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 lym phomas, including AIDS-related lymphomas, Neoplastic transformation of B ce lls is related to expression of a subset of Epstein-Barr virus-derived gene s, affording a potential site of therapeutic attack. Using antisense oligod eoxynucleotides, we now demonstrate that inhibition of Epstein-Barr virus-e ncoded EBNA-1, a gene product required to maintain the transformed phenotyp e, enhances the cytotoxicity of doxorubicin and etoposide (two commonly use d 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 inhibi tion, 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 c ells, were not specifically affected by anti-EBNA-1 oligodeoxynucleotide an tisense treatment, although non-specific cytotoxicity was apparent. Thus, i nhibition of Epstein-Barr virus transforming genes may represent a novel st rategy to augment certain anti-non-Hodgkin's lymphoma chemotherapies, altho ugh the mechanism of chemosensitization remains undefined. These studies wi ll also afford insights into mechanisms of Epstein - Barr virus-related tum origenesis.