Pro-apoptotic therapy with the oligonucleotide Genasense (oblimersen sodium) targeting Bcl-2 protein expression enhances the biological anti-tumour activity of rituximab.
New strategies have evolved in the treatment of patients with non-Hodgkin's lymphoma (NHL). Anti-sense oligonucleotides (ASO) and monoclonal antibody (mAb) therapy, though proven to be safe and effective, have not demonstrated to be curative when used as single agents. We tested an innovative combination strategy involving various mAbs and ASO against Bcl-2 (G3139) in aggressive preclinical models. G3139, under optimal transfection conditions, decreased the proliferation rate of lymphoma cells by 60-75% when compared with controls. In addition, apoptosis was demonstrated in Raji (25%) and DHL-4 cells (30%) treated with Genasense following downregulation of Bcl-2 protein. Downregulation of Bcl-2 by G3139 was associated with a higher degree of rituximab-associated, complement-mediated cytotoxicity and antibody dependent cellular cytotoxicity when compared with rituximab alone-treated controls. In vivo studies in severe combined immunodeficiency (SCID) mice clearly demonstrated synergistic activity between G3139 and rituximab. Treatment of lymphoma-bearing SCID mice with G3139 for two consecutive days prior to each rituximab dose resulted in better disease control and survival than treatment with either agent alone or controls. Our findings suggest that Bcl-2 downregulation by G3139, followed by the administration of rituximab is an efficient anti-tumour strategy associated with improved survival in lymphoma-bearing SCID mice.
Ramanarayanan
Jeyanthi
J
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Hernandez-Ilizaliturri
Francisco J
FJ
Chanan-Khan
Asher
A
Czuczman
Myron S
MS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005786:Gene Expression Regulation; D019254:Genes, bcl-2; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D000069283:Rituximab; D013873:Thionucleotides / Q000627:therapeutic use*; D014162:Transfection / Q000379:methods; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D000069283:Rituximab; C408162:oblimersen