Zidovudine-based lytic-inducing chemotherapy for Epstein–Barr virus-related lymphomas

Abstract Treatment of Epstein–Barr virus (EBV)-related lymphomas with lytic-inducing agents is an attractive targeted approach for eliminating virus-infected tumor cells. Zidovudine (AZT) is an excellent substrate for EBV-thymidine kinase: it can induce EBV lytic gene expression and apoptosis in primary EBV+ lymphoma cell lines. We hypothesized that the combination of AZT with lytic-inducing chemotherapy agents would be effective in treating EBV+ lymphomas. We report a retrospective analysis of 19 patients with aggressive EBV+ non-Hodgkin lymphoma, including nine cases of acquired immune deficiency syndrome-associated primary central nervous system lymphoma (AIDS-PCNSL) treated with AZT-based chemotherapy. Our results demonstrate that high-dose AZT–methotrexate is efficacious in treating highly aggressive systemic EBV+ lymphomas in the upfront setting. In primary EBV+ lymphoma cell lines, the combination of AZT with hydroxyurea resulted in synergistic EBV lytic induction and cell death. Further, AZT–hydroxyurea treatment resulted in dramatic responses in patients with AIDS-PCNSL. The combination of AZT with chemotherapy, especially lytic-inducing agents, should be explored further in clinical trials for the treatment of EBV-related lymphomas.

[1]  Human Herpesvirus , 2016, Red Book Atlas of Pediatric Infectious Diseases, 3rd Ed.

[2]  M. Staudt,et al.  Nuclear Factor kappa B (NFkB) pathway associated biomarkers in AIDS defining malignancies , 2012 .

[3]  Robert M. Williams,et al.  Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents. , 2012, Blood.

[4]  S. Steinberg,et al.  High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy. , 2011, Blood.

[5]  M. Vasconcelos,et al.  Treatment of Akata EBV-Positive Cells with Doxorubicin Causes More EBV Reactivation than Treatment with Etoposide , 2011, Chemotherapy.

[6]  M. Gulley,et al.  Translational Relevance The presence of the EBV genome within malignant cells of endemic , 2010 .

[7]  S. Kenney,et al.  The Epstein-Barr Virus (EBV)-Encoded Protein Kinase, EBV-PK, but Not the Thymidine Kinase (EBV-TK), Is Required for Ganciclovir and Acyclovir Inhibition of Lytic Viral Production , 2010, Journal of Virology.

[8]  I. Lossos,et al.  Primary CNS lymphoma in HIV positive and negative patients: comparison of clinical characteristics, outcome and prognostic factors , 2010, Journal of Neuro-Oncology.

[9]  E. Cesarman,et al.  HIV-associated lymphomas and gamma-herpesviruses. , 2009, Blood.

[10]  L. Pantanowitz,et al.  HIV‐associated plasmablastic lymphoma: Lessons learned from 112 published cases , 2008, American journal of hematology.

[11]  E. Elkin,et al.  Treatment patterns and prognosis in patients with human immunodeficiency virus and primary central system lymphoma , 2008, Leukemia & lymphoma.

[12]  C. Klein,et al.  A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. , 2007, Blood.

[13]  T. Lawrence,et al.  Antimetabolite radiosensitizers. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  D. Huhn,et al.  Acquired immunodeficiency syndrome‐related lymphoma , 2006, Cancer.

[15]  L. Ratner,et al.  Antiviral and immunomodulatory treatment for AIDS-related primary central nervous system lymphoma: AIDS Malignancies Consortium pilot study 019. , 2006, Clinical lymphoma & myeloma.

[16]  E. Cesarman,et al.  Pathogenesis of viral lymphomas. , 2006, Cancer treatment and research.

[17]  Y. Kasamon,et al.  AIDS-related primary central nervous system lymphoma. , 2005, Hematology/oncology clinics of North America.

[18]  G. Barber,et al.  Azidothymidine inhibits NF-κB and induces Epstein-Barr virus gene expression in Burkitt lymphoma , 2005 .

[19]  J. Mate,et al.  The prognosis of HIV-infected patients with diffuse large B-cell lymphoma treated with chemotherapy and highly active antiretroviral therapy is similar to that of HIV-negative patients receiving chemotherapy. , 2005, Haematologica.

[20]  M. Gulley,et al.  Epstein-Barr virus quantitation by real-time PCR targeting multiple gene segments: a novel approach to screen for the virus in paraffin-embedded tissue and plasma. , 2004, The Journal of molecular diagnostics : JMD.

[21]  M. Staudt,et al.  The Tumor Microenvironment Controls Primary Effusion Lymphoma Growth in Vivo , 2004, Cancer Research.

