Thyroidal Radioiodine Accumulation Research Articles

Apigenin in Combination with Akt Inhibition Significantly Enhances Thyrotropin-Stimulated Radioiodide Accumulation in Thyroid Cells

Selectively increased radioiodine accumulation in thyroid cells by thyrotropin (TSH) allows targeted treatment of thyroid cancer. However, the extent of TSH-stimulated radioiodine accumulation in some thyroid tumors is not sufficient to confer therapeutic efficacy. Hence, it is of clinical importance to identify novel strategies to selectively further enhance TSH-stimulated thyroidal radioiodine accumulation. PCCl3 rat thyroid cells, PCCl3 cells overexpressing BRAF(V600E), or primary cultured tumor cells from a thyroid cancer mouse model, under TSH stimulation were treated with various reagents for 24 hours. Cells were then subjected to radioactive iodide uptake, kinetics, efflux assays, and protein extraction followed by Western blotting against selected antibodies. We previously reported that Akt inhibition increased radioiodine accumulation in thyroid cells under chronic TSH stimulation. Here, we identified Apigenin, a plant-derived flavonoid, as a reagent to further enhance the iodide influx rate increased by Akt inhibition in thyroid cells under acute TSH stimulation. Akt inhibition is permissive for Apigenin's action, as Apigenin alone had little effect. This action of Apigenin requires p38 MAPK activity but not PKC-δ. The increase in radioiodide accumulation by Apigenin with Akt inhibition was also observed in thyroid cells expressing BRAF(V600E) and in primary cultured thyroid tumor cells from TRβ(PV/PV) mice. Taken together, Apigenin may serve as a dietary supplement in combination with Akt inhibitors to enhance therapeutic efficacy of radioiodine for thyroid cancer.

Modulation of sodium iodide symporter expression and function by LY294002, Akti-1/2 and Rapamycin in thyroid cells

The selective increase of Na(+)/I(-) symporter (NIS)-mediated active iodide uptake in thyroid cells allows the use of radioiodine I(131) for diagnosis and targeted treatment of thyroid cancers. However, NIS-mediated radioiodine accumulation is often reduced in thyroid cancers due to decreased NIS expression/function. As PI3K signaling is overactivated in many thyroid tumors, we investigated the effects of inhibitors for PI3K, Akt, or mTORC1 as well as their interplay on NIS modulation in thyroid cells under chronic TSH stimulation. PI3K inhibition by LY294002 increased NIS-mediated radioiodide uptake (RAIU) mainly through upregulation of NIS expression, however, mTORC1 inhibition by Rapamycin did not increase NIS-mediated RAIU despite increased NIS protein levels. In comparison, Akt inhibition by Akti-1/2 did not increase NIS protein levels, yet markedly increased NIS-mediated RAIU by decreasing iodide efflux rate and increasing iodide transport rate and iodide affinity of NIS. The effects of Akti-1/2 on NIS-mediated RAIU are not detected in nonthyroid cells, implying that Akti-1/2 or its derivatives may represent potential pharmacological reagents to selectively increase thyroidal radioiodine accumulation and therapeutic efficacy.

Single photon emission computed tomography imaging for temporal dynamics of thyroidal and salivary radionuclide accumulation in 17-allyamino-17-demothoxygeldanamycin-treated thyroid cancer mouse model

Selective iodide uptake and prolonged iodine retention in the thyroid is the basis for targeted radioiodine therapy for thyroid cancer patients; however, salivary gland dysfunction is the most frequent nonthyroidal complications. In this study, we have used noninvasive single photon emission computed tomography functional imaging to quantify the temporal dynamics of thyroidal and salivary radioiodine accumulation in mice. At 60 min post radionuclide injection, radionuclide accumulation in the salivary gland was generally higher than that in thyroid due to much larger volume of the salivary gland. However, radionuclide accumulation per anatomic unit in the salivary gland was lower than that in thyroid and was comparable among mice of different age and gender. Differently, radionuclide accumulation per anatomic unit in thyroid varied greatly among mice. The extent of thyroidal radioiodine accumulation stimulated by a single dose of exogenous bovine TSH (bTSH) in triiodothyronine (T₃)-supplemented mice was much less than that in mice received neither bTSH nor T₃ (nontreated mice), suggesting that the duration of elevated serum TSH level is important to maximize thyroidal radioiodine accumulation. Furthermore, the extent and duration of radioiodine accumulation stimulated by bTSH was less in the thyroids of the thyroid-targeted RET/PTC1 (thyroglobulin (Tg)-PTC1) mice bearing thyroid tumors compared with the thyroids in wild-type (WT) mice. Finally, the effect of 17-allyamino-17-demothoxygeldanamycin on increasing thyroidal, but not salivary, radioiodine accumulation was validated in both WT mice and Tg-PTC1 preclinical thyroid cancer mouse model.

Thyroidal handling of radioiodine in sea level residents exposed to hypobaric hypoxia.

