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Heat-directed suicide gene therapy for breast cancer

Cancer Gene Therapy volume 10, pages 294–301 (2003)Cite this article

Abstract

Adjuvant hyperthermia can improve treatment outcome for locally recurrent breast cancer (LRBC). Previously, we demonstrated that infection of human breast cancer cells with a recombinant adenovirus expressing β-galactosidase from the human hsp70b gene promoter (Ad.70b.βgal) results in 50- to 800-fold increases in reporter gene expression following heat treatment (30 minutes at 43°C). Here, we describe a heat-directed suicide gene therapy strategy based on an adenoviral vector (Ad.70b.CDTK) in which expression of the dual prodrug-activating E. coli cytosine deaminase/herpes simplex virus thymidine kinase (CDTK) fusion gene is under the control of the hsp70b promoter. Treatment of T47D and MCF-7 breast cancer cells with mild hyperthermia (43°C/30 minutes) and prodrugs (100 μg/ml 5-fluorocytosine and 10 μg/ml ganciclovir) following infection with Ad.70b.CDTK (10–100 PFU/cell) resulted in 30- to 60-fold decreases in clonogenic survival relative to control cultures treated with heat or prodrugs alone. Clonogenic survival declined even further (up to 240-fold) following heat treatment at 41.5°C for 120 minutes. A decreased clonogenic survival was accompanied by tumor cell apoptosis. These results demonstrate that this combined treatment strategy can be highly effective against heat- and radiation-resistant breast tumor cells and supports the continued development of heat-directed CDTK suicide gene therapy strategies for LRBC.

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Acknowledgements

We thank our colleagues, in particular M Rauth and M Sherar, for stimulating discussions. This work was supported in part by grants to HJK from the Canadian Breast Cancer Foundation and the Foundation for Gene and Cell Therapy, and to FFL and HJK from the Canadian Institutes of Health Research (CIHR). AMB is a recipient of the Jessie Davidson Medical Research Council of Canada Fellowship, and thanks Drs B Cummings and P Catton and the DRO for their continued support.

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Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, M5G 2M9, Ontario, Canada

    Anthony M Brade, Fei-Fei Liu & Henry J Klamut

  2. Department of Radiation Oncology, University of Toronto, 610 University Avenue, Toronto, M5G 2M9, Ontario, Canada

    Anthony M Brade & Fei-Fei Liu

  3. Division of Experimental Therapeutics, Ontario Cancer Institute, University Health Network, Ontario, Canada

    Paul Szmitko, Duc Ngo & Henry J Klamut

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  1. Anthony M Brade
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Correspondence to Henry J Klamut.

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Brade, A., Szmitko, P., Ngo, D. et al. Heat-directed suicide gene therapy for breast cancer. Cancer Gene Ther 10, 294–301 (2003). https://doi.org/10.1038/sj.cgt.7700570

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