Apoptosis Based Gene Therapy of Breast Cancer

Abstract

Abstract : This project is an attempt to develop a gene therapy model for the treatment of metastatic breast cancer. Our goal is to develop adenoviral vectors that deliver a cytocidal gene selectively to breast cancer cells. We have employed recombinant molecules of caspase-3, a distal effector protein in the apoptotic cascade. Recombinant caspase-3 molecule, unlike the parent molecule, is constitutively active; expression of it in breast cancer cells rapidly induces apoptosis. As expression of caspase-3 in non-malignant cells could be toxic, we are attempting to limit expression to cancer cells by employing breast and tumor specific promoters. We have demonstrated that the promoter of the Hexokinase-Ti gene is tumor specific and the mammoglobin promoter is expressed only in breast cells. In order to tightly control expression to cancer cells we are attempting to employ the CRE I Lox system. One adenovirus would express the CRE gene under the control of the Hexokinase-Il promoter. Another adenovirus would express an inactivated recombinant caspase-3 under control of the mammoglobin promoter. Only the co-infection of these two viruses in cells in which both of these promoters are active, i.e. breast cancer cells, would permit the expression of caspase-3. These viruses are presently being constructed.