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)

Work begun more than 30 years ago at Children's Hospital in Boston led to the publication of an article on the antiangiogenic properties of two compounds, endostatin and angiostatin (J. Folkman, Nature 1997; 390:404-7). It only took weeks for the medias in the US and then in France and the rest of Europe to stimulate the fervor of patients for this new 'cure' for cancer. Insight into the fundamental role of angiogenesis in locoregional and metastatic development of cancer has been accumulated over the last decades. Factors stimulating tumoral angiogenesis include aFGF, bFGF, VEGF, angiogenin, and other more recently discovered substances. Likewise, factors inhibiting tumoral angiogenesis, including angiostatin, have been identified. Angiostatin is a specific inhibitor of endothelial cell growth that migh appear rapidly in the serum of patients with a primary tumor. Angiostatin could have both local and systemic effects and possibly protect against metastatic dissemination in vivo. The importance of angiogenesis inhibitors was emphasized at the recent meeting of the American Association for Cancer Research (New Orleans March 28-April 1, 1998). To date, at least eleven compounds are being tested. Currently, most are in phase 1 or 2; for the few in phase 3, marketing approval will undoubtedly require several years. It is interesting to note that neither endostatin nor angiostatin are among the list of drugs under clinical assessment, first because these small human proteins are not available in sufficient quantity for therapeutic trials and secondly, because the processes necessary to produce pure and safe compounds remain to be developed. Even after these steps have been accomplished, preclinical evaluations will have to be performed before the first clinical trials could be envisaged. For the time being, antiangiogenesis remains a promising avenue of anti-cancer research but neither endostatin nor angiostatin will be available for human research for several months at least.
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PMID:[Tumor angiogenesis inhibitors: media and scientific aspects]. 976 82

The "angiogenic switch" and tumor angiogenesis play a critical role in the growth and metastasis of solid tumors. Tumor angiogenesis is regulated by a balance of stimulators (e.g., VEGF, bFGF) and inhibitors of angiogenesis (e.g., angiostatin, endostatin, angiostatic steroids). Measuring angiogenesis (blood vessel density) and/or its main regulators such as VEGF and bFGF in solid tumors, or the levels of these growth factors in the serum or urine provides new and sensitive markers for tumor progression, metastasis and prognosis.
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PMID:The diagnostic and prognostic value of tumor angiogenesis. 1002 73

Tumor angiogenesis is one of the most important fields of cancer research. It is important to identify the putative targets for antiangiogenic strategies. To date, a number of angiogenic agents have been identified: bFGF, the different VEGF isoforms, integrins, proteases (matrix metalloproteases and serine proteases),... Furthermore, several physiological anti-angiogenic agents have been isolated such as endostatin, angiostatin, 16 K prolactin,.... The recent development of mice deficient for one gene involved during angiogenesis gives a new insight into the molecular mechanisms regulating this process. It leads to the identification of plasminogen activator inhibitor-1 or PAI-1 as a new target for tumor treatment. Although, PAI-1 is very attractive as a target for new therapeutic strategies, a better understanding of its mechanism of action is needed urgently.
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PMID:[Preclinical features of anti-angiogenesis therapy]. 1098 53

Endostatin is a newly found inhibitor of angiogenesis, which is identified as c-terminal 184 amino acid fragment of collagen XVIII NC1-domain. A 570 bp cDNA fragment of endostatin has been amplified by PCR from a commercial human fetal liver cDNA library. After subcloned into the yeast vector pPIC9 and subsequence to prove its correctness, Pichia pastoris was transformed with the recombinant pPIC9-endostatin. The expressed endostatin in P. pastoris was purified by heparin-sapherose affinity chromatography. It's purity identified by SDS-PAGE thin layer scanning analysis was up to 98.7% and its Mol. Weight measured by MS was 20.34 kD. The expression level was up to 40 mg/L. The first fifteen amino acid sequence of the N-terminal was completely identical with the inner sequence C-terminal fragment of collagen XVIII NC1 domain as has been designed. Bioassay indicated that the recombinant endostatin can inhibit angiogenesis stimulated by bFGF in CAM test and also the proliferation of both HUVEC and ECV304 in an in vitro test.
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PMID:[Inhibition effect in vitro of purified endostatin expressed in Pichia pastoris]. 1151

