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Use of the Glucose Starvation-inducible Glucose-regulated Protein 78 Promoter in Suicide Gene Therapy of Murine Fibrosarcoma¹

Department of Biochemistry and Molecular Biology [G. G., X. C., W. F. A., A. S. L.] and the University of Southern California Gene Therapy Laboratories [G. H., W. F. A.], University of Southern California/Norris Comprehensive Cancer Center, University of Southern California School of Medicine, Los Angeles, California 90033

A new strategy in anticancer gene therapy uses stress-responsive cellular promoters that offer the advantage of enhanced gene expression in a variety of tumors. Although the feasibility of their selective expression has been demonstrated, functional evidence of their ability to activate therapeutic agents within the tumor environment leading to tumor eradication has not been established. Glucose deprivation, chronic anoxia, and acidic pH known to persist in poorly vascularized solid tumors strongly induce the transcription of the glucose-regulated protein 78 (grp78) gene, which encodes an M_r 78,000 stress-inducible protein. In this report, we tested directly the efficacy of the grp78 promoter in a retroviral system to drive the expression of the herpes simplex virus-thymidine kinase (HSVtk) suicide gene, using a murine fibrosarcoma model, in the context of their syngeneic, immunocompetent hosts. Our results showed that under glucose starvation conditions, the expression of HSVTK was enhanced in tumor cells where the HSVtk gene was driven by the internal grp78 promoter, in contrast to the Moloney murine leukemia virus long terminal repeat, where suppression was observed. We further demonstrated that in vivo, HSVTK expression was elevated to much higher levels inside tumors when driven by the internal grp78 promoter, resulting in complete eradication of sizable tumor mass, with no recurrence of tumor growth. Our study suggests that the glucose starvation-inducible grp78 promoter could be useful for enhanced expression of a variety of therapeutic agents within the solid tumor environment.

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