http://www.cnr.it/ontology/cnr/individuo/prodotto/ID47650
Biological and molecular properties of a new avb3/avb5 integrin antagonist (Articolo in rivista)
- Type
- Label
- Biological and molecular properties of a new avb3/avb5 integrin antagonist (Articolo in rivista) (literal)
- Anno
- 2005-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1158/1535-7163.MCT-05-0120 (literal)
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- Belvisi L.; Riccioni T.; Marcellini M.; Vesci L.; Chiarucci I.; Efrati D.; Potenza D.; Scolastico C.; Manzoni L.; Lombardo K.; Stasi M.A.; Orlandi A.; Ciucci A.; Nico B.; Ribatti D.; Giannini G.; Presta M.; Carminati P.; Pisano C. (literal)
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- ISI Web of Science (WOS) (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
- Belvisi L.; Potenza D.; Scolastico C.; Università degli Studi di Milano, Dipartimento di Chimica Organica e Industriale. Via Venezia 21, I-20133 Milano
Manzoni L.; CNR - Istituto di Scienze e Tecnologie Molecolari, Via Venezian 21, I-20133 Milano
Riccioni T.; Marcellini M.; Vesci L.; Chiarucci I.; Efrati D.; Lombardo K.; Stasi M.A.; Giannini G.;Carminati P.; Pisano C.; R&D Sigma Tau SpA, Area Oncol, I-00040 Monte Porzio Catone, Italy
Orlandi A.; Ciucci A.; Univ Roma Tor Vergata, Inst Pathol, I-00173 Rome, Italy
Nico B.; Ribatti D.; Univ Bari, Sch Med, Dept Human Anat & Histol, Bari, Italy
Presta M.; Univ Brescia, Sch Med, Dept Biomed Sci & Technol, Unit Gen Pathol & Immunol, Brescia, Italy (literal)
- Titolo
- Biological and molecular properties of a new avb3/avb5 integrin antagonist (literal)
- Abstract
- The aim of the present study was to identify specific alpha(v)beta(3)/alpha(v)beta(5) 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 pseuclopeptides. The results identified ST1646 as a high-affinity specific ligand for alpha(v)beta(3) and alpha(v)beta(5) integrins with negligible interacting with alpha(5)beta(1) 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 choriciallantoic 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)beta(3)/alpha(v)beta(5)-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)beta(3)-bound EMD121974. Accordingly, computer-docking studies indicated that the ST1646-003 integrin complex maintains the ligand-receptor distances and interactions observed in the crystalline EMD121974-alpha(v)beta(3) integrin complex. Taken together, these observations indicate that ST1646 represents a dual alpha(v)beta(3)/alpha(v)beta(5) integrin antagonist with interesting biochemical and biological features to be tested in cancer therapy. (literal)
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