Induction of the Epstein-Barr virus thymidine kinase gene with concomitantnucleoside antivirals as a therapeutic strategy for Epstein-Barr virus-associated malignancies

Lymphoproliferative diseases (LPDs) associated with the Epstein-Barr virus (EBV) include non-Hodgkin lymphomas, which occur in the setting of immunosu ppression, including that induced by human immunodeficiency virus, and post transplant lymphoproliferative disorders. These LPDs are characterized by a ctively proliferating, latently infected EBV-positive B lymphocytes and oft en follow a rapidly progressive fatal clinical course. Pharmacologic treatm ent for herpesvirus infections has targeted the virus-specific enzyme, thym idine kinase (TK), with nucleoside analogs. The lack of viral TK expression in EBV-positive tumors, caused by viral latency, however, makes antiviral therapy alone ineffective as an antineoplastic therapy. Arginine butyrate s electively activates the EBV TK gene in latently infected EBV-positive tumo r cells. We have developed a strategy for treatment of EBV-associated lymph omas using pharmacologic induction of the latent viral TK gene and enzyme i n tumor cells using arginine butyrate, followed by treatment with ganciclov ir. A phase I/II trial, using an intrapatient dose escalation of arginine b utyrate combined with ganciclovir, is underway. This combination therapy ha s produced complete clinical responses in 5 of 10 previously refactory pati ents, with partial responses occurring in 2 additional patients. This virus -targeted antitumor strategy may provide a new therapeutic approach to EBV- associated neoplasms. Curr Opin Oncol 2001, 13:360-367 (C) 2001 Lippincott Williams & Wilkins, Inc.