Abstract 2760: Gemcitabine induced lytic EBV replication and confers ganciclovir susceptibility to EBV-positive gastric cancer

Abstract

Abstract Epstein-Barr virus (EBV) is a dsDNA human gamma herpes virus which infects more than 90% of human populations. It is associated with the development of malignancies such as Burkitt's lymphoma, nasopharyngeal carcinoma, and EBV-associated gastric carcinoma. Gastric cancer is the second most common cancer in the world and the highest incidence is in Korea. The constant presence of the viral genome in EBV associated gastric cancer tissue offers the potential for novel EBV targeted therapies using antiviral nucleoside drug. Ganciclovir (GCV) is the drug of choice in herpes virus infection, however, GCV alone have been unsuccessful in the treatment of EBV associated malignancies because the virus maintains a latent state of replication in tumor, and thymidine kinase (BXLF1) and protein transferase (BGLF4), express only during lytic state of replication. In recent years, novel treatment strategies are being investigated where in lytic replication of the virus in EBV associated cancer is induced prior to the use of GCV. We investigate Gemcitabine (Gem), which is one of newly discovered potential lytic inducers found from FDA approved drug library screen using BZLF1 promoter reporter system. We examined whether the combination of GCV and Gem is more effective than Gem alone for killing EBV-positive gastric cancer cells. We found GCV significantly enhanced the ability of Gem to kill EBV-positive, but not EBV negative, gastric carcinoma cells in vitro. Also we found that low dose (2.5ng/ml) and short term exposures (24hr) of the EBV positive gastric cancer cell line SNU719 to Gem induced expression of the EBV lytic phase proteins. Viral kinases were also induced by short term and low dose exposure. Short term and low dose exposure to Gem in combination with GCV induced tumor cell death and cell proliferation inhibition. In conclusion, pharmacologic induction of the lytic viral kinases in tumor cells using Gem, followed by treatment with GCV is useful in EBV associated gastric cancer in vitro. And this virus-targeted antitumor strategy may provide a new therapeutic approach to EBV-associated gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2760. doi:1538-7445.AM2012-2760