Combining radiation therapy with interstitial radiation-inducible TNF-α expression for locoregional cancer treatment.
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.
Division of Radiation Research, Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057-1482, USA. jungm@georgetown.edu
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Jung
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Dimtchev
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Velena
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Dritschilo
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001918:Brachytherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D005260:Female; D005786:Gene Expression Regulation / Q000528:radiation effects*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000528:radiation effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000628:therapy; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
D051017:Apoptosis Regulatory Proteins; C099815:IER3 protein, human; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha