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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2000-10, Vol.60 (19), p.5354-5358
• Main Authors: GUINNESS, Mary E, KENNEY, Jamie L, REISS, Michael, LACY, Jill
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; B-Lymphocytes - virology; Bcl-2 gene; Biological and medical sciences; Burkitt Lymphoma - metabolism; Burkitt Lymphoma - pathology; Burkitt Lymphoma - virology; Cell Division - drug effects; Cell Line, Transformed; Cell Transplantation; Chemotherapy; Epstein-Barr virus; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - pathology; Epstein-Barr Virus Infections - therapy; Female; Genes, bcl-2 - genetics; Herpesvirus 4, Human; Humans; Lymphoproliferative Disorders - genetics; Lymphoproliferative Disorders - therapy; Lymphoproliferative Disorders - virology; Medical sciences; Mice; Mice, SCID; Oligodeoxyribonucleotides, Antisense - genetics; Oligodeoxyribonucleotides, Antisense - pharmacology; Pharmacology. Drug treatments; posttransplant lymphoproliferative disorders; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism
• ISSN: 0008-5472; 1538-7445

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 Bel-2-expressing, EBV-positive malignancies.