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.

Keywords::

• Zidovudine
• Epstein–Barr virus
• human immunodeficiency virus
• non-Hodgkin lymphoma
• plasmablastic lymphoma
• primary central nervous system lymphoma

Acknowledgements

We would like to especially recognize the late William J. Harrington Jr. for his inspiring translational work with AZT as an effective lytic-inducing agent with anti-neoplastic activity in EBV+ lymphomas.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at http://www.informahealthcare.com/lal.

This work was supported by a translational award from the Leukemia and Lymphoma Society to J.C.R. (initially to the late William Harrington) and D.P.D., NIH-NCI 5R01CA112217 to J.C.R. (initially to the late William Harrington), NIH-NCI 2U01CA121947 (AIDS Malignancy Consortium) to J.C.R., PHS grant CA019014 to D.P.D., NIH-Center for AIDS Research grant 5P30AI073961-05 to J.C.R., NIH-NCI PO1-CA-128115-01A2 grant to J.C.R. and by the University of Miami Sylvester Comprehensive Cancer Center.