Angiostatins
Dependovirus
Injections, Intramuscular
Genetic Vectors
DNA molecules capable of autonomous replication within a host cell and into which other DNA sequences can be inserted and thus amplified. Many are derived from PLASMIDS; BACTERIOPHAGES; or VIRUSES. They are used for transporting foreign genes into recipient cells. Genetic vectors possess a functional replicator site and contain GENETIC MARKERS to facilitate their selective recognition.
Glioma
Benign and malignant central nervous system neoplasms derived from glial cells (i.e., astrocytes, oligodendrocytes, and ependymocytes). Astrocytes may give rise to astrocytomas (ASTROCYTOMA) or glioblastoma multiforme (see GLIOBLASTOMA). Oligodendrocytes give rise to oligodendrogliomas (OLIGODENDROGLIOMA) and ependymocytes may undergo transformation to become EPENDYMOMA; CHOROID PLEXUS NEOPLASMS; or colloid cysts of the third ventricle. (From Escourolle et al., Manual of Basic Neuropathology, 2nd ed, p21)
Brain Neoplasms
Neoplasms of the intracranial components of the central nervous system, including the cerebral hemispheres, basal ganglia, hypothalamus, thalamus, brain stem, and cerebellum. Brain neoplasms are subdivided into primary (originating from brain tissue) and secondary (i.e., metastatic) forms. Primary neoplasms are subdivided into benign and malignant forms. In general, brain tumors may also be classified by age of onset, histologic type, or presenting location in the brain.
Genetic Therapy
Glioblastoma
A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures.
Angiostatin binds ATP synthase on the surface of human endothelial cells. (1/210)
Angiostatin, a proteolytic fragment of plasminogen, is a potent antagonist of angiogenesis and an inhibitor of endothelial cell migration and proliferation. To determine whether the mechanism by which angiostatin inhibits endothelial cell migration and/or proliferation involves binding to cell surface plasminogen receptors, we isolated the binding proteins for plasminogen and angiostatin from human umbilical vein endothelial cells. Binding studies demonstrated that plasminogen and angiostatin bound in a concentration-dependent, saturable manner. Plasminogen binding was unaffected by a 100-fold molar excess of angiostatin, indicating the presence of a distinct angiostatin binding site. This finding was confirmed by ligand blot analysis of isolated human umbilical vein endothelial cell plasma membrane fractions, which demonstrated that plasminogen bound to a 44-kDa protein, whereas angiostatin bound to a 55-kDa species. Amino-terminal sequencing coupled with peptide mass fingerprinting and immunologic analyses identified the plasminogen binding protein as annexin II and the angiostatin binding protein as the alpha/beta-subunits of ATP synthase. The presence of this protein on the cell surface was confirmed by flow cytometry and immunofluorescence analysis. Angiostatin also bound to the recombinant alpha-subunit of human ATP synthase, and this binding was not inhibited by a 2,500-fold molar excess of plasminogen. Angiostatin's antiproliferative effect on endothelial cells was inhibited by as much as 90% in the presence of anti-alpha-subunit ATP synthase antibody. Binding of angiostatin to the alpha/beta-subunits of ATP synthase on the cell surface may mediate its antiangiogenic effects and the down-regulation of endothelial cell proliferation and migration. (+info)Angiostatin formation involves disulfide bond reduction and proteolysis in kringle 5 of plasmin. (2/210)
Plasmin is processed in the conditioned medium of HT1080 fibrosarcoma cells producing fragments with the domain structures of the angiogenesis inhibitor, angiostatin, and microplasmin. Angiostatin consists of kringle domains 1-4 and part of kringle 5, while microplasmin consists of the remainder of kringle 5 and the serine proteinase domain. Our findings indicate that formation of angiostatin/microplasmin involves reduction of plasmin by a plasmin reductase followed by proteolysis of the reduced enzyme. We present evidence that the Cys461-Cys540 and Cys511-Cys535 disulfide bonds in kringle 5 of plasmin were reduced by plasmin reductase. Plasmin reductase activity was secreted by HT1080 and Chinese hamster ovary cells and the human mammary carcinoma cell lines MCF-7, MDA231, and BT20 but not by the monocyte/macrophage cell line THP-1. Neither primary foreskin fibroblasts, blood monocyte/macrophages, nor macrovascular or microvascular endothelial cells secreted detectable plasmin reductase. In contrast, cultured bovine and rat vascular smooth muscle cells secreted small but reproducible levels of plasmin reductase. Reduction of the kringle 5 disulfide bonds triggered cleavage at either Arg529-Lys530 or two other positions C-terminal of Cys461 in kringle 5 by a serine proteinase. Plasmin autoproteolysis could account for the cleavage, although another proteinase was mostly responsible in HT1080 conditioned medium. Three serine proteinases with apparent Mr of 70, 50, and 39 were purified from HT1080 conditioned medium, one or more of which could contribute to proteolysis of reduced plasmin. (+info)Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. (3/210)
Solid tumors depend on angiogenesis for their growth. In a transgenic mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), an angiogenic switch occurs in premalignant lesions, and angiogenesis persists during progression to expansive solid tumors and invasive carcinomas. RIP1-Tag2 mice were treated so as to compare the effects of four angiogenesis inhibitors at three distinct stages of disease progression. AGM-1470, angiostatin, BB-94, and endostatin each produced distinct efficacy profiles in trials aimed at preventing the angiogenic switch in premalignant lesions, intervening in the rapid expansion of small tumors, or inducing the regression of large end-stage cancers. Thus, anti-angiogenic drugs may prove most efficacious when they are targeted to specific stages of cancer. (+info)Systemic gene delivery expands the repertoire of effective antiangiogenic agents. (4/210)
Cationic liposome-DNA complex (CLDC)-based intravenous gene delivery targets gene expression to vascular endothelial cells, macrophages and tumor cells. We used systemic gene delivery to identify anti-angiogenic gene products effective against metastatic spread in tumor-bearing mice. Specifically, CLDC-based intravenous delivery of the p53 and GM-CSF genes were each as effective as the potent antiangiogenic gene, angiostatin, in reducing both tumor metastasis and tumor angiogenesis. Combined delivery of these genes did not increase anti-tumor activity, further suggesting that each gene appeared to produce its antimetastatic activity through a common antiangiogenic pathway. CLDC-based intravenous delivery of the human wild type p53 gene transfected up to 80% of tumor cells metastatic to lung. Furthermore, it specifically induced the expression of the potent antiangiogenic gene, thrombospondin-1, indicating that p53 gene delivery in vivo may inhibit angiogenesis by inducing endogenous thrombospondin-1 expression. CLDC-based delivery also identified a novel anti-tumor activity for the metastasis suppressor gene CC3. Thus, CLDC-based intravenous gene delivery can produce systemic antiangiogenic gene therapy using a variety of different genes and may be used to assess potential synergy of combined anti-tumor gene delivery and to identify novel activities for existing anti-tumor genes. (+info)Angiostatin inhibits endothelial and melanoma cellular invasion by blocking matrix-enhanced plasminogen activation. (5/210)
Angiostatin, a kringle-containing fragment of plasminogen, is a potent inhibitor of angiogenesis. The mechanism(s) responsible for the anti-angiogenic properties of angiostatin are unknown. We now report that human angiostatin blocks plasmin(ogen)-enhanced in vitro invasion of tissue plasminogen activator (t-PA)-producing endothelial and melanoma cells. Kinetic analyses demonstrated that angiostatin functions as a non-competitive inhibitor of extracellular-matrix (ECM)-enhanced, t-PA-catalysed plasminogen activation, with a Ki of 0.9+/-0.03 microM. This mechanism suggests that t-PA has a binding site for the inhibitor angiostatin, as well as for its substrate plasminogen that, when occupied, prevents ternary complex formation between t-PA, plasminogen and matrix protein. Direct binding experiments confirmed that angiostatin bound to t-PA with an apparent Kd [Kd(app)] of 6.7+/-0.7 nM, but did not bind with high affinity to ECM proteins. Together, these data suggest that angiostatin in the cellular micro-environment can inhibit matrix-enhanced plasminogen activation, resulting in reduced invasive activity, and suggest a biochemical mechanism whereby angiostatin-mediated regulation of plasmin formation could influence cellular migration and invasion. (+info)Suppression of angiogenesis and tumor growth by the inhibitor K1-5 generated by plasmin-mediated proteolysis. (6/210)
Proteolytic enzymes are involved in generation of a number of endogenous angiogenesis inhibitors. Previously, we reported that angiostatin, a potent angiogenesis inhibitor, is a proteolytic fragment containing the first four kringle modules of plasminogen. In this report, we demonstrate that urokinase-activated plasmin can process plasminogen to release an angiogenesis inhibitor, K1-5 (protease-activated kringles 1-5). K1-5 inhibits endothelial-cell proliferation with a half-maximal concentration of approximately 50 pM. This inhibitory effect is endothelial-cell-specific and appears to be at least approximately 50-fold greater than that of angiostatin. A synergistic efficacy of endothelial inhibition was observed when angiostatin and kringle 5 (K5) were coincubated with capillary endothelial cells. The synergistic effect is comparable to that produced by K1-5 alone. Systemic treatment of mice with K1-5 at a low dose significantly blocked the fibroblast growth factor-induced corneal neovascularization, whereas angiostatin had no effect at the same dose. K1-5 also suppressed angiogenesis in chicken embryos. Systemic administration of K1-5 at a low dose at which angiostatin was ineffective significantly suppressed the growth of a murine T241 fibrosarcoma in mice. The antitumor effect correlates with the reduced neovascularization. These findings suggest that the plasmin-mediated proteolysis may be involved in the negative switch of angiogenesis. (+info)Therapeutic potentials of angiostatin in the treatment of cancer. (7/210)
The discovery of specific endothelial inhibitors such as angiostatin and endostatin not only increases our understanding of the functions of these molecules in the regulation of physiological and pathological angiogenesis, but also provides an important therapeutic strategy for cancer treatment. Recent studies have demonstrated that the angiostatin protein significantly suppresses the growth of a variety of tumors in mice. However, the dosages of angiostatin protein used in these animal studies seem to be too high for clinical trials. In addition, repeated injections and long-term treatment with angiostatin are required to reach its maximal antitumor effect. In this article, I will discuss several alternative approaches that may become feasible to move angiostatin therapy from animal experiments into the clinic. In particular, I will emphasize the therapeutic potentials of angiostatin gene therapy and more potent angiogenesis inhibitors that are related to angiostatin. (+info)Liposomes complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice. (8/210)
Gene therapy transfer of angiostatin and endostatin represents an alternative method of delivering angiogenic polypeptide inhibitors. We examined whether liposomes complexed to plasmids encoding angiostatin or endostatin inhibited angiogenesis and the growth of MDA-MB-435 tumors implanted in the mammary fat pads of nude mice. We determined that plasmids expressing angiostatin (PCI-Angio) or endostatin (PCI-Endo) effectively reduced angiogenesis using an in vivo Matrigel assay. We then investigated the efficacy of these plasmids in reducing the size of tumors implanted in the mammary fat pad of nude mice. Both PCI-Angio and PCI-Endo significantly reduced tumor size when injected intratumorally (P < 0.05). Compared to the untreated control group, the mice treated with PCI-Angio and PCI-Endo exhibited a reduction in tumor size of 36% and 49%, respectively. In addition, we found that i.v. injections of liposomes complexed to PCI-Endo reduced tumor growth in the nude mice by nearly 40% when compared to either empty vector (PCI) or untreated controls (P < 0.05). These findings provide a basis for the further development of nonviral delivery of antiangiogenic genes. (+info)
Therapeutic potentials of angiostatin in the treatment of cancer | Haematologica
Recombinant Human Plasminogen Angiostatin Kringles 1-3 | Cell Sciences
Human - Angiostatin - for Immunohistochemistry - Antibodies | BioVendor Research and Diagnostics Products
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Definition of angiostatin - NCI Drug Dictionary - National Cancer Institute
Combined effects of angiostatin and ionizing radiation in antitumour therapy
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Migration of MAE cells transfected with angiomotin or w | Open-i
Table of Contents - June 21, 1975, 2 (5972) | The BMJ
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Nucleic acids encoding plasminogen fragments - Patent # 6521439 - PatentGenius
Impaired Coronary Collateral Growth in the Metabolic Syndrome Is in Part Mediated by Matrix Metalloproteinase 12-Dependent...
