title: Defibrotide blunts the prothrombotic effect of thalidomide on endothelial cells.
abstract: Patients with multiple myeloma (MM) are at relatively high risk of developing thromboembolic events such deep venous thrombosis (DVT) where thalidomide therapy has been identified to increase this risk. Defibrotide (DF), a polydisperse oligonucleotide, showed previously to counteract the alterations in endothelial cells (ECs) induced by lipopolysaccharide. It prompts us to investigate the impact of thalidomide on ECs and whether DF modulates changes in fibrinolysis induced by thalidomide. In this in vitro study, MM by itself alters the profibrinolytic potential of ECs decreasing the tissue plasminogen activator (t-PA) and increasing the plasminogen activator inhibitor 1 (PAI-1) levels which is potentiated by thalidomide. Defibrotide was able to counteract these effects. Additionally, DF upregulated the t-PA and downregulated PAI-1 gene expression modulated by thalidomide. Defibrotide also protects ECs from thalidomide-mediated cell death without interfering with its antitumor effects. These findings support DF clinical use for the prevention of DVT induced by immunomodulatory drugs.
authors: Gentium SpA, Villa Guardia, Como, Italy. cechart@gentium.it
authors: C L
authors: CL
authors: Echart
authors: S
authors: S
authors: Somaini
authors: M
authors: M
authors: Distaso
authors: A
authors: A
authors: Palumbo
authors: P G
authors: PG
authors: Richardson
authors: J
authors: J
authors: Fareed
authors: M
authors: M
authors: Iacobelli
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011089:Polydeoxyribonucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D012306:Risk; D013792:Thalidomide / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D020246:Venous Thrombosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D020533:Angiogenesis Inhibitors; D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D013792:Thalidomide; D010959:Tissue Plasminogen Activator