title: Azidothymidine and interferon-alpha induce apoptosis in herpesvirus-associated lymphomas.
abstract: 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-alpha. 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-alpha to potentiate AZT-induced apoptosis. IFN-alpha 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-alpha 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-alpha 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.
authors.affiliation: Department of Microbiology and Immunology, University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Florida 33136, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Lee
authors.forename: J P
authors.initials: JP
authors.lastname: Cai
authors.forename: V
authors.initials: V
authors.lastname: Deyev
authors.forename: P S
authors.initials: PS
authors.lastname: Gill
authors.forename: L
authors.initials: L
authors.lastname: Cabral
authors.forename: C
authors.initials: C
authors.lastname: Wood
authors.forename: R P
authors.initials: RP
authors.lastname: Agarwal
authors.forename: W
authors.initials: W
authors.lastname: Xia
authors.forename: L H
authors.initials: LH
authors.lastname: Boise
authors.forename: E
authors.initials: E
authors.lastname: Podack
authors.forename: W J
authors.initials: WJ
authors.lastname: Harrington
mesh_terms: D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008223:Lymphoma / Q000378:metabolism*; D016483:Lymphoma, AIDS-Related / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D015215:Zidovudine / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D015215:Zidovudine; D020169:Caspases