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.