Lung Overexpression of Angiostatin Aggravates Pulmonary Hypertension in Chronically Hypoxic Mice - Inserm
Increased angiostatin levels in bronchoalveolar lavage fluids from ARDS patients and from human volunteers after lung...
MGCD-265 - Evolution of NADPH Oxidase Inhibitors
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Beta globulins - Wikipedia
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Angiogenesis inhibitor improves brain tumor survival by redu... ( The beneficial effects of anti-angio...)
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Thrombospondin-1 regulates the normal prostate in vivo through angiogenesis and TGF-beta activation
Matrix metalloproteases from chondrocytes generate an antiangiogenic 16 kDa prolactin | Journal of Cell Science
run dream cook: molasses kringles
Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors - Full Text View - ClinicalTrials.gov
The p130 Isoform of Angiomotin Is Required for Yap-Mediated Hepatic Epithelial Cell Proliferation and Tumorigenesis | Science...
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T103N
Summary Report | CureHunter
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C-Met
Moreover, NK4 is structurally similar to angiostatins, which is why it possesses anti-angiogenic activity. Neutralizing anti- ...
Beta globulin
Examples of beta globulins include: beta-2 microglobulin plasminogen angiostatins properdin sex hormone-binding globulin ...
List of MeSH codes (D12.776)
... angiostatins MeSH D12.776.377.715.182.624 - properdin MeSH D12.776.377.715.182.800 - sex hormone-binding globulin MeSH D12.776. ... angiostatins MeSH D12.776.467.100.450.750 - endostatins MeSH D12.776.467.100.800.200 - vascular endothelial growth factor a ...
List of MeSH codes (D12.776.124)
... angiostatins MeSH D12.776.124.790.223.624 - properdin MeSH D12.776.124.790.223.800 - sex hormone-binding globulin MeSH D12.776. ...
Angiostatin
Angiostatins at the US National Library of Medicine Medical Subject Headings (MeSH) (Articles needing additional references ...
List of MeSH codes (D08)
... angiostatins MeSH D08.811.074.124 - deoxyribodipyrimidine photo-lyase MeSH D08.811.074.249 - dna glycosylases MeSH D08.811. ...
List of MeSH codes (D23)
... angiostatins MeSH D23.348.479.311.200.750 - endostatins MeSH D23.348.479.311.300 - fibroblast growth factor 1 MeSH D23.348. ...
List of MeSH codes (D12.644)
... angiostatins MeSH D12.644.276.100.450.750 - endostatins MeSH D12.644.276.100.800 - vascular endothelial growth factors MeSH ...
歯学部門 - 研究成果 - 九州大学
Suppression of intracranial human glioma growth after intramuscular administration of an adeno-associated viral vector...
Robert Duvoisin - Publications
- Oregon Health & Science University
Sansig, G., Bushell, T. J., Clarke, V. R. J., Rozov, A., Burnashev, N., Portet, C., Gasparini, F., Schmutz, M., Klebs, K., Shigemoto, R., Flor, P. J., Kuhn, R., Knoepfel, T., Schroeder, M., Hampson, D. R., Collett, V. J., Zhang, C., Duvoisin, R. M., Collingridge, G. L. & Van Der Putten, H., Nov 15 2001, In: Journal of Neuroscience. 21, 22, p. 8734-8745 12 p.. Research output: Contribution to journal › Article › peer-review ...
DeCS
2004; ANGIOSTATINS was indexed under PEPTIDE FRAGMENTS & PLASMINOGEN 1994-2003. History Note:. 2004; use ANGIOSTATINS (NM) 1994 ... Angiostatins - Preferred Concept UI. M0238172. Scope note. Circulating 38-kDa proteins that are internal peptide fragments of ... Angiostatins contain four KRINGLE DOMAINS which are associated with their potent angiostatic activity.. ... Angiostatins contain four KRINGLE DOMAINS which are associated with their potent angiostatic activity. ...