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Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin

Cancer Gene Therapy volume 12, pages 655–662 (2005)Cite this article

Abstract

Combining gene therapy with radiotherapy and chemotherapy holds potential to increase the efficacy of cancer treatment, while minimizing side effects. We tested the responsiveness of synthetic gene promoters containing CArG elements from the Early Growth Response 1 (Egr1) gene after neutron irradiation, doxorubicin and cisplatin. Human MCF-7 breast adenocarcinoma and U373-MG glioblastoma cells were transfected with plasmids containing CArG promoters controlling the expression of the green fluorescent protein (GFP). Exposing the cells to neutrons, doxorubicin or cisplatin resulted in a significant induction of transgene expression. Therapeutic advantage was demonstrated by replacing the reporter with the herpes simplex virus thymidine kinase (HSVtk), able to convert the prodrug ganciclovir (GCV) into a cytotoxin. A 1.3 Gy neutron dose caused 49% growth inhibition in MCF-7 cells, which increased to 63% in irradiated CArG-HSVtk-transfectants treated with GCV. Exposure to 0.5 μM cisplatin or 0.01 μM doxorubicin induced a growth inhibition of 25–30% in MCF-7 cells. In the presence of GCV, this value increased to 65–70% in cells transfected with the CArG promoter constructs driving the expression of HSVtk. These data indicate that combining CArG-mediated HSVtk/GCV suicide gene therapy with radio- and chemotherapy can enhance antitumor toxicity, and validates future in vivo investigations.

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Acknowledgements

We are very grateful to Mr Abdalla Doleh and Mr Evano Piasentin for excellent technical support and to Dr Mark Yudelev for assistance in neutron irradiation. This work is supported by The Susan G Komen Breast Cancer Foundation, Wayne State University, Academic Radiation Oncologists and Radiation Oncology Research and Development Center, Detroit, MI.

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  1. Department of Radiation Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, Michigan, USA

    Olga Greco, Tanya M Powell, Brian Marples, Michael C Joiner & Simon D Scott

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  1. Olga Greco
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Correspondence to Simon D Scott.

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Greco, O., Powell, T., Marples, B. et al. Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin. Cancer Gene Ther 12, 655–662 (2005). https://doi.org/10.1038/sj.cgt.7700834

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