Endostatin

[2][3][4] It is produced by proteolytic cleavage of collagen XVIII, a member of the multiplexin family that is characterized by interruptions in the triple helix creating multiple domains, by proteases such as cathepsins.

[12] It folds tightly, has a zinc binding domain at the N-terminus of the protein, and has a high affinity for heparin through an 11 arginine basic patch.

[18] In-vitro studies have shown endostatin blocks the proliferation and organization of endothelial cells into new blood vessels.

[24] By binding integrin α5β1 on endothelia cells it inhibits the signaling pathways of Ras and Raf kinases and decreases ERK-1 and p38 activity.

[25] Endostatin binding and clustering of integrins causes co-localization with caveolin-1 and activates non-receptor tyrosine kinases of the Src family involved in the regulation of cell proliferation, differentiation, and mobility.

[1] Although this process by which endostatin works is not fully understood, it involves metalloproteases and endopeptidases that digest components of the extracellular matrix.

Collectively, these products are thought to balance regulation between pro-angiogenic and anti-angiogenic factors outside epithelial and endothelial layers.

The trial, designed primarily to demonstrate safety, indeed showed that the drug was safe and well tolerated (at the dosages used).

A phase III clinical trial was carried out on 493 histology or cytology-confirmed stage IIIB and IV NSCLC patients with a life expectancy >3 months.

Patients were treated with Endostar (rh-endostatin, YH-16), a recombinant endostatin product, in combination with vinorelbine and cisplatin (a standard chemotherapeutic regimen).

The addition of Endostar to the standard chemotherapeutic regimen in these advanced NSCLC patients resulted in significant and clinically meaningful improvement in response rate, median time to progression, and clinical benefit rate compared with the chemotherapeutic regimen alone.

[37] Down syndrome patients seem to be protected from diabetic retinopathy due to an additional copy of chromosome 21, and elevated expression of endostatin.