Treatment of EBV transformed tumors with antisense oligodeoxynucleotides against EBNA-1 enhances tumor chemosensitivity

Epstein-Barr virus infection is associated with certain non-Hodgkin's lymphomas, including AIDS-related lymphomas. Neoplastic transformation of B cells is related to expression of a subset of Epstein-Barr virus-derived genes, affording a potential site of therapeutic attack. Using antisense oligodeoxynucleotides, we now demonstrate that inhibition of Epstein-Barr virus-encoded EBNA-1, a gene product required to maintain the transformed phenotype, enhances the cytotoxicity of doxorubicin and etoposide (two commonly used lymphoma chemotherapy agents) for Epstein-Barr virus transformed B cell tumor cells. Primary AIDS-related lymphoma lines were also susceptible to the chemosensitizing effects of deoxyoligonucleotide-mediated EBNA-1 inhibition, suggesting that the wild type EBNA-1 sequences were targeted. B cell tumor cells not transformed with Epstein-Barr virus, and non-B cell tumor cells, were not specifically affected by anti-EBNA-1 oligodeoxynucleotide antisense treatment, although non-specific cytotoxicity was apparent. Thus, inhibition of Epstein-Barr virus transforming genes may represent a novel strategy to augment certain anti-non-Hodgkin's lymphoma chemotherapies, although the mechanism of chemosensitization remains undefined. These studies will also afford insights into mechanisms of Epstein-Barr virus-related tumorigenesis.