Angiogenesis is a vital component of the development and progression of many human solid tumors. Glioblastoma multiforme is one of the most highly vascularised class of solid tumors. Thus, we have investigated the potential antitumourigenic activity of endostatin, an angiogenic inhibitor, in the rat C6 glioma model. We have engineered C6 cells that endogenously express mouse endostatin in order to assess the growth of C6 tumors in vivo when endostatin is constitutively expressed. Endostatin secreted by stably transfected C6 cells is biologically active as shown by its inhibition (26%) of bFGF-stimulated proliferation of BAECs in culture. The subcutaneous implantation of endostatin-C6 cells in athymic (nu/nu) mice resulted in a reduced tumor growth rate (90% inhibition) compared to control cell lines throughout the duration of our experiments. Tumor inhibition was associated with a 50% reduction in the number of vessels, which were also smaller in morphology. However, endostatin-C6 tumors were no more necrotic than control tumors. The implantation of endostatin-C6 cells into immunocompetent Wistar rat brains also resulted in reduced tumor volumes (71% inhibition) compared to controls. Tumor cells were sparsely localised along the injection tract but had not formed discrete tumors. Despite the inhibitory response mediated by endostatin on C6 growth, complete tumor inhibition or dormancy was not observed in either the athymic or immunocompetent tumor models. These findings demonstrate that the endogenous expression of endostatin by C6 glioma cells results in a reduced tumor growth rate in vivo that is associated with an inhibition of tumor angiogenesis. Our data suggest that endostatin should be developed as an adjuvant gene therapy for the effective treatment of gliomas.
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PMID:Antiangiogenic activity of endostatin inhibits C6 glioma growth. 1185 65

It has become increasingly clear that definitive tests for angiogenesis require in vivo assays. Recently, the Matrigel plug assay has become the method of choice for many studies involving in vivo testing for angiogenesis. In this assay, test angiogenesis-inducing compounds such as bFGF or tumor cells are introduced into cold liquid Matrigel which, after subcutaneous injection, solidifies and permits penetration by host cells and the formation of new blood vessels. Assessment of angiogenesis in the Matrigel plug is achieved either by measuring hemoglobin or by scoring selected regions of histological sections for vascular density. We now describe a modification of the Matrigel plug assay which permits a more precise visualization of the angiogenic reaction, provides directional information, requires no histological analysis, and lends itself to photographic documentation and image analysis protocols. We illustrate the assay by describing dose- and time-dependent responses to tumors of murine and human origin, to angiogenesis-inducing factors such as bFGF (FGF-2) and VEGF and to anti-angiogenic agents such as endostatin. The method has been used as well to demonstrate blood vessel recruitment by embryonic chick aortic arch rudiments. Additionally it has been able to detect strain-dependent differences in susceptibility to angiogenic stimulation.
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PMID:The sponge/Matrigel angiogenesis assay. 1254 62

Endostatin, a potent inhibitor of endothelial cell proliferation, migration, angiogenesis and tumor growth, is proteolytically cleaved from the C-terminal noncollagenous NC1 domain of type XVIII collagen. We investigated the endostatin formation from human collagen XVIII by several MMPs in vitro. The generation of endostatin fragments differing in molecular size (24-30 kDa) and in N-terminal sequences was identified in the cases of MMP-3, -7, -9, -13 and -20. The cleavage sites were located in the protease-sensitive hinge region between the trimerization and endostatin domains of NC1. MMP-1, -2, -8 and -12 did not show any significant activity against the C-terminus of collagen XVIII. The anti-proliferative effect of the 20-kDa endostatin, three longer endostatin-containing fragments generated in vitro by distinct MMPs and the entire NC1 domain, on bFGF-stimulated human umbilical vein endothelial cells was established. The anti-migratory potential of some of these fragments was also studied. In addition, production of endostatin fragments between 24-30 kDa by human hepatoblastoma cells was shown to be due to MMP action on type XVIII collagen. Our results indicate that certain, especially cancer-related, MMP family members can generate biologically active endostatin-containing polypeptides from collagen XVIII and thus, by releasing endostatin fragments, may participate in the inhibition of endothelial cell proliferation, migration and angiogenesis.
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PMID:Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. 1595 Jun 18

