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-4(47-70) 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-4(47-70). On the differentiated chick chorioallantoic membrane, topical application of 40 micro g of modified peptides potently reduces capillary angiogenesis induced by vascular endothelial growth factor(165), a dose where peptide PF-4(47-70) was inactive. Established intracranial glioma in nude mice decreased significantly in size when treated locally with a total dose of 250 micro g of peptide PF-4(47-70)DLR (n = 10) compared with the same dose of the original PF-4(47-70) 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 / M. Hagedorn, L. Zilberberg, J. Wilting, X. Canron, G. Carrabba, C. Giussani, M. Pluderi, L. Bello, A. Bikfalvi. - In: CANCER RESEARCH. - ISSN 0008-5472. - 62:23(2002 Dec 01), pp. 6884-90-6890.

Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors

L. Bello;
2002

Abstract

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-4(47-70) 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-4(47-70). On the differentiated chick chorioallantoic membrane, topical application of 40 micro g of modified peptides potently reduces capillary angiogenesis induced by vascular endothelial growth factor(165), a dose where peptide PF-4(47-70) was inactive. Established intracranial glioma in nude mice decreased significantly in size when treated locally with a total dose of 250 micro g of peptide PF-4(47-70)DLR (n = 10) compared with the same dose of the original PF-4(47-70) 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.
Vascular Endothelial Growth Factor A; Animals; Neovascularization, Physiologic; Humans; Mice, Nude; Rats; Fibroblast Growth Factor 2; Peptide Fragments; Platelet Factor 4; Molecular Sequence Data; Xenograft Model Antitumor Assays; Glioma; Male; Cell Division; Cell Movement; Chick Embryo; Aorta; Allantois; Amino Acid Sequence; Mice; Endothelial Growth Factors; Angiogenesis Inhibitors; Endothelium, Vascular; Structure-Activity Relationship; Brain Neoplasms; Rats, Sprague-Dawley; Cattle; Vascular Endothelial Growth Factors; Intercellular Signaling Peptides and Proteins; Neovascularization, Pathologic; Protein Structure, Tertiary; Chorion; Lymphokines; Female
Settore MED/27 - Neurochirurgia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/199658
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