[22]  D. Thorley-Lawson,et al.  Persistence of the Epstein-Barr virus and the origins of associated lymphomas. , 2004, The New England journal of medicine.

[23]  S. Kenney,et al.  Lytic Induction Therapy for Epstein-Barr Virus-Positive B-Cell Lymphomas , 2004, Journal of Virology.

[24]  D. Skiest,et al.  Survival is prolonged by highly active antiretroviral therapy in AIDS patients with primary central nervous system lymphoma , 2003, AIDS.

[25]  W. Wilson,et al.  Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. , 2003, Blood.

[26]  B. Gazzard,et al.  Leptomeningeal disease in AIDS-related non-Hodgkin's lymphoma , 2003, AIDS.

[27]  G. Barber,et al.  Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-kappa B. , 2003, Blood.

[28]  M. Caligiuri,et al.  Experimental treatment of Epstein-Barr virus-associated primary central nervous system lymphoma. , 2003, Cancer research.

[29]  H. Kantarjian,et al.  Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome‐related burkitt lymphoma/leukemia , 2002, Cancer.

[30]  C. Fletcher,et al.  Clinical Implications of CNS Penetration of Antiretroviral Drugs , 2002, CNS drugs.

[31]  G. Barber,et al.  Induction of a TRAIL mediated suicide program by interferon alpha in primary effusion lymphoma , 2001, Oncogene.

[32]  R. Ambinder,et al.  Induction of Epstein-Barr Virus Kinases To Sensitize Tumor Cells to Nucleoside Analogues , 2001, Antimicrobial Agents and Chemotherapy.

[33]  S. Kenney,et al.  Activation of lytic Epstein-Barr virus (EBV) infection by radiation and sodium butyrate in vitro and in vivo: a potential method for treating EBV-positive malignancies. , 2000, Cancer research.

[34]  L. Boise,et al.  Azidothymidine and Interferon-α Induce Apoptosis in Herpesvirus-associated Lymphomas , 1999 .

[35]  R. Ambinder,et al.  Human Herpesvirus 8-Encoded Thymidine Kinase and Phosphotransferase Homologues Confer Sensitivity to Ganciclovir , 1999, Journal of Virology.

[36]  G. Sfakianakis,et al.  Treatment of AIDS-related primary central nervous system lymphoma with zidovudine, ganciclovir, and interleukin 2. , 1999, AIDS research and human retroviruses.

[37]  L. Boise,et al.  Azidothymidine and interferon-alpha induce apoptosis in herpesvirus-associated lymphomas. , 1999, Cancer research.

[38]  D. Sage,et al.  The Epstein-Barr Virus Thymidine Kinase Does Not Phosphorylate Ganciclovir or Acyclovir and Demonstrates a Narrow Substrate Specificity Compared to the Herpes Simplex Virus Type 1 Thymidine Kinase , 1998, Antimicrobial Agents and Chemotherapy.

[39]  V. Godfrey,et al.  Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Faller,et al.  Arginine butyrate-induced susceptibility to ganciclovir in an Epstein-Barr-virus-associated lymphoma. , 1998, Blood cells, molecules & diseases.

[41]  P. Pellett,et al.  Human herpesvirus 6 , 1997, Clinical microbiology reviews.

[42]  D. Huhn,et al.  Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. , 1997, Blood.

[43]  F. Gherlinzoni,et al.  3'-Azido 3'-deoxythymidine + methotrexate as a novel antineoplastic combination in the treatment of human immunodeficiency virus-related non-Hodgkin's lymphomas. , 1997, Blood.

[44]  E. Klein,et al.  Induction of the lytic viral cycle in Epstein Barr virus carrying Burkitt lymphoma lines is accompanied by increased expression of major histocompatibility complex molecules. , 1993, Immunology letters.

[45]  B. Nathwani,et al.  Epstein-Barr virus-associated non-Hodgkin's lymphoma in patients infected with the human immunodeficiency virus. , 1993, Blood.

[46]  G. Brosch,et al.  Histone deacetylase , 1993, FEBS Letters.

[47]  P. Tosi,et al.  Azidothymidine-induced cytotoxicity and incorporation into DNA in the human colon tumor cell line HCT-8 is enhanced by methotrexate in vitro and in vivo. , 1992, Cancer research.

[48]  R. Ambinder,et al.  Epstein-Barr virus in AIDS-related primary central nervous system lymphoma , 1991, The Lancet.

[49]  J. Rachlin,et al.  Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiency syndrome. , 1990, Journal of neurosurgery.

[50]  J. C. Martin,et al.  9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: a new potent and selective antiherpes agent. , 1983, Journal of medicinal chemistry.