Eradication of murine mammary adenocarcinoma through HSVtk expression directed by the glucose-starvation inducible grp78 promoter

Gene therapy strategies employing the HSVtk/ganciclovir (GCV) suicide gene offer promising approaches towards the treatment of metastatic breast cance r. These include bystander effects on non-transduced tumor cells, lower sys temic toxicity, and the possibility of inducing immunity against the tumor. Previously we have demonstrated the ability of the grp78 stress-inducible promoter to stimulate expression of reporter genes within the tumor microen vironment. However, experimental evidence demonstrating the ability of this promoter to activate therapeutic agents within the breast cancer environme nt causing tumor eradication is needed prior to clinical trials. In this re port, we test the efficacy of the grp78 promoter in a retroviral system to drive the expression of the HSVtk suicide gene in a murine mammary adenocar cinoma cell line (TSA) in syngeneic, immune-competent hosts. Our results sh ow that under glucose-starvation conditions in vitro, the expression of HSV tk and GCV induced cell death are enhanced in tumor cells in which the HSVt k gene is driven by the internal grp78 promoter compared to cells in which the Moloney murine leukemia virus LTR drives HSVtk. In in vivo studies, in tumors in which the HSVtk gene is driven by the grp78 promoter, GCV treatme nt causes complete tumor eradication, whereas tumors persist when the HSVtk gene is driven by the retroviral LTR. Our study suggests that the grp78 pr omoter may be useful to enhance the effectivity of therapeutic agents withi n a breast tumor. In addition, it is shown that immune memory is induced in syngeneic, immune-competent hosts. This new retroviral vector might theref ore be useful for breast cancer gene therapy.