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)

Fetal mouse metatarsals are well-known models to study cartilage differentiation and osteoclastic resorption. We show here the outgrowth of PECAM-1 positive tubelike structures from the bone rudiments. This feature can be used to study angiogenesis in vitro. The area of outgrowth significantly increased with culture time, as shown by computerized image analysis of PECAM-1 positive tubelike structures. Treatment with recombinant human vascular endothelial growth factor (rhVEGF-A) stimulated the formation of tubelike structures. Treatment of explants with the angiogenesis inhibitor endostatin, the chemokine IP-10, and the thalidomide derivative phatolyl glutamic acid (PG-acid) resulted in an inhibition of the formation of PECAM-1 positive tubelike structures of 48.8% (+/- 4%), 50.2% (+/- 12%), and 80.8% (+/- 3%), respectively. Outgrowth of tubelike structures was partly dependent on endogenous VEGF-A because treatment with anti-mVEGF-A and truncated VEGF receptor 1 (soluble fms-like tyrosine kinase 1, sFIt1) strongly inhibited the formation of tubelike structures 74% (+/- 4%) and 38% (+/- 5%), respectively. Neither onset of tube formation nor total area of tubelike structures were changed when metatarsals were cultured on a fibrin gel or collagen type I gel. Tube formation required activation of matrix metalloproteinases because treatment of the bones with an inhibitor of matrix metalloproteinases completely inhibited migration and tube formation, whereas treatment with an inhibitor of plasmin had no effect. In conclusion, we describe a new in vitro model to study angiogenesis that can be used to test the angiogenic or antiangiogenic potential of novel test compounds that also combines the multicellularity of in vivo assays with the accessibility and flexibility of in vitro assays.
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PMID:Effect of angiogenic and antiangiogenic compounds on the outgrowth of capillary structures from fetal mouse bone explants. 1120 73

In the recent years, several pieces of evidence have pointed out that disease progression in multiple myeloma (MM) is characterized by an increased bone marrow neovascularization. Targeting the mechanisms that control angiogenesis could thus represent an innovative therapeutic approach to MM. Thalidomide, a glutamic acid derivative with sedative properties, is able to inhibit angiogenesis in murine models; this compound has recently demonstrated to be effective in relapsed/refractory MM, leading to a 30-40% response, coupled with mild systemic toxicity. Inhibition of angiogenesis is probably just one of the mechanisms by which thalidomide exerts its action in MM, as immunomodulation and inhibition of cytokine production by bone marrow stroma could also be involved. At present, several studies are ongoing, aiming at testing thalidomide-based drug combinations, mainly with dexamethasone, but also with conventional chemotherapy; the results that have been obtained so far show a synergistic effect of the drug combinations, with a response rate ranging from 50 to 70% in pretreated patients. There is now growing interest in novel compounds with potential antiangiogenic effects, among them a promising activity both in vitro and in animal models has been displayed by thalidomide analogs, inhibitors of vascular endothelial growth factor receptor-2 and endostatin.
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PMID:Antiangiogenic therapy in multiple myeloma. 1181 18

Initial work has shown that clonal B cells from B-chronic lymphocytic leukemia (B-CLL) are able to synthesize pro-angiogenic molecules. In this study, our goal was to study the spectrum of angiogenic factors and receptors expressed in the CLL B cell. We used ELISA assays to determine the levels of basic fibroblast growth factors (bFGF), vascular endothelial growth factor (VEGF), endostatin, interferon-alpha (IFN-alpha) and thrombospondin-1 (TSP-1) secreted into culture medium by purified CLL B cells. These data demonstrated that CLL B cells spontaneously secrete a variety of pro- and anti-angiogenic factors, including bFGF (23.9 pg/ml +/- 7.9; mean +/- s.e.m.), VEGF (12.5 pg/ml +/- 2.3) and TSP-1 (1.9 ng/ml +/- 0.3). Out of these three factors, CLL B cells consistently secreted bFGF and TSP-1, while VEGF was expressed in approximately two-thirds of CLL patients. Of interest, hypoxic conditions dramatically upregulated VEGF expression at both the mRNA and protein levels. We also employed ribonuclease protection assays to assay CLL B cell expression of a variety of other angiogenesis-related molecules. These analyses revealed that CLL B cells consistently express mRNA for VEGF receptor 1 (VEGFR1), thrombin receptor, endoglin, and angiopoietin. Further analysis of VEGFR expression by RT-PCR revealed that CLL B cells expressed both VEGFR1 mRNA and VEGFR2 mRNA. In summary, these data collectively indicate that CLL B cells express both pro- and anti-angiogenic molecules and several vascular factor receptors. Because of the co-expression of angiogenic molecules and receptors for some of these molecules, these data suggest that the biology of the leukemic cells may also be directly impacted by angiogenic factors as a result of autocrine pathways of stimulation.
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PMID:B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules. 1198 54

