Azidothymidine inhibits NF- B and induces Epstein-Barr virus gene expression in Burkitt lymphoma

The antiviral compound azidothymidine (AZT), alone or in combination with other agents, induces apoptosis in earlypassage, Epstein-Barr virus–positive Burkitt lymphoma (EBV BL) lines and has clinical activity in EBV BL. We report here a mechanism of AZT’s antitumor activity. The nuclei of these cells contain activated nuclear factorB (NFB) subunits p50, c-Rel, RelB, and p52, but not p65. Treatment of primary EBV BL lines with AZT inhibited NFB within 1 to 2 hours. This was followed by up-regulation of EBV gene expression including viral thymidine kinase (vTK) and apoptosis. Subclones of EBV BL cells that demonstrated activated p65 were resistant to AZT. In EBV BLs, AZT but not ganciclovir (GCV) was highly phosphorylated to its monophosphate form (AZTMP). Phosphorylation, as well as apoptosis, was markedly enhanced in the presence of hydroxyurea. AZT inhibits NFB and up-regulates EBV gene expression in primary EBV BLs. AZT with hydroxyurea may represent an inexpensive, targeted regimen for endemic BL. (Blood. 2005;106:235-240)