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.

Feasibility of Adenovirus-Mediated hNIS Gene Transfer and 131I Radioiodine Therapy as a Definitive Treatment for Localized Prostate Cancer

“…Such improvements might include (i) escalating the adenovirus dose beyond 5 × 10 12 vp, 24 (ii) use of an adenovirus with more robust replicative, but not oncolytic, properties (i.e., one with a wild-type E1 region but does not lyse the cell), (iii) implementation of radiosensitizing genes, 2 or (iv) concomitant use of agents that prevent the repair of double stranded DNA breaks. 25 However, probably the best way to increase the absorbed dose is to develop ways to trap 131 I inside the cell once it is transported by hNIS. 131 I radioiodine therapy is efficacious in the treatment of thyroid cancer because iodine becomes covalently fixed to thyroglobulin (via thyroid peroxidase) once inside the cell thereby preventing its rapid efflux as is observed in nonthyroid hNIS-expressing tissues.…”

The sodium iodide symporter (NIS): Regulation and approaches to targeting for cancer therapeutics

“…E. Kim et al, 2011), have been studied, resulting in significant growth inhibition or eradication of tumor (Tables 2 and 3). Inhibition of DNA repair by the DNA-dependent protein kinase inhibitor (DNA-PKi) enhanced the antitumor effects by combination treatment with 131 I and external beam radiotherapy in colorectal cancer cells, as well as head and neck cancer cells (Hingorani et al, 2010b). …”

Tumor microenvironment affects exogenous sodium/iodide symporter expression

“…Attempts to increase radioactive retention by co-expression of NIS and exogenous thyroperoxidase [ 35 , 36 , 37 ] have been implemented, but they have produced insufficient synergistic benefits. Enhancement strategies were also developed to increase the dose in situ using either radioactive substrates with higher destructive potential such as the alpha-particle emitter 211 At [ 38 , 39 , 40 ] and the beta-emitting radiometal 188 Re [ 41 , 42 , 43 ] or by various radio-sensitizing approaches [ 34 , 44 , 45 ]. Improving exogenous NIS expression within non-thyroidal neoplasms has also been largely explored through direct protein delivery [46] and various gene transfer strategies.…”