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)

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

EntreMed has licensed the worldwide rights to the angiogenesis inhibitor Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, from the Children's Hospital of Boston, a teaching affiliate of Harvard Medical School. It is being developed as a potential cancer treatment and may also be useful in certain types of blindness and arthritis [227427]. EntreMed filed an IND for Endostatin in June 1999 [334125] and as of September 1999, phase I trials were underway [341462]. As of April 2000, the company had initiated plans for testing low doses of Endostatin in cancer patients using continuous infusion and sc administration in a further phase I study to be conducted in Europe [361594]. A phase I trial of Endostatin which will evaluate the safety and efficacy of Endostatin at a range of doses in no more than 100 cancer patients has been initiated. The trial will take place at the University of Texas MD Anderson Medical Center and the University of Wisconsin Cancer Center in Madison. The National Cancer Center will be sponsoring the trial, which is expected to be completed in late 2000. As of March 2000, there had been no serious adverse events attributable to Endostatin administration. The first report from this trial is expected in autumn 2000 [341462], [366312]. The mechanism of action for Endostatin remains unclear, although reports from the 91st AACR Meeting in April 2000 showed that recombinant human endostatin bound to a number of tropomyosin cDNAs in a library screen [362039]. In preclinical studies, repeated administration of Endostatin consistently shrank primary tumors and did not produce any drug resistance. In mice, a variety of tumors which had progressed to 1 to 2% of total body weight, regressed to microscopic, dormant lesions following Endostatin treatment [231418], [231470], [270673]. Types of cancers which respond to Endostatin include lung, skin, vascular and fibrosarcomas. Toxicology studies in cynomolgus monkeys showed that bolus injections of human endostatin at doses up to 300 mg/kg produced no toxic effects [317916]. Research presented at the 91st Annual Meeting of the AACR (San Francisco, April 2000), demonstrated that peritumoral administration of Endostatin, at concentrations 2000-fold less than that required to inhibit tumor progression in previously published reports using systemic dosing, significantly deters the development of a variety of tumors in mice [361584]. Other research presented at the meeting demonstrated a role for tropomysin as a molecular target for Endostatin [361680]. In August 1997, EntreMed and the NCI signed letters of intent to commence research collaborations for developing anti-angiogenic therapies, including Endostatin, in preclinical and clinical studies [258354], while in August 1998, EntreMed entered into an agreement with Covance Biotechnology Services for the production of Endostatin [304919]. In August 1999, Entremed and Cell Genesys entered a collaboration to combine Entremed's Endostatin genes with Cell Genesys's gene delivery system as a possible treatment for cancer [336909]. In December 1999, EntreMed signed an agreement with Chiron for the production of bulk Endostatin for phase II clinical trials [350397]. In April 1999, analysts at First Security Van Kasper predicted a US launch for Endostatin in 2004, with first-year revenues of US 320 million dollars, including 70 million dollars in royalties to EntreMed. European launch was predicted for 2005, with total revenues from Europe and the US for that year of US 760 milion dollars (160 million dollars royalties to EntreMed), rising to 1600 million dollars (335 million dollars royalties to EntreMed) in 2007 [370813].
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PMID:Endostatin (EntreMed). 1608 55

High molecular weight kininogen (HK) is an abundant, multi-domain plasma protein that circulates in plasma primarily in its single chain form. Proteolytic cleavage of HK by plasma kallikrein releases the vasoactive nanopeptide bradykinin (BK), and converts HK into two-chain HK (HKa). BK appears to have pro-angiogenic activity, most likely mediated through binding to B1 and B2 receptors on endothelial cells. Conversely, HKa and its domain 5, but not (single chain) HK, have potent anti-angiogenic activity comparable to other endogenous angiogenesis inhibitors. The mechanism by which HKa exerts its anti-angiogenic activity remains controversial, but appears to involve binding to cell surface tropomyosin and induction of apoptosis of proliferating endothelial cells. A role for tropomyosin in mediating the anti-angiogenic signals of other anti-angiogenic proteins such as endostatin and histidine-proline-rich glycoprotein (HPRG) has also been reported. Here we review the physiological importance of high molecular weight kininogen in angiogenesis, with emphasis on the mechanism(s) by which this activity is mediated.
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PMID:Inhibition of angiogenesis by cleaved high molecular weight kininogen (HKa) and HKa domain 5. 1630 48