title: Epstein--Barr virus post-transplant lymphoproliferative disease and virus-specific therapy: pharmacological re-activation of viral target genes with arginine butyrate.
abstract: Lymphoproliferative disorders associated with the Epstein-Barr virus (EBV) include non-Hodgkin's lymphoma, Hodgkin's lymphoma, and "post-transplant lymphoproliferative disorders" (PTLD), which occur with immunosuppression after marrow and organ transplantation. PTLD is characterized by actively proliferating, latently infected EBV(+) B-lymphocytes, and often manifests a rapidly progressive fatal clinical course if the immunosuppression cannot be reversed. Lung transplant recipients are a subset of patients at special risk for developing PTLD. The incidence of PTLD development in these patients has been estimated at 5--10%. Whereas immunologic and antiviral therapy have been moderately effective for treating EBV-associated infections in the lytic phase, they have been less useful in the more common latent phase of the disease. One common treatment for herpesvirus infections has targeted the virus-specific enzyme thymidine kinase (TK). The lack of viral TK expression in EBV(+) tumor cells, due to viral latency, makes anti-viral therapy alone ineffective as an anti-neoplastic therapy, however. We have developed a strategy for the treatment of EBV-associated lymphomas/PTLD using pharmacologic induction of the latent viral TK gene and enzyme in the tumor cells, followed by treatment with ganciclovir. Arginine butyrate selectively activates the EBV TK gene in latently EBV-infected human lymphoid cells and tumor cells. A Phase I/II trial has been initiated, employing an intra-patient dose escalation of arginine butyrate combined with ganciclovir. In six patients with EBV-associated lymphomas or PTLD, all of which were resistant to conventional radiation and/or chemotherapy, this combination produced complete clinical responses in four of six patients, with a partial response occurring in a fifth patient. Pathologic examination in two of three patients demonstrated complete necrosis of the EBV lymphoma, with no residual disease, following a single three-week course of the combination therapy. Possible side-effects of the therapy included nausea and reversible lethargy at the highest doses. One patient suffered acute liver failure, thought to be secondary to release of FasL from the necrotic tumor. Analysis of patient-derived tumor cells in culture demonstrated that arginine butyrate produced selective induction of the EBV TK gene, which then conferred sensitivity to ganciclovir, resulting in tumor apoptosis. Additional patient accrual is sought for further evaluation of this therapy.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, and the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. smentzer@partners.org
authors.forename: S J
authors.initials: SJ
authors.lastname: Mentzer
authors.forename: S P
authors.initials: SP
authors.lastname: Perrine
authors.forename: D V
authors.initials: DV
authors.lastname: Faller
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D015774:Ganciclovir / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology; D016040:Lung Transplantation / Q000009:adverse effects*; D008232:Lymphoproliferative Disorders / Q000188:drug therapy / Q000209:etiology*; D011183:Postoperative Complications / Q000188:drug therapy / Q000821:virology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D017735:Virus Latency
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002087:Butyrates; D001120:Arginine; C033018:arginine butyrate; D015774:Ganciclovir