There are a number of novel, biologically targeted therapies, including anti-epidermal growth factor receptor agents (eg, ZD1839 and C225 [cetuximab]), anti-angiogenic agents (eg, vascular endothelial growth factor receptor inhibitors endostatin and angiostatin), and vascular targeting agents (eg, ZD6126), currently undergoing clinical development for a range of human cancers. These agents generally have milder toxicity profiles than conventional cytotoxic agents, and have the potential to be combined effectively with radiotherapy and other conventional modalities in the treatment of malignancies. In this review we consider the mechanistic rationale for combining biologically targeted agents with radiotherapy, present preclinical data to validate this hypothesis, and discuss early clinical investigations of these novel combination therapies, with an emphasis on ongoing trials in non-small cell lung cancer.
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PMID:The rationale and potential of combining novel biologic therapies with radiotherapy: focus on non-small cell lung cancer. 1290 42

The vascular endothelial growth factor (VEGF) tyrosine kinase receptors KDR and Flt-1 are targets of current interest in anticancer drug research. PTK787/ZK222584 is a potent inhibitor of these enzymes in clinical evaluation as an antiangiogenic agent. The development of a hypothesis concerning the bioactive conformation of this compound has led to the discovery of a new class of potent inhibitors of KDR and Flt-1, the anthranilamides. This could be achieved with a limited experimental effort, which only involved the testing of one archive compound and the synthesis and testing of one appropriate analogue.
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PMID:Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching. 1294 13

Circulating endothelial cells (CECs) are present in peripheral blood and have been shown to contribute to normal and pathological neovascularization. Antiangiogenic molecules can inhibit neovascularization in tumors and other sites, but their effect on CECs has not yet been determined. We hypothesize that angiogenic factors will increase the number of CECs, and conversely, antiangiogenic treatment will reduce these numbers. Mice treated with high levels of vascular endothelial growth factor (VEGF) showed increased numbers of Flk-1-positive cells in peripheral blood and endothelial cell colonies compared with vehicle-treated controls. These changes were accompanied by increased bone marrow neovascularization. In contrast, mice that received VEGF and endostatin had significantly lower numbers of CECs and reduced bone marrow vascularization. Endostatin-induced apoptosis was probably responsible for the decreased number of CECs. Systemic delivery of a VEGF antagonist, soluble Flt-1, also inhibited the VEGF-induced increase in CECs. These results were further confirmed in a Tie2/LacZ mouse model, in which endostatin reduced the number of beta-galactosidase-expressing peripheral blood mononuclear cells. We propose that endothelial progenitor cells are a novel target for endostatin and suggest that the relative numbers of CECs can serve as a surrogate marker for the biological activity of antiangiogenic treatment.
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PMID:Endostatin inhibits the vascular endothelial growth factor-induced mobilization of endothelial progenitor cells. 1467 95

Angiogenesis, the development of new vessels from a pre-existing vasculature, accompanies the growth and malignant transformation of astrocytic brain tumors. Neovascularization is essential for sustained tumor growth, and with increasing grade, astrocytic tumors undergo an, angiogenic switch, manifested by marked increases in vessel density and changes in vascular morphology. In the quiescent state, endogenous anti-angiogenic factors including endostatin, thrombospondin, and soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) balance the actions of pro-angiogenic stimuli and restrain the angiogenic switch. Once activated, pro-angiogenic factors including most notably basic fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF-A), and platelet-derived growth factor (PDGF) incite robust astrocytoma neovascularization. Recent studies have also explored the expression patterns and functional importance of the angiopoietins, Tie2 and neuropilin receptors, and hepatocyte growth factor/scatter factor (HGF). Together these angiogenic factors have diverse actions on endothelium and perivascular supporting cells that engender tumor neovessels with a unique phenotype, distinct from normal vessels. Properties of the astrocytoma neovasculature contribute to tumor growth, malignant progression, invasion, hemorrhage, and edema formation. Thus, the mechanistic actions of angiogenic factors on cerebral microvessels and the nature of the resultant tumor neovasculature establish a framework for understanding many of the characteristic behaviors of astrocytoma tumors.
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PMID:Angiogenesis and its role in the behavior of astrocytic brain tumors. 1535 41

