OLIGONUCLEOTIDES 16:105–114 (2006) © Mary Ann Liebert, Inc. Review Defibrotide, a Polydisperse Mixture of Single-stranded Phosphodiester Oligonucleotides with Lifesaving Activity in Severe Hepatic Veno-occlusive Disease: Clinical Outcomes and Potential Mechanisms of Action NOAH KORNBLUM, 1,* KANYALAKSHMI AYYANAR, 1,* LUBA BENIMETSKAYA, 1 PAUL RICHARDSON, 2 MASSIMO IACOBELLI, 3 and C.A. STEIN 1 ABSTRACT Veno-occlusive disease of the liver (VOD) remains a troubling and potentially fatal complication of high-dose chemotherapy and hematopoietic stem cell transplantation conditioning regimens. No ef- fective therapy has been available for these patients to date, and the best supportive care measures remain woefully inadequate. Defibrotide (DF) (Gentium, S.p.A., Como, Italy), a polydisperse mix- ture of all the single-stranded phosphodiester oligodeoxyribonucleotides that can be obtained from the controlled depolymerization of porcine intestinal mucosal genomic DNA, seems to offer a safe and effective treatment for some patients suffering from severe VOD, a condition for which no ac- cepted standard therapy currently exists. Early clinical studies evaluating the efficacy of DF for the treatment of severe VOD in patients undergoing hematopoietic stem cell transplantation have been very encouraging. Approximately 45% of the patients treated in multiple initial phase II clinical tri- als achieved a complete response at day 100, demonstrating normalization of serum bilirubin and resolution of the clinical syndrome. However, although multi-institutional, these represented single arm studies. A large, FDA-approved, pivotal, prospective, multi-institutional, global phase III trial of DF vs. historical controls (best available therapy) commenced in the first quarter of 2006 and should provide further validation of DF’s efficacy. The drug seems to have few significant side ef- fects, and almost all test subjects who have received this treatment have tolerated it well. Although the mechanism of action remains unclear, the drug exerts minimal systemic anticoagulant effects yet appears to induce numerous antithrombotic and profibrinolytic effects both in vitro and in vivo. It may function as an adenosine receptor agonist and causes increased concentrations of endogenous prostaglandins, which modulate thrombomodulin, platelets, and fibrinolysis. It also appears to block lipopolysaccharide (LPS)-induced tissue factor (TF) expression. However, despite the fact the DF is composed of oligonucleotides, its mechanism of action, which at the present time is unclear, is not re- lated to Watson-Crick base pair-dependent downregulation of gene expression but is rather likely a result of its polyanionic nature. 1 Albert Einstein-Montefiore Cancer Center, Montefiore Medical Center, Bronx, NY 10467. 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115. 3 Gentium S.p.A., 22079 Villa Guardia, Italy. *These authors contributed equally to this work 105