TY - JOUR
T1 - Effects of recombinant human thyroid-stimulating hormone superagonists on thyroidal uptake of 18f-fluorodeoxyglucose and radioiodide
AU - Reinfelder, Julia
AU - Maschauer, Simone
AU - Foss, Catherine A.
AU - Nimmagadda, Sridhar
AU - Fremont, Valerie
AU - Wolf, Vladimir
AU - Weintraub, Bruce D.
AU - Pomper, Martin G.
AU - Szkudlinski, Mariusz W.
AU - Kuwert, Torsten
AU - Prante, Olaf
PY - 2011/7/1
Y1 - 2011/7/1
N2 - Background: Superagonist analogs of human thyroid-stimulating hormone (hTSH) may stimulate the uptake of 131I-iodide and 18F-fluorodeoxyglucose (18F-FDG) in thyroid carcinomas to a greater degree than hTSH. We herein report the potency and efficacy of two hTSH analogs, TR1401 and TR1402, to stimulate radioiodide and 18F-FDG uptake in FRTL-5 cells and compared the effects of hTSH and TR1401 on radioiodide uptake in the thyroid in vivo in mice. Methods: The effects of hTSH analogs on intracellular levels of cAMP, uptake of 131I-iodide, and 18F-FDG were studied in FRTL-5 cells to determine the stimulatory potency and efficacy of the compounds by calculating half-maximum effective concentration (EC50) values and maximal stimulatory effects (E max). Biodistribution studies (n=96) and positron emission tomography/computed tomography imaging studies (single animals) on thyroid 125I/124I-iodide uptake were performed with T3-suppressed CD-1 mice in a dose-dependent manner (3, 10, and 30μg/animal). Results: The EC50 values of TR1401 and TR1402 demonstrated a 90-fold or 800-fold higher potency for their capacity to increase intracellular cAMP levels in comparison with hTSH (p<0.05). Similar results were demonstrated for the stimulation of 18F-FDG uptake. Bovine TSH, TR1401, and TR1402 were 85%-490% more potent to increase iodide uptake than hTSH (p<0.05). TR1402 was 30% more efficacious to stimulate iodide uptake than hTSH. The agonist-induced increase in radiotracer uptake was paralleled by increases in NIS and GLUT-1 expression. Ex vivo biodistribution studies showed an increased iodide uptake in the thyroid of TR1401-treated mice at the low dose of 3μg/animal in comparison with hTSH-treated mice (n=16, p<0.05). Positron emission tomography/computed tomography imaging studies confirmed the increased thyroidal iodide uptake in TR1401-treated mice in vivo. Conclusions: TR1401 and TR1402 have considerably higher potency than hTSH to stimulate thyroidal iodide and 18F-FDG uptake in vitro. Moreover, in vivo studies indicated that at low but not higher doses, TR1401 induced an enhanced ability for the thyroid to concentrate iodide compared with hTSH. These properties makes TR1401 and TR1402 interesting candidates for use in humans to enhance uptake of radioiodine and 18F-FDG by metastases and recurrences of thyroid carcinoma.
AB - Background: Superagonist analogs of human thyroid-stimulating hormone (hTSH) may stimulate the uptake of 131I-iodide and 18F-fluorodeoxyglucose (18F-FDG) in thyroid carcinomas to a greater degree than hTSH. We herein report the potency and efficacy of two hTSH analogs, TR1401 and TR1402, to stimulate radioiodide and 18F-FDG uptake in FRTL-5 cells and compared the effects of hTSH and TR1401 on radioiodide uptake in the thyroid in vivo in mice. Methods: The effects of hTSH analogs on intracellular levels of cAMP, uptake of 131I-iodide, and 18F-FDG were studied in FRTL-5 cells to determine the stimulatory potency and efficacy of the compounds by calculating half-maximum effective concentration (EC50) values and maximal stimulatory effects (E max). Biodistribution studies (n=96) and positron emission tomography/computed tomography imaging studies (single animals) on thyroid 125I/124I-iodide uptake were performed with T3-suppressed CD-1 mice in a dose-dependent manner (3, 10, and 30μg/animal). Results: The EC50 values of TR1401 and TR1402 demonstrated a 90-fold or 800-fold higher potency for their capacity to increase intracellular cAMP levels in comparison with hTSH (p<0.05). Similar results were demonstrated for the stimulation of 18F-FDG uptake. Bovine TSH, TR1401, and TR1402 were 85%-490% more potent to increase iodide uptake than hTSH (p<0.05). TR1402 was 30% more efficacious to stimulate iodide uptake than hTSH. The agonist-induced increase in radiotracer uptake was paralleled by increases in NIS and GLUT-1 expression. Ex vivo biodistribution studies showed an increased iodide uptake in the thyroid of TR1401-treated mice at the low dose of 3μg/animal in comparison with hTSH-treated mice (n=16, p<0.05). Positron emission tomography/computed tomography imaging studies confirmed the increased thyroidal iodide uptake in TR1401-treated mice in vivo. Conclusions: TR1401 and TR1402 have considerably higher potency than hTSH to stimulate thyroidal iodide and 18F-FDG uptake in vitro. Moreover, in vivo studies indicated that at low but not higher doses, TR1401 induced an enhanced ability for the thyroid to concentrate iodide compared with hTSH. These properties makes TR1401 and TR1402 interesting candidates for use in humans to enhance uptake of radioiodine and 18F-FDG by metastases and recurrences of thyroid carcinoma.
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U2 - 10.1089/thy.2010.0394
DO - 10.1089/thy.2010.0394
M3 - Article
C2 - 21568725
AN - SCOPUS:79959858680
SN - 1050-7256
VL - 21
SP - 783
EP - 792
JO - Thyroid
JF - Thyroid
IS - 7
ER -