Eradication of human non-Hodgkin's lymphoma in SCID mice by BCL-2 antisense oligonucleotides combined with low-dose cyclophosphamide

Cancers overexpressing Bcl-2 protein, which prevents programmed cell death (apoptosis), are less sensitive to stresses that produce cellular damage, i ncluding chemotherapy, If the level of Bcl-2 protein can be reduced suffici ently using antisense oligonucleotides (ASOs) targeting the gene message, t hen cytotoxic agents may be rendered more effective in eliminating disease and increasing cure rate. Preclinical studies in SCID mice bearing Bcl-2 ov erexpressing systemic human B-cell lymphoma (DoHH2) were undertaken to supp ort development of a clinical trial. These data confirm that a combination of an ASO (5 mg/kg) targeting bcl-2 and a low dose of cyclophosphamide (35 mg/kg) was an effective strategy, leading to the eradication of the DoHH2 c ells in vivo and cure of the animals. When mice deficient in natural killer cell activity were treated with an ASO, similar results were observed, sug gesting that ASO stimulation of the host immune system was not a significan t factor in elimination of lymphoma cells. These studies indicate that ther apeutic strategies involving the use of an ASO targeting bcl-2 in combinati on with a cytotoxic agent may improve clinical outcomes.