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Azidothymidine and Interferon- Induce Apoptosis in Herpesvirus-associated Lymphomas¹

Department of Microbiology and Immunology [R. K. L., V. D., L. H. B., E. P.] and Division of Hematology/Oncology, Department of Medicine [J-P. C., L. C., R. P. A., W. X., W. J. H.], University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida 33136; Departments of Medicine and Pathology, University of Southern California, Los Angeles, California 90033 [P. S. G.]; and Department of Microbiology and Immunology, University of Nebraska, Lincoln, Nebraska 68588 [C. W.]

Lymphoproliferative diseases that occur in immunocompromised patients are frequently associated with herpesviruses. These patients often fare poorly after treatment with conventional chemotherapy. We reported previously that patients with AIDS-related Burkitt’s lymphoma (BL) responded to parenteral azidothymidine (AZT) and IFN-. We found that EBV-positive lymphoma cells derived from these patients cultured with AZT express CD95 and undergo apoptosis. AZT-mediated apoptosis was caspase dependent and occurred despite Fas receptor blockade. In contrast, EBV-negative lymphomas were resistant to AZT-induced apoptosis, as were EBV-positive lymphomas that expressed high levels of bcl-2. Primary effusion lymphoma (PEL) cell lines infected with human herpesvirus type 8 required IFN- to potentiate AZT-induced apoptosis. IFN- did not up-regulate CD95 in BL or PEL but did induce expression of the death receptor ligand, CD95 ligand. AZT-sensitive lymphomas also accumulated significantly higher intracellular AZT monophosphate than did resistant lymphomas. Our data demonstrated distinct apoptotic responses to AZT and IFN- in herpesvirus-associated lymphomas. EBV-positive BL cells that expressed low BCL-2 levels were sensitive to AZT alone; PEL cells required the addition of IFN- to enhance apoptosis, and EBV-negative lymphomas were insensitive to both agents. AZT-sensitive BL cells transfected with BCL-2 became resistant. Susceptibility to antivirus-mediated apoptosis may be exploited to improve the therapy of certain herpesvirus-associated lymphomas.

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