Establishment of radioactive astatine and iodine uptake in cancer cell lines expressing the human sodium/iodide symporter

The sodium/iodide symporter (NIS) has been recognized as an attractive target for radioiodine-mediated cancer gene therapy. In this study we investigated the role of human NIS for cellular uptake of the high LET alpha-emitter astatine-211 (At-211) in comparison with radioiodine as a potential radionuclide for future applications. A mammalian NIS expression vector was constructed and used to generate six stable NIS-expressing cancer cell lines (three derived from thyroid carcinoma, two from colon carcinoma, one from glioblastoma). Compared with the respective control cell lines, steady state radionuclide uptake of NIS-expressing cell lines increased up to 350-fold for iodine-123 (I-123), 340-fold for technetium-99m pertechnetate ((TcO4-)-Tc-99m) and 60-fold for At-211. Cellular At-211 accumulation was found to be dependent on extracellular Na+ ions and displayed a similar sensitivity towards sodium perchlorate inhibition as radioiodide and (TcO4-)-Tc-99m uptake. Heterologous competition with unlabelled NaI decreased NIS-mediated At-211 uptake to levels of NIS-negative control cells. Following uptake both radioiodide and At-211 were rapidly (apparent t(1/2) 3-15 min) released by the cells as determined by wash-out experiments. Data of scintigraphic tumour imaging in a xenograft nude mice model of transplanted NIS-modified thyroid cells indicated that radionuclide uptake in NIS-expressing tumours was up to 70 times (I-123), 25 times ((TcO4-)-Tc-99m) and 10 times (At-211) higher than in control tumours or normal tissues except stomach (3-5 times) and thyroid gland (5-10 times). Thirty-four percent and 14% of the administered activity of I-123 and At-211, respectively, was found in NIS tumours by region of interest analysis (n=2). Compared with cell culture experiments, the effective half-life in vivo was greatly prolonged (6.5 h for I-123, 5.2 h for At-211) and preliminary dosimetric calculations indicate high tumour absorbed doses (3.5 Gy/MBq(tumour) for I-131 and 50.3 Gy/MBq(tumour) for At-211). In conclusion, NIS-expressing tumour cell lines of different origin displayed specific radionuclide uptake in vitro and in vivo. We provide first direct evidence that the high-energy alpha-emitter At-211 is efficiently transported by NIS. Application of At-211 may direct higher radiation doses to experimental tumours than those calculated for I-131. Thus, At-211 may represent a promising alternative radionuclide for future NIS-based tumour therapy.