Arginine butyrate-induced susceptibility to ganciclovir in an Epstein-Barr-virus-associated lymphoma.
Lymphoproliferative disorders associated with Epstein-Barr virus (EBV) infections can occur in the setting of immunosuppression. In some patients, the lymphoproliferative disorder can resemble an aggressive monoclonal non-Hodgkins lymphoma (NHL). These NHL are poorly responsive to conventional therapy. Similarly, antiviral therapy with synthetic nucleosides such as ganciclovir are ineffective because the genes that render the virus susceptible to therapy are not expressed in EBV+ lymphomas. Using a cell line derived from a lung transplant recipient with an EBV+ immunoblastic NHL, we studied the ability of arginine butyrate to induce the expression of EBV thymidine kinase. Arginine butyrate was not only effective in inducing EBV thymidine kinase transcription, but also acted synergistically with the antiviral agent ganciclovir to inhibit cell proliferation and decrease cell viability. Based on these findings, the patient from whom the cell line was derived was treated with arginine butyrate/ganciclovir as well as conventional cytotoxic chemotherapy. No additional toxicity was observed with the arginine butyrate/ganciclovir therapy. Histologic examination of the tumor showed substantial necrosis. These observations suggest the feasibility of arginine butyrate induction of ganciclovir susceptibility in patients with EBV-associated lymphomas.
Mentzer
S J
SJ
Department of Surgery and Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Fingeroth
J
J
Reilly
J J
JJ
Perrine
S P
SP
Faller
D V
DV
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001228:Aspergillosis / Q000150:complications; D002087:Butyrates / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy*; D017809:Fatal Outcome; 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 / Q000201:enzymology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D016040:Lung Transplantation; D009336:Necrosis; D011183:Postoperative Complications / Q000188:drug therapy / Q000821:virology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D011241:Prednisone / Q000008:administration & dosage; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000821:virology; D014750:Vincristine / Q000008:administration & dosage; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000998:Antiviral Agents; D002087:Butyrates; D017361:Viral Nonstructural Proteins; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D001120:Arginine; D013937:Thymidine Kinase; C033018:arginine butyrate; D015774:Ganciclovir; D011241:Prednisone