Glioblastoma is a fatal brain tumor that becomes highly vascularized by secreting proangiogenic factors and depends on continued angiogenesis to increase in size. Consequently, a successful antiangiogenic therapy should provide long-term inhibition of tumor-induced angiogenesis, suggesting long-term gene transfer as a therapeutic strategy. In this study a soluble vascular endothelial growth factor receptor (sFlt-1) and an angiostatin-endostatin fusion gene (statin-AE) were codelivered to human glioblastoma xenografts by nonviral gene transfer using the Sleeping Beauty (SB) transposon. In subcutaneously implanted xenografts, co-injection of both transgenes showed marked anti-tumor activity as demonstrated by reduction of tumor vessel density, inhibition or abolition of glioma growth, and increase in animal survival (P = 0.003). Using luciferase-stable engrafted intracranial gliomas, the anti-tumor effect of convection-enhanced delivery of plasmid DNA into the tumor was assessed by luciferase in vivo imaging. Sustained tumor regression of intracranial gliomas was achieved only when statin-AE and sFlt-1 transposons were coadministered with SB-transposase-encoding DNA to facilitate long-term expression. We show that SB can be used to increase animal survival significantly (P = 0.008) by combinatorial antiangiogenic gene transfer in an intracranial glioma model.
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PMID:Combinatorial antiangiogenic gene therapy by nonviral gene transfer using the sleeping beauty transposon causes tumor regression and improves survival in mice bearing intracranial human glioblastoma. 1615 Jun 49

Angiogenesis is essential for solid tumor growth. Although successful antiangiogenic therapies have been demonstrated in animal models, a systematic comparison of the efficacy of different antiangiogenic factors has not been described in the hepatic environment. To address this issue, CT26 murine colon carcinoma cells were transfected with retroviral vectors encoding murine endostatin (mEndostatin), human angiostatin (hAngiostatin), murine-soluble vascular endothelial growth factor receptor-2, (msFlk-1), or murine-soluble Tie2 (msTie2). The transfected cells were then subjected to another round of transfection with a luciferase cDNA-encoding retroviral vector. Expression of these putative antiangiogenic proteins inhibited the proliferation of human umbilical vein endothelial cells in vitro but not tumor cells. To examine effects on tumor growth in vivo, modified cells were delivered via intrasplenic injection into BALB/c mice to induce liver metastases. Tumor burden was measured weekly by bioluminescence. Growth of hepatic metastases in vivo was significantly reduced in mice that were administered cells expressing msTie2 (76% reduction compared with control cells 21 days after intrasplenic inoculation; P < 0.05). Similar results were observed with cells that expressed msFlk-1 and hAngiostatin. However, expression of mEndostatin had no significant effect on the growth of liver metastases compared with control animals. These findings indicate that multiple antiangiogenic pathways are necessary for the growth of hepatic metastases, and each of these pathways is a potential clinically relevant antiangiogenic target for the treatment of this disease.
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PMID:A comparison of antiangiogenic therapies for the prevention of liver metastases. 1624 20

We developed a cultivated oral mucosal epithelial sheet (COE) transplantation system to address severe human ocular surface disorders. Unlike the cultivated corneal epithelial sheet (CCE), the COE induces mild superficial peripheral neovascularization although central clarity is maintained. To evaluate the characteristic differences between CCE and COE regarding to angiogenesis, we examined the expression of angiogenesis-related factors in CCE and COE. Using samples of CCE and COE, we immunohistochemically determined protein expression of the angiogenesis related factors: Thrombospondin-1 (TSP-1), pigment epithelium derived factor (PEDF), endostatin, angiostatin, vascular endothelial growth factor (VEGF), Fms-like tyrosine kinase 1 (Flt-1), kinase insert domain receptor (KDR), and basic fibroblast growth factor (bFGF). We used Western blot analysis to confirm the factors that were immunohistochemically different in CCE and COE. The immunohistochemical staining intensity of TSP-1 was higher in CCE than COE and by Western blot analysis the expression of TSP-1 was significantly higher in CCE than COE (P<0.05). PEDF and endostatin stained moderately stronger in CCE than COE. Immunohistochemically there was no obvious difference between CCE and COE with respect to angiostatin, VEGF, Flt-1, KDR, and bFGF. In comparison with CCE, COE showed decreased expression of anti-angiogenic factors particularly TSP-1. This different expression may relate to the superficial peripheral neovascularization encountered after COE transplantation.
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PMID:Different expression of angiogenesis-related factors between human cultivated corneal and oral epithelial sheets. 1672 21


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