Bcl-2 antisense oligodeoxynucleotide therapy of Epstein-Barr virus-associated lymphoproliferative disease in severe combined immunodeficient mice

Bcl-2 is upregulated by Epstein-Barr virus (EBV) in immortalized lymphoblas toid (LCL) B cells and is expressed in the majority of EBV-associated postt ransplant lymphoproliferative disorders (PTLDs), Given the antiapoptotic fu nction and chemoprotective effects of Bcl-2, it represents a rational targe t for modulation using antisense oligodeoxynucleotides in Bcl-2-expressing, EBV-associated lymphoproliferative disorders. Using a fully phosphorothioa ted oligodeoxynucleotide targeted to the first six codons of Bcl-2, we exam ined the effects of Bcl-2 antisense both in vitro in LCLs and in vivo in th e human/severe combined immunodeficient chimeric model of EBV-associated ly mphoproliferative disorders. In vitro treatment of LCLs with Bcl-2 antisens e in the presence of cationic Lipid was associated with decreased expressio n of Bcl-2 protein, inhibition of proliferation, and stimulation of apoptot ic cell death; these effects were sequence-dependent. Furthermore, treatmen t 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 ill vivo. These studies demonstrate that Bcl-2 antisense oligodeoxynucleoti des mediate sequence-dependent antitumor effects in EBV-associated B-cell l ymphoproliferations 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 malignanc ies.