Cidovir suppresses the Epstein-Barr Virus viral oncoproteins and enhances the radiation-induced apoptosis in EBV-related malignancies

Bassam Abdulkarim, Siham Sabri, Eric Deutsch, Diana Zelenika, Jerzy Klijanienko, Francois Eschwege, William Vainchenker, Jean Bourhis1

1Laboratoire UPRES EA No27-1O Radiosensibilite-Radiocarcinogenese humaine and unite METSI, 2INSERM U362, Institut Gustave-Roussy, 94805 Villejuif Cedex, France. 3Service d'anatomie pathologique, Institut Curie, rue d'Ulm, Paris, e-mail

The Epstein Barr virus (HBV) is involved in the carcinogenesis of several human cancers (nasopharynx, Burkitt lymphoma and other malignancies). Given the consistent expression of EBV genes in several EBV-related cancers, antiviral strategies provide an attractive approach to target EBV-expressing cells, The acyclic nucleoside phosphonate analog Cidofovir has been shown to exert a modest anti-proliferative activity in various human virus-related tumors. Combining Cidofovir to irradiation in vitro resulted in enhancement of radiosensitivity in Burkitt lymphoma arid nasopharyngeal cancer cell lines (Raji and C15 ), which was not observed in virus- negative cells (Ramos). A down regulation of the EBV oncoprotein LMP1 was induced by Cidofovir with subsequent modulation of the anti-apoptotic proteins Bcl2. The Burkitt lymphoma cell line BL2 B95-8 (infected with the EBV strain B95-8) was used to study the effect of Cidofovir on viral oncoproteins expression and modulation of radiation-induced apoptosis. Cidofovir reduced significantly oncoprotein expression LMP1 and EBNA2 at the transcript levels (real-time PCR). Radiation-induced apoptosis was enhanced in BL2 B95-8 cells by Cidofovir treatment, whereas the apoptic rate was not modified in EBV-negative BL2 cells, The combined treatment in nude mice led to a complete tumor remission in two human EBV-related cancer xenografts (Raji and C15 ). These results support an attractive basis for a new anti-cancer strategy to enhance the ariti-tumor efficacy in EBV-related cancers, without increasing deleterious effects.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Viral Oncogenesis.