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 language | English |
|---|---|
| Pages (from-to) | 6884-6890 |
| Number of pages | 7 |
| Journal | Cancer Research |
| Volume | 62 |
| Issue number | 23 |
| Publication status | Published - Dec 1 2002 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
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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 journal › Article
}
TY - JOUR
T1 - Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors
AU - Hagedorn, Martin
AU - Zilberberg, Lior
AU - Wilting, Jörg
AU - Canron, Xavier
AU - Carrabba, Giorgio
AU - Giussani, Carlo
AU - Pluderi, Mauro
AU - Bello, Lorenzo
AU - Bikfalvi, Andreas
PY - 2002/12/1
Y1 - 2002/12/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0036897077&partnerID=8YFLogxK
M3 - Article
C2 - 12460903
AN - SCOPUS:0036897077
VL - 62
SP - 6884
EP - 6890
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 23
ER -