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 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.
Guinness
M E
ME
Department of Internal Medicine and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8032, USA.
Kenney
J L
JL
Reiss
M
M
Lacy
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D017690:Cell Transplantation; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics*; D004854:Herpesvirus 4, Human; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000628:therapy* / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D020319:Oligodeoxyribonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2