title: Therapeutic effect of sodium iodide symporter gene therapy combined with external beam radiotherapy and targeted drugs that inhibit DNA repair.
abstract: Adenoviral (AdV) transfer of sodium iodide symporter (NIS) gene has translational potential, but relatively low levels of transduction and subsequent radioisotope uptake limit the efficacy of the approach. In previous studies, we showed that combining NIS gene delivery with external beam radiotherapy (EBRT) and DNA damage repair inhibitors increased viral gene expression and radioiodide uptake. Here, we report the therapeutic efficacy of this strategy. An adenovirus expressing NIS from a telomerase promoter (Ad-hTR-NIS) was cytotoxic combined with relatively high-dose (50 microCi) (131)I therapy and enhanced the efficacy of EBRT combined with low-dose (10 and 25 microCi) (131)I therapy in colorectal and head and neck cancer cells. Combining this approach with ataxia-telangiectasia mutated (ATM) or DNA-dependent protein kinase (DNA-PK) inhibition caused maintenance of double-stranded DNA breaks (DSBs) at 24 hours and increased cytotoxicity on clonogenic assay. When the triplet of NIS-mediated (131)I therapy, EBRT, and DNA-PKi was used in vivo, 90% of mice were tumor-free at 5 weeks. Acute radiation toxicity in the EBRT field was not exacerbated. In contrast, DNA-PKi did not enhance the therapeutic efficacy of EBRT plus adenovirus-mediated HSVtk/ganciclovir (GCV). Therefore, combining NIS gene therapy and EBRT represents an ideal strategy to exploit the therapeutic benefits of novel radiosensitizers.
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London, UK.
authors.forename: Mohan
authors.initials: M
authors.lastname: Hingorani
authors.forename: Christine L
authors.initials: CL
authors.lastname: White
authors.forename: Shane
authors.initials: S
authors.lastname: Zaidi
authors.forename: Hardev S
authors.initials: HS
authors.lastname: Pandha
authors.forename: Alan A
authors.initials: AA
authors.lastname: Melcher
authors.forename: Shreerang A
authors.initials: SA
authors.lastname: Bhide
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Nutting
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Syrigos
authors.forename: Richard G
authors.initials: RG
authors.lastname: Vile
authors.forename: Georges
authors.initials: G
authors.lastname: Vassaux
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000532:radiotherapy / Q000628:therapy; D004260:DNA Repair / Q000235:genetics* / Q000528:radiation effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000532:radiotherapy / Q000628:therapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011878:Radiotherapy / Q000379:methods*; D011897:Random Allocation; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D027981:Symporters; D000099209:Sodium-Iodide Symporters