Radiation-Induced Thyroid Stunning: Differential Effects of ¹²³I, ¹³¹I, ^99mTc, and ²¹¹At on Iodide Transport and NIS mRNA Expression in Cultured Thyroid Cells

Abstract

Recent clinical and experimental data demonstrate that thyroid stunning is caused by previous irradiation and may influence the efficacy of 131 I radiation therapy of thyroid cancer and possibly hyperthyroidism. To avoid stunning, many clinics have exchanged 131 I for 123 I for pretherapeutic diagnostic imaging and dose planning. Furthermore, recent in vitro studies indicate that 131 I irradiation reduces iodide uptake by downregulating the expression of the sodium iodide symporter (NIS). The rationale for this study was therefore to study effects on iodide transport and NIS messenger RNA (mRNA) expression in thyrocytes exposed to both 123 I and 131 I in addition to some other potentially interesting radionuclides. Methods: Thyrotropin-stimulated thyroid cell monolayers were exposed to 0.5 Gy of 123 I, 131 I, 99m Tc, or 211 At, all being radionuclides transported via NIS, in the culture medium for 6 h, or to various absorbed doses of 123 I or 131 I for 48 h. NIS mRNA expression was analyzed using quantitative reverse-transcriptase polymerase chain reaction. Results: Iodide transport and NIS mRNA expression were reduced by all radionuclides. At the same absorbed dose, iodide transport was reduced the most by 211 At, followed by 123 I and 99m Tc (equally potent), whereas 131 I was least effective. The onset of NIS downregulation was rapid (,1 d after irradiation) in cells exposed to 123 I or 211 At and was delayed in cells irradiated with 131 I or 99m Tc. Iodide transport and NIS expression were recovered only for 211 At. 123 I reduced the iodine transport and the NIS mRNA expression more efficiently than did 131 I at an equivalent absorbed dose, with a relative biological effectiveness of about 5. Conclusion: The stunning effect per unit absorbed dose is more severe for 123 I than for 131 I. Despite the lower absorbed dose per unit activity for 123 I than for 131 I, stunning by 123 I cannot be excluded in patients. The degree to which iodide transport capacity and NIS mRNA expression are reduced seems to be related to the biological effectiveness of the type of radiation delivering the absorbed dose to the target, with 211 At (which has the highest relative biological effectiveness) causing the highest degree of stunning per unit absorbed dose in the present study.

Microarray Studies on211At Administration in BALB/c Nude Mice Indicate Systemic Effects on Transcriptional Regulation in Nonthyroid Tissues

“…The a-emitter 211 At is proposed for targeted radiotherapy of various malignancies, in particular metastasized tumors (11)(12)(13)(14). A certain percentage of the labeled compound, however, usually degrades and accumulates in the thyroid and to a lesser degree in various other tissues (15)(16)(17)(18)(19)(20), resulting in differential low-dose IR exposure within the body.…”

Comparative Analysis of Transcriptional Gene Regulation Indicates Similar Physiologic Response in Mouse Tissues at Low Absorbed Doses from Intravenously Administered211At

“…211 Atlabeled tumor-seeking agents have been investigated for treatment of various tumor types, showing good prospects (3)(4)(5)(6). However, during metabolism or degradation of radiolabeled compounds, 211 At might be released and accumulated in the thyroid gland via mechanisms similar-if to a lesser degree-to radioiodine (7)(8)(9)(10)(11). Unbound 211 At has been proposed for therapy of anaplastic thyroid carcinoma, yet the high uptake or retention in other normal tissues-for example, the kidneys, liver, lungs, and spleen-would limit successful therapy (12).…”

Impact of Post-Thyroidectomy I-123 Versus I-131 Whole Body Scan on the Outcome of Radioactive Iodine (I-131) Ablation for Differentiated Thyroid Carcinoma

“…They concluded that I-131 ablation has the same outcome whether (2 mCi) 74 MBq of I-131 used as a diagnostic agent or (400 µCi) 14.8 MBq of I-123 used for imaging prior to I-131 ablation. Although these conflicting results could be attributed to the fact that iodide transport and NIS messenger RNA (NIS mRNA) expression were reduced by both I-131 and I-123 (29) , the stunning observed following I-123 could not be explained by errors in the estimation of relative uptake due to different tissue absorption of the I-131 and I-123 photons, nor by the radiation dose delivered by the I-123 (30) . The resultant radiation dose to the thyroid remnant, as the therapeutic radioiodine is being taken up, may be sufficient to inhibit the uptake process, thus leading to a reduction in maximum uptake when compared with that of a diagnostic activity of radioiodine (30) .A unique advantage of this study is that it is one of a few studies that compared outcome of I-131 ablation in age-, gender-, histopathology-matched patient groups following either post-thyroidectomy I-123 or I-131WBS.…”