmented inflammatory cell mass in rheumatoid arthritis (RA). Angiogenesis inhibition is not dependent on a down-regulated immune system. Therefore, angiogenesis is an attractive target in treating rheumatoid arthritis. To confirm the effect of recombinant human endostatin, an angiogenesis inhibitor, on inflammatory angiogenesis and to elucidate the related mechanisms, rat adjuvant arthritis model induced by Freund's complete adjuvant was used. The secondary arthritis was evaluated by using clinical scores and determining the volume of hind paw swelling. The number of new blood vessels was counted under microscope based on HE (hematoxylin and eosin) staining and positive immunoreactivity of factor VIII related antigen. factor VIII related antigen and vascular endothelial growth factor (VEGF) expressions in synovial tissue were determined by using immunohistochemistry. It was found that endostatin attenuated rat secondary paw swelling induced by Freund's complete adjuvant in a dose-dependent manner. Meanwhile, the number of new blood vessels in synovial tissue stained with HE was reduced after treatment with endostatin, which was proved by the positive immunostaining of factor VIII related antigen. Further, endostatin decreased the expression of VEGF in both cartilage and synovial tissue. These suggest that endostatin inhibiting VEGF expression contributes to the regression of rat adjuvant arthritis.
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PMID:Blockage of the formation of new blood vessels by recombinant human endostatin contributes to the regression of rat adjuvant arthritis. 1749 Jun 37


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