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Bcl-2 Antisense Oligodeoxynucleotide Therapy of Epstein-Barr Virus-associated Lymphoproliferative Disease in Severe Combined Immunodeficient Mice¹

Department of Internal Medicine and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8032

Bcl-2 is upregulated by Epstein-Barr virus (EBV) in immortalized lymphoblastoid (LCL) B cells and is expressed in the majority of EBV-associated posttransplant lymphoproliferative disorders (PTLDs). Given the antiapoptotic function and chemoprotective effects of Bcl-2, it represents a rational target for modulation using antisense oligodeoxynucleotides in Bcl-2-expressing, EBV-associated lymphoproliferative disorders. Using a fully phosphorothioated oligodeoxynucleotide targeted to the first six codons of Bcl-2, we examined the effects of Bcl-2 antisense both in vitro in LCLs and in vivo in the human/severe combined immunodeficient chimeric model of EBV-associated lymphoproliferative disorders. In vitro treatment of LCLs with Bcl-2 antisense in the presence of cationic lipid was associated with decreased expression of Bcl-2 protein, inhibition of proliferation, and stimulation of apoptotic cell death; these effects were sequence-dependent. Furthermore, treatment of LCL-bearing severe combined immunodeficient mice with Bcl-2 antisense but not control oligodeoxynucleotides completely prevented or significantly delayed the development of fatal EBV-positive lymphoproliferative disease in vivo. These studies demonstrate that Bcl-2 antisense oligodeoxynucleotides mediate sequence-dependent antitumor effects in EBV-associated B-cell lymphoproliferations both in vitro and in vivo. These findings suggest that Bcl-2 antisense therapy may represent a novel antitumor treatment strategy for EBV-associated PTLDs and other Bcl-2-expressing, EBV-positive malignancies.

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