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Use of the Stress-inducible grp78/BiP Promoter in Targeting High Level Gene Expression in Fibrosarcoma in Vivo¹

Departments of Biochemistry and Molecular Biology [G. G., A. S. L.] and Pathology [P. N.], and the Norris Cancer Center [G. G., P. N., A. S. L.], University of Southern California School of Medicine, Los Angeles, California 90033-0800, and Department of Cell and Tumor Biology, City of Hope National Medical Center, Duarte, California 91010-3000 [S. E. K.]

Current advances in human gene therapy open up new frontiers for molecular 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 of the therapeutic reagent in malignantly transformed but not normal tissues. Hallmark features of solid tumors such as glucose deprivation, chronic anoxia, and acidic pH induce the glucose-regulated proteins, in particular, GRP78/BiP, a M_r 78,000 endoplasmic reticulum-localized protein with chaperone and calcium-binding properties. We report here that a truncated rat grp78 promoter 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 delivery systems targeting transcription in tumorigenic cells.

¹ Supported in part by NIH Grants CA27607 (A. S. L.) and CA59308 (S. E. K.). G. G. is a recipient of the NIH predoctoral fellowship T32 CA09569.

² To whom requests for reprints should be addressed, at Norris Comprehensive Cancer Center, University of Southern California School of Medicine, P.O. Box 33800, 1441 Eastlake Avenue, Los Angeles, CA 90033-0800.

Received 2/ 9/95. Accepted 3/ 2/95.

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