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

The consistent presence of the EBV genome in certain tumors offers the pote ntial fur novel EBV-directed therapies. Switching the latent form of EBV in fection present in most EBV-positive tumor cells into the cytolytic form ma y be clinically useful because lytic EBV infection leads to host cell destr uction, and very few normal cells contain the EBV genome. It would also be therapeutically advantageous to induce expression of EBV-encoded lyric prot eins that convert the nucleoside analogues ganciclovir (GCV) and 3'-azido-3 ' deoxythymidine (AZT) into their active, cytotoxic forms. In this report, we have explored two different approaches for activating the lyric form of EBV infection in tumors. We show that gamma -irradiation at clinically rele vant doses induces lytic EBV infection in lymphoblastoid cell lines irt vit ro as well as in EBV-positive B-cell tumors in SCID mice. In addition, sodi um butyrate (given as a single i.p, dose) is effective for activating lyric viral infection in some EBV tumor types in SCID mice. We also examined whe ther low-dose gamma -irradiation treatment of EBV-positive lymphoblastoid c ells in vitro promotes GCV or AZT susceptibility. The combination of radiat ion with either GCV or AZT induced significantly more cell killing in vitro than either radiation or prodrug treatment alone, Most importantly, we fou nd that the combination of gamma -irradiation and GCV was much more effecti ve in treating EBV-positive lymphoblastoid tumors In SCID mice than either agent alone. Thus, GCV or AZT treatment could potentially enhance the thera peutic efficacy of radiation therapy for EBV-positive lymphomas in patients .