Therapeutic effect of sodium iodide symporter gene therapy combined with external beam radiotherapy and targeted drugs that inhibit DNA repair.
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.
Hingorani
Mohan
M
Targeted Therapy Team, The Institute of Cancer Research, London, UK.
White
Christine L
CL
Zaidi
Shane
S
Pandha
Hardev S
HS
Melcher
Alan A
AA
Bhide
Shreerang A
SA
Nutting
Christopher M
CM
Syrigos
Konstantinos N
KN
Vile
Richard G
RG
Vassaux
Georges
G
Harrington
Kevin J
KJ
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
D027981:Symporters; D000099209:Sodium-Iodide Symporters