The long term objective of this research is to develop new approaches to the therapy of Epstein-Barr virus (EBV)-related lymphomas. In its latent phase, EBV is associated with Burkitt's lymphoma (BL),nasophayngeal carcinoma, Hodgkin's disease, and fatal lymphoproliferative diseases in immunocompromised hosts. Although most are responsive to cytotoxic chemotherapy, relapsed disease or primary malignancies during acquired immunodeficiencies (AIDS, transplantation) often lack effective therapies with acceptable attendant toxicities. Little consideration has been given to EBV-targeted therapeutic strategies, first,because latent herpesviruses are intractable to available antiviral chemotherapy and, second, because of the uncertainty that EBV has any role in long-term maintenance of the malignant cell phenotype. We hypothesize that such an approach may be effective in treatment of EBV lymphomas, based on preliminary data that show successful eradication of EBV episOmes from BL cells treated in vitro with the ribonucleotide reductase inhibitor hydroxyurea, with concurrent loss of the malignant cell phenotype.
Specific aims to test this hypothesis are: I. Determine the susceptibility to, and the consequences of; hydroxyurea (HU)-mediated episome loss in a variety of EBV- infected B cells. 2. Determine the mechanism of hydroxyurea (HU)-mediated EBV episome loss: selective interference with episome replication versus physical loss. 3. Evaluate the activity of HU in the treatment of biologically distinct, EBV-associated lymphomas.
