Endostatin is a natural 20-kDa C-terminal fragment derived from collagen type XVIII. Reported to function as an anti-angiogenic agent, similar to angiostatin and thrombospondine.
Endostatin is a broad-spectrum angiogenesis inhibitor and may interfere with pro-angiogenic action of growth factors such as basic fibroblast growth factor (bFGF/FGF-2) and vascular endothelial growth factor (VEGF).
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Endostatin is an endogenous angiogenesis inhibitor. It was first discovered secreted in the media of non-metastasizing mouse cells from the hemangioendothelioma cell line in 1997 and subsequently found in humans. This is generated by the proteolytic cleavage of collagen XVIII, a member of the multiplexin family characterized by an interruption in the triple helix that creates many domains, by proteases such as cathepsin. Collagen is an epithelial and endothelial basement membrane component. Endostatin, as a fragment of collagen 18, shows the role of ECM in suppression of neoangiogenesis. Pro-angiogenic and anti-angiogenic factors can also be made by proteolysis during coagulation cascade. Endogenous angiogenesis inhibitors present both in normal tissue and cancer tissue. Overall, endostatin down regulates many cascades signaling such as ephrin, TNF-?, And NF? B signaling as well as coagulation and cascade adhesion. Other antiangiogenic factors derived from collagen include arresten, canstatin, tumstatin ,? 6 collagen type IV antiangiogenic fragments, and restants.
Maps Endostatin
Structure
The human monomer endostatin is a globular protein containing two disulfide bonds: Cys162-302 and Cys264-294. The folds are dense, have zinc binding domains on N-terminus proteins, and have a high affinity for heparin through the basic 11 arginine patch. Endostatin also binds all proteoglikan heparan sulfate with low affinity. Oligomeric endostatin (trimer or dimer) binds primarily with laminin from the basal lamina.
Biological Activity
In-vitro studies have shown endostatin to block the proliferation and organization of endothelial cells into new blood vessels. In animal studies endostatin inhibits angiogenesis and growth of both primary tumors and secondary metastases.
Mechanism
Endostatin suppresses angiogenesis through many pathways that affect cell viability and movement. Endostatin represses control of cell cycle and anti-apoptotic gene in proliferating endothelial cells, resulting in cell death. Endostatin blocks the expression of pro-angiogenic genes controlled by c-Jun N terminal kinase (JNK) by interfering with TNF? activation of JNK. This reduces the growth of new cells by inhibiting cyclin D1. As a result, cells capture during G1 phase and enter apoptosis. Changes in FGF signal transduction by endostatin inhibit the migration of endothelial cells through matrix-cell adhesion disorders, cell adhesion, and cytoskeletal reorganization. With integrin binding? 5? 1 in endothelial cells inhibits the signal path of Ras and Raf kinase and decreases ERK-1 and p38 activity. Endostatin binding and integrin groupings cause co-localization with caveolin-1 and activate non-receptor tyrosine kinases from Src families involved in cell proliferation, differentiation, and mobility regulation. Other receptor interactions include the VEGF-R2/KDR/Flk-1 receptor on human umbilical vein endothelial cells.
Endostatin may prevent the activity of certain metalloproteinases. Several studies have focused on the downstream effects of endostatin acceptance. These studies estimate that endostatin can significantly affect the 12% of genes used by human endothelial cells. Although endostatin signaling can affect a large number of these genes, the effects of downstream appear to be very limited. The acceptance of endostatin appears to affect only the angiogenesis that comes from pathogenic sources, such as tumors. The processes associated with angiogenesis, such as wound healing and reproduction, do not appear to be affected by endostatin. The result is possible because pathogenic angiogenesis usually involves signaling through integrins, which are directly affected by endostatin.
Cancer
Although the process by which the endostatin works is not fully understood, it involves metalloproteases and endopeptidases that digest the components of the extracellular matrix. Several similar endogenous angiogenic factors are generated from the matrix component in this mode. For example, degradation perlecan may produce endorepellin which functions as an anti-angiogenic factor. Collectively, this product is considered to balance the regulation between pro-angiogenic and anti-angiogenic factors beyond the epithelial and endothelial layers. Among the anti-angiogenesis inhibitors, endostatin has various targets of the anti-cancer spectrum, increasing its significance because synthetic inhibitors usually have a single target and struggle with toxicity. Endostatin has several characteristics that may be beneficial for cancer therapy. First of all, endogenous endostatin has been described as "the most non-toxic anti-cancer drug in mice". Furthermore, both resistance and toxicity to endostatin occur in humans. Also, endostatin has been estimated to affect 12% of the human genome. It reveals a broad spectrum of activities focused on preventing angiogenesis. This is very different from single-molecule therapy, and can change the way cancer therapies are designed: drugs may be designed to target different genes rather than one particular protein. However, endostatin does not affect all tumors. For example, a cancer that may have extreme pro-angiogenic activity through VEGF may overcome the anti-angiogenic effects of endostatin.
Possible cancer treatment
Endostatin is currently being studied as part of a cancer research. Previous results show that endostatin may be useful in combination with other drugs, but endostatin alone does not provide significant improvement in tumor/disease progression.
Phase I
In clinical trials of Endostatin Phase, of the 19 treated patients, 12 patients were replaced by doctors due to progression of the disease. Two patients continue to be treated, and the remaining patient resigns. Experiments, designed primarily to show safety, do show that the drug is safe and well tolerated (at the doses used).
Phase II
In Phase II trials of endostatin, 42 patients with pancreatic endocrine tumors or carcinoid tumors were treated. Of the 40 patients who could be evaluated for radiological response, none had a partial response to therapy, as defined by World Health Organization criteria.
The conclusion of the trial was that, "Treatment with Endostatin did not result in significant tumor regression in patients with advanced neuroendocrine tumors."
Phase III
A phase III clinical trial was performed on 493 histologic or confirmed patients stage IIIB and IV NSCLC confirmed with life expectancy & gt; 3 months. Patients were treated with Endostar (rh-endostatin, YH-16), endostatin recombinant products, in combination with vinorelbine and cisplatin (standard chemotherapy regimen). The addition of Endostar to standard chemotherapy regimens in advanced NSCLC patients results in significant and clinically meaningful improvement in response, median to progression, and clinical benefit rates compared to chemotherapy regimens alone.
Clinical interests
Endostatin can also be useful as a therapy for inflammatory diseases such as rheumatoid arthritis as well as Crohn's disease, diabetic retinopathy, psoriasis, and endometriosis by reducing infiltration of inflammatory cells through angiogenesis invasion. Down syndrome patients seem to be protected from diabetic retinopathy due to additional copies of chromosome 21, and increased endostatin expression.
References
External links
- Endostatin at US National Library of Medicine Subject Medical Headings (MeSH)
- The Nova PBS program explores Endostatin in 2001
Source of the article : Wikipedia
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