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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4343-4352. Prepublished online as a Blood First Edition Paper on August 18, 2008; DOI 10.1182/blood-2008-04-149682. This Article Full Text (PDF) All Versions of this Article: blood-2008-04-149682v1 112/10/4343    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Benimetskaya, L. Articles by Stein, C. A. Search for Related Content PubMed PubMed Citation Articles by Benimetskaya, L. Articles by Stein, C. A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 2, 2008 Accepted July 7, 2008 Angiogenesis-alteration by defibrotide: Implications for its mechanism of action in severe hepatic veno-occlusive disease Luba Benimetskaya, Sijian Wu, Anatoliy M. Voskresenskiy, Cinara Echart, Jin-Feng Zhou, Joongho Shin, Massimo Iacobelli, Paul Richardson, Kanyalakshmi Ayyanar, and C. A. Stein* Department of Oncology, Montefiore Medical Center, Bronx, NY, United States Gentium, S.p.A., Como, Italy Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States * Corresponding author; email: cstein{at}montefiore.org. Defibrotide (DF) is a mixture of porcine-derived single-stranded phosphodiester oligonucleotides (9-80mer, average = 50mer) that has been successfully used to treat severe hepatic venoocclusive disease (sVOD) With multi-organ failure (MOF) in patients who have received cytotoxic chemotherapy in preparation for bone marrow transplantation. However, its mechanism of action is unknown. Herein, we show that DF and phosphodiester oligonucleotides can bind to heparin-binding proteins (e.g. bFGF, but not VEGF165) with low nanomolar affinity. This binding occurred in a length and concentration-dependent manner. DF can mobilize pro-angiogenic factors such as bFGF from their depot or storage sites on bovine corneal endothelial matrix. However, these molecules do not interfere with high affinity binding of bFGF to FGFR1c, but can replace heparin as a required co-factor for binding and hence, cellular mitogenesis. DF also protects bFGF against digestion by trypsin and chymotrypsin, and from air oxidation. In addition, DF binds to collagen I with low nanomolar affinity, and can promote HMEC-1 cell mitogenesis and tubular morphogenesis in 3D collagen I gels. Thus, our data suggests that DF may provide a stimulus to the sinusoidal endothelium of a liver that has suffered a severe angiotoxic event, thus helping to ameliorate the clinical sVOD/MOF syndrome. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: SOS! Defibrotide to the rescue Hillard M. Lazarus and Keith R. McCrae Blood 2008 112: 3924-3925. [Full Text] [PDF] This article has been cited by other articles: C.A. Stein, S. Wu, A. M. Voskresenskiy, J.-F. Zhou, J. Shin, P. Miller, N. Souleimanian, and L. Benimetskaya G3139, an Anti-Bcl-2 Antisense Oligomer That Binds Heparin-Binding Growth Factors and Collagen I, Alters In vitro Endothelial Cell Growth and Tubular Morphogenesis Clin. Cancer Res., April 15, 2009; 15(8): 2797 - 2807. [Abstract] [Full Text] [PDF]

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