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)

Fibrinolysis is a precisely orchestrated process in which fibrin-containing thrombi are solubilized. Several receptors regulate this process by localizing proteolytic activity to the cell surface. One such receptor is annexin II, a calcium and phospholipid-binding protein. Annexin II serves as a profibrinolytic coreceptor for both plasminogen and tissue plasminogen activator on the surface of endothelial cells and facilitates the generation of plasmin. The dysregulation of fibrinolytic assembly on endothelial cells may lead to atherothrombotic disease. In addition to its role in fibrinolysis at the surface of endothelial cells, annexin II may play other potential cellular roles. For example, the overexpression of annexin II on the surface of leukemic cells and cell lines derived from acute promyelocytic leukemia correlates with both the clinical manifestation of bleeding and the in vitro ability of the leukemic cells to generate plasmin. The abundant presence of annexin II on the surface of other cell types including monocytic cell lines and different cancer cells may contribute to their invasive potential through extracellular matrix either by generation of plasmin or, by plasmin-mediated proteolytic activation of other metalloproteinases. This dissolution of extracellular matrix may also cause the release of potent matrix-bound angiogenic factors such as VEGF and FGF. On the other hand, by increasing the pool of plasmin, a precursor to an important anti-angiogenic factor, angiostatin, and by fragmentation of collagen XVIII (a precursor to the anti-angigenic factor, endostatin) by plasmin-activated metalloproteases, annexin II could play a pivotal physiological role in the pro- and anti-angiogenic switch mechanism.
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PMID:Annexin II: a plasminogen-plasminogen activator co-receptor. 1181 88

In this review, the cellular and molecular mechanisms underlying angiogenesis in lymphoproliferative disorders are summarized, alongside with possible therapeutic applications. Although most of the initial studies in angiogenesis were done on solid tumors, recent data demonstrate the importance of angiogenesis in hematological malignancies including leukemia, lymphoma, and multiple myeloma. Expression of angiogenic polypeptides vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) correlate with clinical characteristics in leukemia and lymphoma, and their serum concentrations serve as predictors of poor prognosis. Antiangiogenic drugs, including thalidomide, arsenic trioxide, endostatin, vasostatin, and neutralizing antibodies to VEGF receptors, used alone or in combination with established chemo- or immunotherapy regimens, constitute a promising approach for the treatment of lymphoproliferative disorders.
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PMID:Angiogenesis in lymphoproliferative disorders. 1181 16

Angiogenesis, an essential process for tumor growth, is regulated by endothelial proliferation factors and their inhibitors such as endostatin. Endostatin, a carboxyl-terminal fragment of type XVIII collagen, inhibits endothelial proliferation, angiogenesis, and tumor growth. Ornithine decarboxylase (ODC), a molecule that is overexpressed in various cancers, is associated with promoting tumor growth and angiogenesis. We found that ODC-overexpressing human cancer cells and breast cancer specimens showed suppressed expression of type XVIII collagen and endostatin. We hypothesized that ODC overexpression may facilitate angiogenesis in tumors by suppressing endostatin expression. ODC-overexpressing COS cells, which showed suppressed type XVIII collagen and endostatin expression, were established. Conditioned media derived from these cells, containing decreased levels of endostatin, induced significant endothelial proliferation. ODC-overexpressing cells, when transplanted into nude mice, suppressed type XVIII collagen expression and promoted neovascularization in vivo. Thus, overexpression of ODC facilitates endothelial proliferation by suppressing endostatin expression.
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PMID:Overexpression of ornithine decarboxylase enhances endothelial proliferation by suppressing endostatin expression. 1183 May 3

Many new biotherapy agents to treat cancer are being studied as single agents and in combination with conventional cancer therapy, such as chemotherapy. These agents include the monoclonal antibodies, rituximab, trastuzumab, alemtuzumab, and IMC-C225. Radioimmunotherapy, a type of biotherapy that combines a radioactive isotope with a monoclonal antibody, also is being studied and has shown promise in the treatment of lymphoma. A tyrosine kinase inhibitor, STI 571, has been approved recently by the U.S. Food and Drug Administration. Several vaccines as cancer treatment are currently under investigation. Other biotherapy agents being investigated include angiogenesis inhibitors, such as endostatin, antivascular endothelial cell growth factor, and thalidomide, an agent that inhibits the formation of blood vessels that supply tumors.
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PMID:New agents and future directions in biotherapy. 1184 84

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.
Int J Cancer 2002 Feb 20
PMID:Antiangiogenic activity of endostatin inhibits C6 glioma growth. 1185 65

The use of tumor angiogenesis as a therapeutic target is based on extensive literature showing the dependence of tumors on the process of angiogenesis for growth, invasion, and metastasis. Seminal work performed by Folkman three decades ago determined that tumors beyond the size of approximately 2 mm require angiogenesis for subsequent growth and development. This basic hypothesis stimulated research in the field of angiogenesis and has resulted in the identification of factors that both enhance and inhibit this "angiogenic switch." The intent of this article is to present data on several angiogenesis inhibitors that are currently undergoing clinical evaluation in cancer patients. These agents may be particularly useful in the treatment of lung cancer, both as adjunctive therapy in early-stage or locally advanced disease, as well as in combination strategies with platinum-based therapy in metastatic disease. Although angiogenesis inhibitors have been in clinical trials for the past decade, there has been a shift in recent years towards the development of more mechanism-based and receptor-targeted agents. Interestingly, no antiangiogenic agent has been approved as such for use in cancer, perhaps because of the challenges involved in the clinical development of these novel agents. These include the potential requirement for long-term administration, difficulties in deriving biologically efficacious doses in early clinical trials, and the inability to use tumor regression as a primary endpoint in phase II trials.
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PMID:Angiogenesis inhibitors in clinical development for lung cancer. 1189 16

