Rat Sodium Iodide Symporter for Radioiodide Therapy of Cancer

Abstract

Design and development of new approaches for targeted radiotherapy of cancer and improvement of therapeutic index by more local radiation therapy are very important issues. Adenovirus-mediated delivery of the sodium iodide symporter (NIS) gene to cancer cells is a powerful technique to concentrate lethal radiation in tumor cells and eradicate tumors with increased therapeutic index. A replicationdefective adenoviral vector expressing the rat NIS gene (Ad-rNIS) was used for in vitro gene delivery and into human prostate cancer xenografts to study antitumor effect. Robust function of the rat symporter was detected in DU145, T47D, and HCT-15 human cancer cell lines transduced with Ad-rNIS. All three cancer cell lines successfully transferred functionally active rat symporter to the plasma membrane, resulting in very high levels of iodine-125 accumulation. Three-dimensional multicellular tumor spheroids derived from DU145 human prostate cancer cells were transduced with Ad-rNIS and incubated with 131 I for 24 hours. After treatment, spheroids rapidly decreased in size and disappeared within 10 days. In vivo data revealed an inhibition of tumor growth in athymic nude mice after intratumoral Ad-rNIS injection followed by 131 I administration. Eightyeight percent of experimental mice survived >30 days, whereas control groups had only 18% survival >30 days. This is the first report that demonstrates the rat NIS gene can effectively induce growth arrest of human tumor xenografts after in vivo adenoviral gene delivery and 131 I administration. The data confirm our hypothesis that the rat NIS gene is an attractive suicide gene candidate for cancer treatment.

Rat sodium iodide symporter allows using lower dose of 131I for cancer therapy

“…19 We further demonstrated that the rat NIS gene can effectively induce growth arrest of human prostate tumor xenografts in mice after in vivo adenoviral gene delivery and administration of 3 mCi of 131 I. 16 Recently, we reported the capability of the rat NIS to effectively induce growth arrest of relatively large tumors (about 800 mm 3 ) in mice when treated with 3 mCi of 131 I. 20 The central limitation when translating NIS-131 I therapy from mouse models to humans is the inability to achieve an effective lethal dose per body weight equivalent to that observed in mice with 3 mCi of 131 I.…”

“…12,13 Our group and others previously reported very high levels of radioiodine uptake can be reached in vitro and in vivo after adenoviral delivery of NIS gene to nonthyroid tumor cells. 1,12,[14][15][16][17][18] Using in vitro clonogenic assays we demonstrated that 50% of non-thyroid cancer cells transduced with rat NIS gene were killed after incubation with 131 I compared with nontransduced cells. 12 To evaluate the therapeutic efficacy of rat NIS and 131 I, Boland and colleagues 1 administered 30-90 mCi of 131 I to mice bearing Ad-NIS-injected tumors.…”

“…Iodide uptake was initiated by adding HBSS containing 0.057-0.345 nM carrier-free Na 125 I and 5-300 mM NaI. 16 Cells were incubated (371C, 5% CO 2 ) for 30 min. Reactions were rapidly terminated by washing the cells with ice-cold HBSS, and cells were solubilized in 1% Triton X-100.…”

“…In a separate experiment, spheroids transduced with 10 MOI (a dose was estimated per total number of cells in an average spheroid) of Ad-NIS were killed by incubation with 20 mCi of 131 I. 16 Noticeably, spheroids transduced with 10 MOI of adenoviral vector encoding enhanced green fluorescent protein (GFP) revealed GFP expression exclusively in cells localized on the surface of the spheroids (Figure 2b). Thus, concentration of 131 I radiation in NIS-positive cells was lethal to adjacent cells inside tumor spheroids, establishing an effective radiological bystander effect.…”

“…Using the rat NIS and 3 mCi of 131 I, our group also demonstrated a strong antitumor effect against DU145 human prostate tumor xenografts. 16 Both these studies utilized adenoviral delivery of human or rat NIS gene to already established tumors in mice. Using tumor cells that were stably transduced or transfected with the human NIS gene, two other groups demonstrated the therapeutic effectiveness of the human NIS gene followed by 1 mCi of 131 I administration.…”