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Combining radiation therapy with interstitial radiation-inducible TNF-α expression for locoregional cancer treatment

Cancer Gene Therapy volume 18, pages 189–195 (2011)Cite this article

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Abstract

Brachytherapy (BRT) is used in the treatment of human cancers, including the cervix, breast, prostate and head and neck cancers. The primary advantage of BRT lies in the spatial conformation of the radiation deposition. Previously, we have shown that similar techniques (using hollow metallic cylinders) may be used to deliver gene-therapy vectors capable of expressing the radiation-sensitizing cytokine, tumor necrosis factor (TNF)-α, within a restricted volume of tissue. Herein, we report radiation sensitization of cancer cells using a TNF-α expressing vector driven by the radiation-inducible immediate-early gene-1 (IEX-1) promoter (pIEX-TNF-α). TNF-α, determined by ELISA assays using culture medium, increased between 5 and 10 fold, 48 h following exposure to radiation, and radiation sensitization was comparable with that observed in cells in which TNF-α was constitutively expressed under cytomegalo viral (CMV) promoter using the plasmid vector (pCMV-TNF-α). This efficiency of induced TNF-α radiation sensitization was also observed in cervix (SW756) and prostate tumor (PC-3) xenograft models. IEX-1-driven TNF-α expression following external radiation exposure resulted in enhanced regression of tumor xenografts as compared with radiation alone. A feasibility of using radioactive Pd-103 seeds with GeneSeeds was further examined using PC-3 xenograft models. The data showed substantial tumor growth suppression following co-implantation with a metal seed containing Pd-103. Taken together, these results show the enhanced effect on tumor regression by treatment with radiation-inducible TNF-α expression in combination with radiation and support for the IEX-1 promoter as a useful regulator for temporal activation of radiation-sensitizing gene expression.

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Acknowledgements

We thank Larry Maxwell, MD Colonel, US Army Medical Corps, Director, Gynecologic Cancer Translational Research Center Chief, for valuable scientific discussion and the Best Medical Industries for manufacturing and providing GeneSeeds, the Biostatistics Resource in the Vincent T Lombardi Cancer Center for statistical collaboration in experimental design and interpretation of results, and Y Zhang, J Tuturea, A Foxworth and T Carr for technical assistance. This work was supported by grants, W81XWH-GDP and PC010401 (to MJ), from the Department of Defense.

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  1. Division of Radiation Research, Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    M Jung, A Dimtchev, A Velena & A Dritschilo

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  1. M Jung
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  2. A Dimtchev
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Correspondence to M Jung.

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Jung, M., Dimtchev, A., Velena, A. et al. Combining radiation therapy with interstitial radiation-inducible TNF-α expression for locoregional cancer treatment. Cancer Gene Ther 18, 189–195 (2011). https://doi.org/10.1038/cgt.2010.69

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