Angiogenesis is essential for growth and metastasis of solid tumors and probably also for hematological malignancies. Angiogenic inhibitors, like endostatin (ES) and PI-88, retard cancer growth. We tested these in mice with juvenile myelomonocytic leukemia (JMML), and in rats with acute myeloid leukemia (BNML). Eight weeks after transplantation and with a continuous drug treatment for the last 4 weeks, the leukemic cell mass decreased from almost 90% of all bone marrow cells to about 15 and 45% with ES, to about 35 and 55% with PI-88, and to about 10 and 25% with ES + PI-88 in the leukemic mice and rats, respectively. The numbers of normal human bone marrow cells transplanted into mice were unchanged by the treatments. The microvessel density in leukemic animals given ES or PI-88 was 10-50% of that in untreated animals. Notably, simultaneous treatment with ES and PI-88 led to a reduction of about 95% in JMML mice and 85% in BNML rats. In vitro proliferation of either JMML or BNML cells was not significantly altered by either drug, demonstrating the selectivity of ES and PI-88 as angiogenic inhibitors. In conclusion, anti-angiogenic therapy may be a valuable adjunct to conventional treatment of leukemia.
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PMID:Inhibitors of angiogenesis selectively reduce the malignant cell load in rodent models of human myeloid leukemias. 1189 41

Endostatin, an endogenous angiogenesis inhibitor, attenuates endothelial cell migration through an unknown mechanism. We show that endostatin induced tyrosine phosphorylation of focal adhesion kinase and paxillin, and promoted formation of focal adhesions and actin stress fibers, similar to fibroblast growth factor-2 (FGF-2). In cells cotreated with endostatin and FGF-2, focal adhesions and actin stress fibers were decreased, indicating that endostatin disturbs cell-matrix adhesion. Reduced tyrosine phosphorylation and cytoplasmic relocalization of beta-catenin in cells treated with FGF-2 and endostatin indicates that loosening of cell-cell adhesion is also disturbed by endostatin. These data provide a molecular basis both for the lack of effect of endostatin on the normal, quiescent vasculature, and its antagonistic effects on stimulated tumor vessels.
Cancer Res 2002 Apr 01
PMID:Endostatin regulates endothelial cell adhesion and cytoskeletal organization. 1192 7

Endostatin, a 20-kDa carboxy-terminal fragment of collagen XVIII, is the leading member of a class of physiologic inhibitors of angiogenesis with potent antitumor activity. Repeated subcutaneous administration of recombinant endostatin in mice led to permanent regression of established tumors to a microscopic dormant state and prompted the initiation of human clinical trials. However, a discrepancy remained unresolved: sustained tumor regression has only been observed with a non-soluble, precipitated form of recombinant endostatin produced in bacteria. To shed light on this question and establish a model of systemic anti-angiogenic gene therapy of cancer that may surmount obstacles in protein production and delivery, we transduced murine hematopoietic stem cells with a retrovirus encoding a secretable form of endostatin. Despite continuous, high-level secretion of endostatin in the vasculature of all transplanted mice, we detected neither inhibition of in vivo neoangiogenesis nor antitumor activity. Resolution of this paradox may come from human trials of endostatin now underway.
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PMID:Continuous intravascular secretion of endostatin in mice from transduced hematopoietic stem cells. 1194 58

Retroviral transduction of hematopoietic stem cells (HSCs) offers an attractive strategy for treating malignancies that home to the marrow. This approach should therefore be of interest for evaluating the therapeutic activity of anti-angiogenic agents on hematopoietic malignancies whose growth has been associated with enhanced angiogenesis. A variety of studies have indicated endostatin to be a potent anti-angiogenic agent both in vitro and in vivo, and a human malignancy that might be sensitive to endostatin is human B-lineage acute lymphoblastic leukemia (B-ALL). The demonstrated ability of human B-ALL cells to engraft the marrow of immunodeficient mice suggested the potential of this system for testing an endostatin delivery strategy using co-transplanted non-obese diabetic-scid/scid (NOD/SCID) HSCs engineered to express endostatin. Here we show that, in spite of their mutant scid gene, NOD/SCID HSCs can be transduced with an endostatin-encoding retrovirus at efficiencies that result in a several-fold increase in endostatin serum levels in transplanted recipients. However, this did not alter the regrowth of co-transplanted human B-ALL blasts. These findings validate this gene transfer approach for investigating effects of novel therapeutics on primary human malignant cells that engraft NOD/SCID mice and question the utility of native endostatin for controlling human B-ALL in vivo.
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PMID:Unfulfilled promise of endostatin in a gene therapy-xenotransplant model of human acute lymphocytic leukemia. 1194 58


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