USE OF THE STRESS-INDUCIBLE GRP78 BIP PROMOTER IN TARGETING HIGH-LEVEL GENE-EXPRESSION IN FIBROSARCOMA IN-VIVO/

Current advances in human gene therapy open up new frontiers for molec ular therapies of cancer. However, one major limitation in cancer gene therapy is the lack of a general tumor-specific promoter which allows stringent and high level expression or the therapeutic reagent in mal ignantly transformed but not normal tissues. Hallmark features of soli d tumors such as glucose deprivation, chronic anoxia, and acidic pH in duce the glucose-regulated proteins, in particular, GRP78/BiP, a M(r) 78,000 endoplasmic reticulum-localized protein with chaperone and calc ium-binding properties. We report here that a truncated rat grp78 prom oter with most of the distal basal elements removed can be utilized as a potent internal promoter in a retroviral vector to drive high level expression of a reporter gene in a murine fibrosarcoma model system. The stress-inducible grp78 promoter offers a novel approach for gene d elivery systems targeting transcription in tumorigenic cells.