Bcl-2 Antisense Oligonucleotides Enhance the Cytotoxicity of Chlorambucil in B-Cell Chronic Lymphocytic Leukaemia Cells

Abstract

We have previously shown that the Bcl-2 antisense oligonucleotide ODN 2009 can induce apoptosis in B-cell chronic lymphocytic leukaemia (B-CLL) cells. In this study we evaluated whether ODN 2009 could increase the sensitivity of B-CLL cells to Chlorambucil-induced cell death in vitro in order to establish whether the notion of antisense-mediated chemosensitisation could be applied to B-CLL. Bcl-2 antisense in combination with Chlorambucil resulted in a more marked reduction in Bcl-2 protein expression (p = 0.003), enhanced Bax expression (p < 0.0001) and increased apoptosis when compared to cells incubated with Chlorambucil alone (p = 0.03). This increased in vitro cytotoxicity demonstrates a proof of the concept that a combination of Bcl-2 antisense Oligonucleotides with conventional chemotherapeutic drugs may elicit an enhanced therapeutic effect in B-CLL and should therefore be considered for further investigation in the form of a clinical trial.

Key Words:

• Bcl-2
• antisense Oligonucleotides Cytototoxicity
• B-cell CLL
• Chlorambucil
• chronic lymphocytic leukaemia