California Breast Cancer Research Program

Extensive experimental evidence suggests that Bcl-2 promotes cell survival by preventing the onset of apoptosis induced by a variety of stimuli. In addition, Bcl-2 expression has been correlated with resistance and poor response to chemotherapy in a number of cell types. Therefore, this protein represents a logical target for gene therapy strategies designed to achieve selective gene product ablation. In this study, we have developed an approach based upon intracellular expression of single-chain antibodies (sFvs) to achieve modulation of Bcl-2 protein levels in target cells. Using a transient expression system, we show that this intracellular anti-Bcl-2 sFv mediates specific reduction of Bcl-2 levels. This effect significantly enhances drug-mediated cytotoxicity in Bcl-2-overexpressing tumor cells, whereas transfection of the anti-Bcl-2 sFv did not affect the growth rate of the tumor cell lines. This method thus represents a novel and efficient way to selectively abrogate the activity of Bcl-2.