Induction of the Epstein-Barr virus thymidine kinase gene with concomitant nucleoside 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 immunosuppression, including that induced by human immunodeficiency virus, and posttransplant lymphoproliferative disorders. These LPDs are characterized by actively proliferating, latently infected EBV-positive B lymphocytes and often follow a rapidly progressive fatal clinical course. Pharmacologic treatment for herpesvirus infections has targeted the virus-specific enzyme, thymidine 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 selectively activates the EBV TK gene in latently infected EBV-positive tumor cells. We have developed a strategy for treatment of EBV-associated lymphomas using pharmacologic induction of the latent viral TK gene and enzyme in tumor cells using arginine butyrate, followed by treatment with ganciclovir. A phase I/II trial, using an intrapatient dose escalation of arginine butyrate combined with ganciclovir, is underway. This combination therapy has produced complete clinical responses in 5 of 10 previously refractory patients, with partial responses occurring in 2 additional patients. This virus-targeted antitumor strategy may provide a new therapeutic approach to EBV-associated neoplasms.
Faller
D V
DV
Cancer Research Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA. dfaller@bu.edu
Mentzer
S J
SJ
Perrine
S P
SP
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D004790:Enzyme Induction; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D015774:Ganciclovir / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy* / Q000821:virology*; D011379:Prognosis; D013937:Thymidine Kinase / Q000096:biosynthesis* / Q000378:metabolism
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002087:Butyrates; D001120:Arginine; D013937:Thymidine Kinase; C033018:arginine butyrate; D015774:Ganciclovir