Antisense-mediated suppression of Bcl-2 highlights its pivotal role in failed apoptosis in B-cell chronic lymphocytic leukaemia

Although advances have been made in the development of more effective treat ment modalities, B-cell chronic lymphocytic leukaemia (B-CLL) remains incur able due to the development of drug resistance. Defective programmed cell d eath mechanisms rather than dysregulation of cell cycle appears to predomin ate in B-CLL and it is likely that a failure to initiate apoptosis contribu tes to chemoresistance. Most B-CLL cells contain high levels of the anti-ap optotic protein Bcl-2 and high Bcl-2/Bax ratios have been associated with i n vitro resistance to cytotoxic agents, In this study we evaluated the cell ular responses to a Bcl-2 antisense oligonucleotide in terms of Bcl-2 mRNA and protein expression and the induction of apoptosis. The antisense molecu le induced a specific reduction in Bcl-2 mRNA and protein expression over t he 48 h culture period and was associated with increased apoptosis. The stu dy indicates that Bcl-2 protein is central to the mediation of resistance t o apoptosis in B-CLL. Therefore Bcl-2 antisense oligonucleotides might be u seful in the treatment of B-CLL.