|
Angiogenesis, the development of new blood vessels from the existing vasculature, and haemostasis, the coagulation cascade leading to formation of a clot, are among the most consistent host responses associated with cancer. A number of haemostatic proteins have been found to contain peptides which are anti-angiogenic. We recently identified a a 24 amino-acid peptide derived from the amino-terminus of the α-chain of FgnE, named Alphastatin, that has similar potent anti-angiogenic properties, inhibiting both the migration and tubule formation of human endothelial cells in response to bFGF, VEGF and EGF in vitro. Moreover, Alphastatin markedly inhibits the growth of tumours in a syngeneic murine model by selectively disrupting activated endothelial cells, leading to intravascular thrombosis and the formation of large areas of necrosis. Importantly, Alphastatin administration had no effect on vessels in the healthy tissues. Amino acid substitution and peptide truncation studies have shown that a hydrophobic cluster (Phe8, Leu9, and Val15) and such regions as the SGEG and Pro-Arg-Val, are required for the full anti-angiogenic activity of Alphastatin. Taken together, these data indicate that Alphastatin is a potent new anti-angiogenic agent capable of inhibiting the actions of multiple pro-angiogenic growth factors in vitro, and selectively disrupting tumour vessels in vivo. It remains to be seen whether the structural elements mediating these effects are similar to those present in other anti-angiogenic/anti-vascular agents.
|
J. Vasc. Biol. 42, Sup:2 (2005) p84