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Breast Cancer Research and Treatment

, Volume 59, Issue 1, pp 81–90 | Cite as

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

  • Xinke Chen
  • Daixin Zhang
  • Gunther Dennert
  • Gene Hung
  • Amy S. Lee
Article

Abstract

Gene therapy strategies employing the HSVtk/ganciclovir (GCV) suicide gene offer promising approaches towards the treatment of metastatic breast cancer. These include bystander effects on non-transduced tumor cells, lower systemic 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 microenvironment. However, experimental evidence demonstrating the ability of this promoter to activate therapeutic agents within the breast cancer environment causing tumor eradication is needed prior to clinical trials. In this report, 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 adenocarcinoma cell line (TSA) in syngeneic, immune-competent hosts. Our results show that under glucose-starvation conditions in vitro, the expression of HSVtk and GCV induced cell death are enhanced in tumor cells in which the HSVtk 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 treatment causes complete tumor eradication, whereas tumors persist when the HSVtk gene is driven by the retroviral LTR. Our study suggests that the grp78 promoter may be useful to enhance the effectivity of therapeutic agents within a breast tumor. In addition, it is shown that immune memory is induced in syngeneic, immune-competent hosts. This new retroviral vector might therefore be useful for breast cancer gene therapy.

breast cancer suicide gene therapy retroviral vector grp78 promoter immune memory 

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Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Xinke Chen
    • 1
  • Daixin Zhang
    • 1
  • Gunther Dennert
    • 2
  • Gene Hung
    • 3
  • Amy S. Lee
    • 1
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Southern California Keck School of MedicineLos AngelesUSA
  2. 2.University of Southern California Keck School of MedicineLos AngelesUSA
  3. 3.USC Gene Therapy Laboratories, USC/Norris Comprehensive Cancer CenterUniversity of Southern California Keck School of MedicineLos AngelesUSA

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