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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2765-2775. Prepublished online as a Blood First Edition Paper on December 5, 2007; DOI 10.1182/blood-2007-07-100651. This Article Full Text (PDF) All Versions of this Article: blood-2007-07-100651v1 111/5/2765    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Piva, R. Articles by Inghirami, G. Search for Related Content PubMed PubMed Citation Articles by Piva, R. Articles by Inghirami, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 11, 2007 Accepted November 2, 2007 CEP-18770: a novel orally-active proteasome inhibitor with a tumor-selective pharmacological profile competitive with bortezomib Roberto Piva, Bruce Ruggeri*, Michael Williams, Giulia Costa, Ilaria Tamagno, Dario Ferrero, Valentina Giai, Marta Coscia, Silvia Peola, Massimo Massaia, Gabriella Pezzoni, Cecilia Allievi, Nicoletta Pescalli, Mara Cassin, Stefano di Giovine, Paola Nicoli, Paola de Feudis, Ivan Strepponi, Ilaria Roato, Riccardo Ferracini, Benedetta Bussolati, Giovanni Camussi, Susan Jones-Bolin, Kathryn Hunter, Hugh Zhao, Antonino Neri, Antonio Palumbo, Celia Berkers, Huib Ovaa, Alberto Bernareggi, and Giorgio Inghirami Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy Discovery Research, Cephalon Inc, West Chester, PA, United States Hematology Division, University of Torino, Torino, Italy Sede Secondaria Della Cell Therapeutics, Inc., Bresso, Italy Orthopedic and Traumatology, San Giovanni Battista of Torino, Torino, Italy Department of Internal Medicine, University of Torino, Torino, Italy Laboratory of Experimental Hematology and Molecular Genetics, Ospedale Maggiore IRCCS, Milano, Italy Cellular Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands RBM SpA, Merck Serono S.A. Italy, Serono, Italy Department of Biomedical Sciences and Human Oncology, University of Torino, Torino, Italy * Corresponding author; email: bruggeri{at}cephalon.com. Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, owing to the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome which down-modulates the NF-B activity and the expression of several NF-B downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong anti-angiogenic activity and potently represses RANKL – induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally-active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020