Abstract
1335
Objectives: Since its initial approval by the US FDA in 1998 recombinant human TSH (Thyrogen, Genzyme) has been widely used to preserve quality of life in thyroid cancer patients. Trophogen has developed novel superagonist analogs of hTSH with greatly increased potency and, under certain conditions, increased maximal efficacy. The current studies focus on the clinically relevant endpoints of radioiodide uptake and 18F-FDG uptake in both rat thyroid FRTL-5 and human thyroid carcinoma ML-1 cells.
Methods: Highly purified preparation of human TSH analog (TR-1401) was compared to rhTSH and bTSH in several in vitro assays including stimulation of cAMP production, 18F-FDG and 131I-iodide uptake. Cells were incubated with 0.1 MBq/mL 18F-FDG for 1 h or 20 kBq/mL 131I-iodide for 10 min in the presence and absence of various concentrations of rhTSH, bTSH and TR-1401 (0.6-2400 ng/ml). LY294002 was used as irreversible inhibitor of PI3-kinase.
Results: TR-1401 was 40-50 fold more potent than Thyrogen in cAMP stimulation in both FRTL-5 and ML-1 cells. TR-1401 displayed 33-fold increase in potency for 18F-FDG uptake in FRTL-5 cells. Stimulation of radioiodide uptake showed 43-fold increase in potency. (Bu)2cAMP mimicked the effect of hTSH and TR-1401 on 18F-FDG uptake, whereas LY294002 inhibited 18F-FDG uptake by 58%. H89 inhibited bTSH- and TR-1401-induced radioiodide uptake by >95%, suggesting that increased radioiodide uptake was mainly mediated through the PKA pathway.
Conclusions: TR-1401 showed increased potency suggesting that such new analogs could serve as second generation recombinant TSH for the diagnosis and treatment of thyroid carcinomas with limited number of TSH receptors and modified signaling pathways.
- Society of Nuclear Medicine, Inc.