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      Cilengitide: The First Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis and Clinical Evaluation

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          Abstract

          Cilengitide, a cyclic RGD pentapeptide, is currently in clinical phase III for treatment of glioblastomas and in phase II for several other tumors. This drug is the first anti-angiogenic small molecule targeting the integrins αvβ3, αvβ5 and α5β1. It was developed by us in the early 90s by a novel procedure, the spatial screening. This strategy resulted in c(RGDfV), the first superactive αvβ3 inhibitor (100 to 1000 times increased activity over the linear reference peptides), which in addition exhibited high selectivity against the platelet receptor αIIbβ3. This cyclic peptide was later modified by N-methylation of one peptide bond to yield an even greater antagonistic activity in c(RGDf( NMe)V). This peptide was then dubbed Cilengitide and is currently developed as drug by the company Merck-Serono (Germany).

          This article describes the chemical development of Cilengitide, the biochemical background of its activity and a short review about the present clinical trials. The positive anti-angiogenic effects in cancer treatment can be further increased by combination with “classical” anti-cancer therapies. Several clinical trials in this direction are under investigation.

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          Most cited references 134

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          Angiogenesis in cancer, vascular, rheumatoid and other disease.

           J Folkman (1994)
          Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
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            Integrin ligands at a glance.

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              Requirement of vascular integrin alpha v beta 3 for angiogenesis.

              Angiogenesis depends on the adhesive interactions of vascular cells. The adhesion receptor integrin alpha v beta 3 was identified as a marker of angiogenic vascular tissue. Integrin alpha v beta 3 was expressed on blood vessels in human wound granulation tissue but not in normal skin, and it showed a fourfold increase in expression during angiogenesis on the chick chorioallantoic membrane. In the latter assay, a monoclonal antibody to alpha v beta 3 blocked angiogenesis induced by basic fibroblast growth factor, tumor necrosis factor-alpha, and human melanoma fragments but had no effect on preexisting vessels. These findings suggest that alpha v beta 3 may be a useful therapeutic target for diseases characterized by neovascularization.
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                Author and article information

                Journal
                Anticancer Agents Med Chem
                CMCACA
                Anti-Cancer Agents in Medicinal Chemistry
                Bentham Science Publishers Ltd
                1871-5206
                1875-5992
                December 2010
                : 10
                : 10
                : 753-768
                Affiliations
                Institute for Advanced Study, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany
                Author notes
                [* ]Address correspondece to this author at the Institute for Advanced Study, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany; Tel: +49 89 289 13300; Fax: +49 89 289 13210; E-mail: Kessler@ 123456tum.de
                Article
                CMCACA-10-753
                10.2174/187152010794728639
                3267166
                21269250
                © 2010 Bentham Science Publishers Ltd

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

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