Endostatin is a potent inhibitor of angiogenesis and tumor growth. Here, we used human endothelial cells from lung capillaries to investigate if endostatin competes with the proangiogenic growth factors, bFGF and VEGF, for binding to costimulatory heparan sulfate molecules. Endostatin inhibited 79% and 95% of the increase in proliferation induced by bFGF and VEGF165, respectively. The stimulatory effect of VEGF165 was not affected by the presence of exogenous heparin, while that of bFGF was further enhanced in the presence of up to 0.1 microg/ml heparin. The heparin-binding protein protamine completely blocked bFGF-stimulated proliferation, while it did not affect the response to VEGF165. Simultaneous addition of endostatin and protamine led to additive effects both in inhibition of proliferation and induction of apoptosis. Although bFGF was found to bind more strongly to heparin-Sepharose than endostatin, the latter, but not the former, displaced protamine from heparin in solution, which supports the notion that endostatin can compete with bFGF for binding to heparan sulfate in vivo. Taken as a whole, our results demonstrate that there is a direct connection between the dependence of endostatin activity on heparin-like glycosaminoglycans and its ability to antagonize bFGF.
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PMID:Endostatin competes with bFGF for binding to heparin-like glycosaminoglycans. 1598 16

Standard chemotherapeutic drugs, when modified by the frequency and dose of administration, can target angiogenesis. This approach is referred to as antiangiogenic chemotherapy, low-dose chemotherapy, or metronomic chemotherapy. This study evaluated the feasibility of 6 months of metronomic chemotherapy, its toxicity and tolerability, surrogate markers of activity, and preliminary evidence of activity in children with recurrent or progressive cancer. Twenty consecutive children were enrolled and received continuous oral thalidomide and celecoxib with alternating oral etoposide and cyclophosphamide every 21 days for a planned duration of 6 months using antiangiogenic doses of all four drugs. Surrogate markers including bFGF, VEGF, endostatin, and thrombospondin were also evaluated. Therapy was well tolerated in this heavily pretreated population. Toxicities (predominantly reversible bone marrow suppression) responded to dose modifications. Sixty percent of the patients received less than the prescribed 6 months of therapy due to toxicity (one case of deep vein thrombosis), personal choice (1 patient), or disease progression (10 patients). Forty percent of the patients completed the 6 months of therapy, resulting in prolonged or persistent disease-free status. One quarter of all patients continue to be progression free more than 123 weeks from starting therapy. Sixteen percent of patients showed a radiographic partial response. Only elevated thrombospondin-1 levels appeared to correlate with prolonged response. This oral antiangiogenic chemotherapy regimen was well tolerated in this heavily pretreated pediatric population, which showed prolonged or persistent disease-free status, supporting the continued study of antiangiogenic/metronomic chemotherapy in human clinical trials.
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PMID:A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. 1628 85

Imiquimod (imidazoquinoline 5%) is a topical immune response modifier agent that inhibits angiogenesis, the growth of new blood vessels. In addition to its stimulation of cell-mediated immunity, imiquimod's antiangiogenic activity contributes to its clinical efficacy by interfering with pathological neovascularization that promotes disease progression. The antiangiogenic mechanisms of imiquimod are due to its: 1) induction of cytokines that themselves inhibit angiogenesis (interferons, IL-10, IL-12); 2) local up-regulation of endogenous angiogenesis inhibitors (TIMP, TSP-1); 3) local down-regulation of pro-angiogenic factors (bFGF, MMP-9); and 4) promotion of endothelial cell apoptosis. This report discusses these mechanisms and the rationale for imiquimod's use as an antiangiogenic agent. Key principles of antiangiogenic therapy are presented to describe how imiquimod may be applied in a well-tolerated fashion to treat a broad range of angiogenesis-dependent dermatological conditions, including actinic keratosis (AK), basal cell carcinoma (BCC), squamous cell carcinoma (SCC), lentigo maligna, hemangiomas, Kaposi's sarcoma, pyogenic granuloma, and external genital warts.
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PMID:Imiquimod as an antiangiogenic agent. 1630 56


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