A few peptide residues in structurally important locations often determine biological functions of proteins implicated in the regulation of angiogenesis. We have shown recently that the short COOH-terminal segment PF-447-70 derived from platelet factor 4 (PF-4) is the smallest sequence that conserves potent antiangiogenic activity in vitro and in vivo. Here we show that modified COOH-terminal PF-4 peptides containing the sequence ELR (or related DLR), a critical domain present in proangiogenic chemokines, surprisingly elicit several times greater antiangiogenic potential than the original peptide. The modified peptides inhibit binding of iodinated vascular endothelial growth factor and fibroblast growth factor 2 to endothelial cell receptors, endothelial cell proliferation, migration, and microvessel assembly in the rat aortic ring model at lower doses than PF-447-70. On the differentiated chick chorioallantoic membrane, topical application of 40 μg of modified peptides potently reduces capillary angiogenesis induced by vascular endothelial growth factor 165, a dose where peptide PF-447-70 was inactive. Established intracranial glioma in nude mice decreased significantly in size when treated locally with a total dose of 250 μg of peptide PF-447-70 DLR (n = 10) compared with the same dose of the original PF-447-70 peptide (n = 10) or controls (n = 30). Tailored PF-4 peptides represent a new class of antiangiogenic agents with a defined mode of action and a strong in vivo activity.
Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors / Hagedorn M, Zilberberg L, Wilting J, Canron X, Carrabba G, Giussani C, Pluderi M, Bello L, Bikfalvi A. - In: CANCER RESEARCH. - ISSN 0008-5472. - 62:23(2002), pp. 6884-6890.
|Titolo:||Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors|
|Settore Scientifico Disciplinare:||Settore MED/27 - Neurochirurgia|
|Data di pubblicazione:||2002|
|Appare nelle tipologie:||01 - Articolo su periodico|