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.