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.