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Biological and molecular properties of a new alpha(v)beta3/alpha(v)beta5 integrin antagonist.

PRESTA, Marco;
2005-01-01
2005
MIUR (compresi PRIN FIRB,FISR)
LS7_13 Medical ethics
MOLECULAR CANCER THERAPEUTICS
2-s2.0-28044458526
WOS:000233265900004
Inglese
4
1670
1680
10
16275988
The aim of the present study was to identify specific alpha(v)beta3/alpha(v)beta5 integrin antagonists active on tumor-induced angiogenesis. To this purpose, in vitro integrin-binding assays were used to screen a library of conformationally constrained bicyclic lactam Arg-Gly-Asp-containing pseudopeptides. The results identified ST1646 as a high-affinity specific ligand for alpha(v)beta3 and alpha(v)beta5 integrins with negligible interacting with alpha5beta1 integrin. In all the assays, ST1646 was equipotent to or more potent than the well-characterized integrin antagonists c(RGDfV) and cyclo(Arg-Gly-Asp-d-Phe-[NMe]Val) (EMD121974). In the chorioallantoic membrane assay, topical administration of ST1646 was able to prevent the angiogenic responses elicited by recombinant fibroblast growth factor-2 or vascular endothelial growth factor. In addition, systemic administration of ST1646 in mice exerted a significant antiangiogenic activity on neovascularization triggered by mammary carcinoma MDA-MB435 cells implanted s.c. in a dorsal air sac via a (Millipore Filter Corporation, Bedford, MA) chamber. Moreover, ST1646 delivery via an osmotic pump inhibited the growth and vascularization of tumor xenografts originating from the injection of alpha(v)beta3/alpha(v)beta5-expressing human ovarian carcinoma cells in nude mice. In agreement with the biochemical and pharmacologic studies, Monte Carlo/Stochastic Dynamics simulation showed that the bicyclic scaffold in ST1646 forced the compound to assume a preferred conformation superimposable to the X-ray conformation of alpha(v)beta3-bound EMD121974. Accordingly, computer-docking studies indicated that the ST1646-alpha(v)beta3 integrin complex maintains the ligand-receptor distances and interactions observed in the crystalline EMD121974-alpha(v)beta3 integrin complex. Taken together, these observations indicate that ST1646 represents a dual alpha(v)beta3/alpha(v)beta5 integrin antagonist with interesting biochemical and biological features to be tested in cancer therapy.
Animals; Antineoplastic Agents; Arginine; Aspartic Acid; Cattle; Cell Adhesion; Cell Line; Tumor; Cell Proliferation; Chickens; Crystallography; X-Ray; Dose-Response Relationship; Drug; Endothelium; Vascular; Fibroblast Growth Factor 2; Glycine; Guinea Pigs; Humans; Inhibitory Concentration 50; Integrin alphaVbeta3; Integrins; Ligands; Mice; Nude; Microcirculation; Models; Chemical; Molecular; Molecular Conformation; Monte Carlo Method; Neoplasm Transplantation; Neovascularization; Pathologic; Oligopeptides; Peptides; Cyclic; Platelet Aggregation; Protein Binding; Protein Conformation; Receptors; Vitronectin; Recombinant Proteins; Stochastic Processes; Vascular Endothelial Growth Factor A
Sogg. privati ital. no profit
http://dx.doi.org/10.1158/1535-7163.MCT-05-0120
19
info:eu-repo/semantics/article
262
L., Belvisi; T., Riccioni; M., Marcellini; L., Vesci; I., Chiarucci; D., Efrati; D., Potenza; C., Scolastico; L., Manzoni; K., Lombardo; M. A., Stasi;...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11379/31958
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