Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)-induced lymphoproliferative disease and lytic viral replication

• DOI: 10.18632/oncotarget.17863
• Publication Date: 2017-05-24T15:14:38Z
• Authors: Andrea Bilger; Julie Plowshay; Shidong Ma; Dhananjay Nawandar; Elizabeth A. Barlow; James C. Romero-M...; Jillian A. Bristol; Zhe Li; Ming-Han Tsai; Henri-Jacques Del...; Shannon C. Kenney
• Keywords: Leflunomide; Teriflunomide

// Andrea Bilger 1 , Julie Plowshay 2, 6 Shidong Ma 1, 5 Dhananjay Nawandar 3, 7 Elizabeth A. Barlow James C. Romero-Masters 4 Jillian Bristol Zhe Li 8 Ming-Han Tsai Henri-Jacques Delecluse and Shannon Kenney 2 Department of Oncology, School Medicine Public Health, University Wisconsin-Madison, Madison, Wisconsin, USA Medicine, 3 Cellular Molecular Biology, Pathology, Sanofi Pharmaceuticals, Cambridge, Massachusetts, Rocky Mountain Infectious Disease Specialists, Aurora, Colorado, Cancer Biology Immunology, Dana-Farber Institute Harvard Medical School, Joint DKFZ Inserm Unit U1074, German Center (DKFZ), Heidelberg, Germany Correspondence to: Kenney, email: [e-mail] Keywords: therapy, lymphoma, lymphoproliferative disease, humanized mouse model, FDA-approved Received: March 17, 2017      Accepted: April 27, Published: May 15, 2017 ABSTRACT EBV infection causes mononucleosis is associated with specific subsets B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced disease (LPD), which can be fatal. Leflunomide (a drug used treat rheumatoid arthritis) its active metabolite teriflunomide (used multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T proliferation. also inhibits replication cytomegalovirus BK virus via both “on target” “off mechanisms increasingly these viruses in recipients. However, whether leflunomide/teriflunomide block or EBV-mediated transformation currently unknown. We show that proliferation, promotes apoptosis, EBV-transformed cells vitro at a clinically relevant dose. In addition, prevents development lymphomas model xenograft model. Furthermore, lytic preventing initial steps viral reactivation, blocking DNA replication. Leflunomide/teriflunomide might therefore useful for LPD who have high loads yet require continued immunosuppression.