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

Martin Hagedorn, Lior Zilberberg, Jörg Wilting, Xavier Canron, Giorgio Carrabba, Carlo Giussani, Mauro Pluderi, Lorenzo Bello, Andreas Bikfalvi

Research output: Contribution to journalArticle

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-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.

Original languageEnglish
Pages (from-to)6884-6890
Number of pages7
JournalCancer Research
Volume62
Issue number23
Publication statusPublished - Dec 1 2002

Fingerprint

Platelet Factor 4
Angiogenesis Inhibitors
Peptides
Endothelial Cells
Chorioallantoic Membrane
Fibroblast Growth Factor 2
Microvessels
Chemokines
Nude Mice
Glioma
Vascular Endothelial Growth Factor A
Cell Movement
Cell Proliferation
PF 70

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hagedorn, M., Zilberberg, L., Wilting, J., Canron, X., Carrabba, G., Giussani, C., ... Bikfalvi, A. (2002). Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors. Cancer Research, 62(23), 6884-6890.

Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors. / Hagedorn, Martin; Zilberberg, Lior; Wilting, Jörg; Canron, Xavier; Carrabba, Giorgio; Giussani, Carlo; Pluderi, Mauro; Bello, Lorenzo; Bikfalvi, Andreas.

In: Cancer Research, Vol. 62, No. 23, 01.12.2002, p. 6884-6890.

Research output: Contribution to journalArticle

Hagedorn, M, Zilberberg, L, Wilting, J, Canron, X, Carrabba, G, Giussani, C, Pluderi, M, Bello, L & Bikfalvi, A 2002, 'Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors', Cancer Research, vol. 62, no. 23, pp. 6884-6890.
Hagedorn M, Zilberberg L, Wilting J, Canron X, Carrabba G, Giussani C et al. Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors. Cancer Research. 2002 Dec 1;62(23):6884-6890.
Hagedorn, Martin ; Zilberberg, Lior ; Wilting, Jörg ; Canron, Xavier ; Carrabba, Giorgio ; Giussani, Carlo ; Pluderi, Mauro ; Bello, Lorenzo ; Bikfalvi, Andreas. / Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors. In: Cancer Research. 2002 ; Vol. 62, No. 23. pp. 6884-6890.
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