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)

Endostatin has demonstrated potent antiangiogenic and antitumor activity in mouse models. We have investigated the ex vivo rat aortic ring assay and a human vein model to assess the biological activity of murine and human endostatin. Rat aortic rings were exposed to recombinant murine endostatin (Spodoptera frugipera; Calbiochem, San Diego, CA) or recombinant human endostatin (Pichia pastoris; EntreMed, Rockville, MD). After 5 days, murine endostatin (500 microgram/ml) demonstrated inhibition of microvessel outgrowth with dose-dependent effects (down to 16 microgram/ml). No significant inhibition was observed with human endostatin in the rat assay. Human endostatin at 250 and 500 microgram/ml inhibited outgrowths from human saphenous vein rings after a 14-day incubation. Electron microscopy assessed the formation of basal lamina, confirming that the microvessels were progenitors of patent vessels. Immunostaining for Factor VIII or CD34 demonstrated that the microvessel cells were endothelial. BrdU incorporation assays supported the presence of proliferating endothelial cells, correlating with neovascularization from the aortic wall. We conclude that the rat aortic ring assay confirms the antiangiogenic activity of murine but not human endostatin, suggesting that the model may have species specificity. However, the human form shows biological activity against human vascular tissue.
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PMID:Endostatin inhibits microvessel formation in the ex vivo rat aortic ring angiogenesis assay. 1065 34

Endostatin is a 20-kDa endogenous angiogenesis inhibitor that has recently been shown to inhibit the expression of vascular endothelial growth factor (VEGF), an angiogenic growth factor that is up-regulated by hypoxia via the HIF-1 transcription factor complex. To determine if the anti-angiogenic activity of endostatin involves a modulation of the HIF-1/VEGF pathway in cancer cells, experiments were conducted to establish what effect endostatin has on HIF-1 activity, HIF-1alpha protein production, and cellular localization in prostate cancer cells and endothelial cells. Endothelial cell tube formation was inhibited by endostatin purchased from Calbiochem (San Diego, CA) but not endostatin obtained from EntreMed (Rockville, MD). Subsequent experiments using Calbiochem endostatin showed that it did not alter HIF-1alpha protein production or cellular localization in any of the cell lines tested, nor did it alter HIF-1 transactivational activity in hypoxia. Whether or not this is also true in vivo remains to be determined. Nevertheless, these data suggest that the anti-angiogenic activity of endostatin is independent of the HIF-1/VEGF pathway. Immunocytochemical staining results do not indicate a decreased production of VEGF in Calbiochem endostatin-treated LNCaP or human umbilical vein endothelial cells (HUVEC). Treatment of rat aortic cross sections with human endostatin from Calbiochem resulted in a dose-dependent inhibition of microvessel outgrowth. Importantly, inhibition of vessel outgrowth by Calbiochem endostatin in a human saphenous vein angiogenesis assay required early treatment. In view of this in vitro data, we suggest that clinical trials involving endostatin treatment of late-stage disease may not adequately represent the efficacy of this drug in early-stage cancer.
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PMID:Anti-angiogenic activity of human endostatin is HIF-1-independent in vitro and sensitive to timing of treatment in a human saphenous vein assay. 1455 3

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

Judah Moses Folkman, M.D., director of the Vascular Biology Program at Childrens Hospital and Julia Dyckman Andrus Professor of Pediatric Surgery at Harvard Medical School, Boston, died suffering a heart attack at Denver Airport on January 14, 2008, at the age of 74. Folkman is recognized as a pioneer in the study of angiogenesis (the formation of new blood vessels), and in particular in its application in translational research in oncology. He was born in 1933 in Cleveland, Ohio, and as a child he sometimes accompanied his father, a rabbi, on visits to hospital patients. This experience resulted in an early wish to become a doctor. Under the mentorship of Dr Zollinger (then president of the American College of Surgeons), he exhibited extraordinary surgical abilities at a very young age. As a 19-year-old student at Harvard Medical School he participated in the creation of the first implantable heart pacemaker. Subsequently he served as a pediatric surgeon at the Massachusetts General Hospital and the National Naval Medical Center in Bethesda. At the age of 34 Folkman was the youngest appointed surgeon-in-chief at the Childrens Hospital in Boston, where he served in that position for 14 years to then devote his efforts to basic research, being also professor of cell biology at Harvard Medical School. From 1968 Folkman directed the Surgical Research Laboratories, which became the Vascular Biology Program. In 1971 he published a seminal paper in the New England Journal of Medicine, proposing the revolutionary concept that tumors cannot grow without adequate blood supply and that invasive tumors secrete specific angiogenic factors. He hypothesized that, as a consequence, the inhibition of angiogenesis could be a novel anticancer therapeutic strategy. For three decades Folkmans work was looked upon with skepticism by the scientific community but he and his team persevered in their research, discovering the first selective proangiogenic factor, namely basic fibroblast growth factor, followed by the natural antiangiogenic agents, angiostatin and endostatin. The initial skepticism turned to overwhelming enthusiasm and in May 1998 the New York Times quoted the Nobel laureate James Watson as saying, ''Judahs going to cure cancer in two years''. In reply, Folkman ironically stated, ''if you are a mouse, we can take very good care of you''. He was a superb physician, a brilliant and creative scientist, an extraordinary mentor and, with his contagious enthusiasm, an example for young scientists. Folkman authored more than 400 peer-reviewed paperspapers and some 100 book chapters and monographs. His work was published in all of the most prestigious journals including the New England Journal of Medicine, Lancet, PNAS, Cell, Science, Nature, Nature Medicine, Journal of the National Cancer Institute, Cancer Research and others. He was awarded honorary degrees worldwide and was elected member of the National Academy of Science, the American Academy of Arts and Sciences and the American Philosophy Society, and he was recently appointed by President Bush to the National Cancer Advisory Board of the National Institutes of Health. I first met Judah Folkman in 1990 and had the honor to publish a paper with him in the Journal of the National Cancer Institute in 1992 reporting on the first study on the prognostic value of the degree of microvessel density in invasive breast cancer. In 1993 I spent a three-month period at Folkmans laboratory, where I had the opportunity to appreciate not only his exceptional scientific culture but also his human qualities. Judah Folkman greatly influenced my knowledge and my scientific interest and he was always available to help me in my projects. I am extremely grateful to Judah for having invited me to contribute a chapter to his last monograph entitled Angiogenesis: An Integrative Approach from Science to Medicine. Folkman leaves the oncological community a vast biological patrimony on the mechanisms of control of angiogenesis and has had a profound influence on generations of researchers, with today over 1,000 laboratories worldwide engaged in angiogenesis research. Having contributed to the development of more than 10 antiangiogenic agents, which have improved the clinical outcome of certain tumor types, he has generated new hopes and possibilities of cure for cancer patients. Giampietro Gasparini Head, Medical Oncology San Filippo Neri Hospital, Rome, Italy REFERENCES 1. Cooke R. M. Judah Folkman, biomedical pioneer, dies at 47. http://harvardscience.harvard.edu/medicine-health/articles/ m-judah-folkman-biomedical-pioneer-dies-74 (Accessed March 20, 2008).
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PMID:Remembering Judah Moses Folkma. 2820 7