Chemotherapy induces lytic EBV replication and confers ganciclovir susceptibility to EBV-positive epithelial cell tumors.

EBV is an oncogenic herpesvirus associated with a number of human malignancies. The consistent presence of the EBV genome in certain tumors offers the potential for novel EBV-targeted therapies. EBV can infect cells in either a latent or lytic form. Here we demonstrate that a variety of chemotherapeutic agents, including cis-platinum, 5-fluorouracil (5-FU), and taxol, induce the switch from the latent to lytic form of EBV infection in tumor cells. This effect requires the protein kinase C delta, phosphatidylinositol 3'-kinase, and p38 stress mitogen-activated protein kinase signaling pathways but not caspase 3 activation. Because the lytic but not latent form of EBV infection converts the cytotoxic prodrug, ganciclovir (GCV), into its active form, we examined whether the combination of GCV and chemotherapy is more effective than chemotherapy alone for killing EBV-positive tumor cells. GCV significantly enhanced the ability of 5-FU and cis-platinum to kill EBV-positive, but not EBV-negative, gastric carcinoma cells in vitro. Most importantly, the combination of GCV and 5-FU (or GCV and cis-platinum) was much more effective in the treatment of EBV-positive nasopharyngeal carcinomas passaged in nude mice than either agent alone. These data suggest that GCV enhances the efficacy of conventional chemotherapy for the treatment of EBV-positive epithelial cell tumors.