Stunning is the decrease in radioiodide uptake in thyroid tissue caused by previous exposure of the tissue to a tracer dose of the radioisotope for dosimetry. Stunning was first described almost 50 years ago (69), and since then, several clinical studies have been carried out to investigate its deleterious effect on radioiodide therapy. Before treatment with radioiodide, patients usually undergo diagnostic and dosimetric studies. After administering a tracer dose of radioiodide, the percentage of radioiodide uptake in the tumor tissue is determined and used as a basis to calculate the appropriate therapeutic dose. However, stunning is often observed, so that the percentage of radioiodide uptake measured upon administration of the therapeutic dose is significantly lower than that when the tracer dose was first administered for dosimetry. It is hypothesized that stunning is caused by radiation damage to the cells from the previously administered tracer dose. When stunning occurs, the delivered radioiodide therapeutic dose is insufficient for successful ablation of the malignant tissue (70). While most studies have investigated stunning in vivo during the treatment of patients (71), Postgard et al (72) recently reported an in vitro study revealing more about the possible mechanism of stunning. These investigators used porcine thyroid cell primary cultures grown on a filter in a bicameral chamber. The apical and basolateral media were separated by the cells assembled into a monolayer. Thyroid cells kept in TSH- and methimazole-supplemented medium were exposed to different amounts of131I. Stable iodide (10 nM) was administered to control cells. Transepithelial transport (from the basal to the apical membrane) was evaluated after a 3-day washout period. Iodide transport decreased 50% with a 3-Gy absorbed dose, and it was almost completely inhibited with an 80-Gy dose. The transepithelial electrical resistance of the cell monolayer was unchanged, showing that the integrity of the epithelial mono-layer remained intact. The presence of perchlorate - the competitive inhibitor of I" transport - during 1311 incubation, partially prevented the reduction of 125I transport. Considering that there was no cell damage from radiation exposure and that the same amount of stable iodide had no effect on transport, these authors concluded that decreased I" transport after 1311 exposure was most probably the result of a direct effect of radiation on thyroid function.
To achieve an optimal therapeutic effect with maximum radioiodide uptake in thyroid carcinoma metastases, TSH has to be above 30 mU/l in thyroidectomized patients, who must be on a low iodide diet for two weeks prior to treatment (1, 73).
Radioiodide uptake in thyroid cancer could be increased by stimulation of NIS activity. Experimental therapies aiming at restoring NIS function in thyroid cancer have concentrated only on increasing NIS transcription. However, as mentioned earlier, TSH and are the main regulators of NIS expression and plasma membrane targeting; therefore, high TSH and low I" levels are optimal for upregulating NIS expression and cell surface targeting. Clearly, elucidation of the mechanisms involved in NIS targeting to and retention at the plasma membrane may result in novel therapies for thyroid cancer treatment, since NIS is overexpressed in 70% of thyroid cancers but not properly targeted to the plasma membrane (20).
Several groups have attempted to induce NIS transcription in non-NIS-expressing thyroid carcinoma cell lines. Transcriptionally inactive promoter regions often contain hypermethylated CpG rich regions (5-methylcytidine immediately followed by guanidine). These methylated sites of the DNA were found to bind specifically to histone-deacetylase complexes. The N-terminal lysines of unacetylated histones are positively charged and interact with DNA phosphates preventing the binding of transcription factors. When the positive charge of the N-terminus is neutralized via acety-lation of the lysines, their electrostatic interaction with the DNA is disrupted, making the binding of transription factors to the DNA possible. Therefore, inhibiting histone deacetylase activity and/or demethylating CpG-rich promoter regions would initiate transcriptional activity.
As the hNIS promoter has CpG-rich regions, Venkataraman et al. (74) hypothesized that hypermethylation of the hNIS promoter resulting in transcriptional failure could be responsible for decreased or absent NIS expression. These authors were able to restore hNIS mRNA expression in 4 out of 7 cell lines using 5-azacytidine and sodium butyrate treatment. The increase in NIS mRNA transcritpion correlated with demethylation of the untranslated region in the first exon of the hNIS gene. They also investigated NIS mRNA expression by Northern blot and methylation status of the hNIS promoter in proximity to the TATA box in human thyroid tumors. NIS mRNA expression was observed in 16 out of 22 carcinomas, including papillary, follicular, and anaplastic subtypes. These findings suggest that, in these cases, posttranscriptional mechanisms are probably responsible for decreased uptake. In the six non-NIS-mRNA-expressing papillary carcinomas, the hNIS promoter was strongly methylated.
Kitazono et al. (75) reported increased NIS mRNA expression detected by Northern blot and quantitative RT-PCR in four human thyroid carcinoma cell lines (two follic-ular and two anaplastic) in vitro after treatment with depsipeptide, a histone deacetylase inhibitor. This increase in NIS mRNA expression was accompanied by an increase in P uptake.
Zarnegar et al. (76) used another histone-deacetylase inhibitor, trichostatin, in papillary, Hurthle, and follicular carcinoma-derived cell lines, and found increased NIS mRNA expression by quantitative PCR. NIS protein levels and uptake activity were not determined.
Other investigators have tried to achieve redifferentiation of thyroid cancer cells with trans-retinoic acid (tRa) treatment in thyroid carcinomas to restore radioiodide uptake. Schmutzler et al (77) were able to upregulate NIS mRNA expression by growing follicular thyroid carcinoma-derived cell lines in media supplemented with 1 |aM tRa for one week, but no effect was observed on either protein expression or uptake ability. Surprisingly, the same treatment decreased uptake activity in the highly differentiated FRTL-5 cell line (78).
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