In the present investigation thyroidal accumulation of radioiodine and its release were assessed by direct testing of thyroid function using radioactive iodine, in vivo, in sea level residents intermittently exposed to hypobaric hypoxia. Thyroidal accumulation of radioiodine and its turnover were examined daily for 14 days. Twelve healthy human male volunteers were divided into three groups, with an equal number of individuals in each group. A decompression chamber was used to expose each group of subjects to hypoxic conditions at a simulated altitude of 3810 m for 8 h/day for 14 days. An oral dose of 25 mu Ci iodine-131 was administered to each individual of the first group immediately before the initiation of intermittent hypoxia. The second group of subjects received a tracer dose at the beginning of the 4th day of the 14 days, intermittent exposure to hypoxia, while the third group received the tracer dose 1 week after the completion of the exposure. Control studies were carried out on the subjects before they were subjected to the experimental conditions. Thyroidal accumulation of 131I in experimental subjects during the hypoxic state and in the post-hypoxic state was higher than in the control studies. The pattern of accumulation during exposure to hypoxia and in the post-hypoxic state showed multiple peaks of radioactive iodine uptake (PRAIU), a unique feature. The multiple PRAIU by the thyroid in experimental subjects were sharp and of short duration, reflecting an increased rate of 13I release from the thyroid. Control subjects had a single PRAIU by the thyroid 24 h after the administration of tracer.

Scintigraphic Endocrine Mimicry

The control of hormone secretion and substrate uptake by the thyroid and inner adrenal cortex is similar because both glands undergo hypothalamic-pituitary trophic hormone modulation and negative feedback by their respective major secretory products: thyroid hormone and cortisol, respectively. As a result of these parallel mechanisms of endocrine function, thyroidal accumulation of radioiodine or Tc-99m pertechnetate and adrenal cortical accumulation of I-131-6 beta-iodomethylnorcholesterol (NP-59) and other radiocholesterol analogs are strikingly similar. The patterns of imaging of these glands are thus functional maps of the process(es) of substrate accumulation and depict the endocrine pathophysiology of these glands in a variety of dysfunctional states. The well-recognized patterns of thyroid imaging can be shown analogous to those of the adrenal cortex.

Prostaglandin administration to pregnant rats: effects on pituitary-target gland systems of mother, fetus and neonate (38512).

Acute administration of PGE-1 in graded doses (0.25-1.0 mg) to pregnant rats in late gestation (21st day) induced significant release of TSH, prolactin and LH from the maternal, pituitary. Plasma levels of PRL and TSH were elevated (three- to fivefold) in cesarean sectioned mothers given 4-5 sc injections of PGE-1; higher doses also stimulated LH release. Comparable increases in blood TSH and PRL levels were also found in their newborn but no indication of enhanced hormone release from the fetal hypophysis was noted. Histologic alterations were observed in the ovary (luteal cell hypertrophy, cytopasmic clearing, nuclear condensation, sinusoidal distension) of mothers receiving PGE-1 treatment. Thyroidal radioiodine accumulation in mother, fetus and neonate were usually decreased whereas thyroid: blood radioactivity ratios were consistently incrased. It is concluded that PGE-1 treatment of th pregnant rat near term stimulates release of hormones from the pituitary in mothers (TSH, LH, PRL) and in their newborn (TSH, PRL). The results also strongly suggest that PGE-1 administration may induce morphologic and functional changes in target endocrines (ovary, thyroid) by direct and separate actions.

Hyperthyroidism after iodinated contrast medium.

INORGANIC iodine administration can precipitate hyperthyroidism in susceptible patients.1 , 2 The patient with an autonomous nodule of the thyroid described below appeared clinically euthyroid despite a slightly elevated serum tri-iodothyronine level, but became clinically hyperthyroid after administration of organic iodine in the course of intravenous pyelography.Case ReportA 57-year-old woman was seen in 1969 because of a thyroid mass. 131I scan of the thyroid revealed uptake mainly by the mass in the right lobe. Thyroidal accumulation of radioiodine was 11 per cent in four hours (normal, less than 15 per cent), and 29 per cent in 24 hours (normal, 15 . . .

Thyroid function in breast cancer.

ABSTRACT Thyroidal radio-131I clearance rate measured at one hour after intravenous injection of a tracer dose was significantly higher in 29 breast cancer patients with local disease only than in 37 with blood borne metastases or in 117 normal subjects. Chemical protein bound iodine was significantly higher in 13 patients with blood borne metastases than in 311 normal subjects. Ten patients with a history of proven breast cancer, but no present clinical or radiographic evidence of disease, evidenced a clearance rate consistent with that of patients with blood borne metastases. The PBI, however, was normal. Measurements were made of 24 hour uptake, extra-thyroidal retained radioiodide at 24 hours, thyroidal radioiodine accumulation curves, renal radioiodine clearance rates and serum thyroid stimulating hormone level, with no significant findings.

Inhibition by thiocyanate of accumulation of radioiodine by thyroid gland.

An investigation was made to determine whether the inhibition by thiocyanate of the thyroidal accumulation of radioiodine can be accounted for by the well-known inhibition of the iodide concentrating mechanism, or whether, in addition, there is a direct effect on the iodination process. At the lower concentrations of serum thiocyanate the decrease in the thyroidal accumulation of radioiodine was proportional to the ratio of the thyroid and serum radioiodide concentrations (T/S) and no appreciable effect on the rate of incorporation of radioiodide per unit of thyroidal radioiodide into protein-bound I131 (PBI131) was observed. At higher serum thiocyanate concentrations the fraction of the thyroid radioiodide incorporated into PBI131 per minute decreased as the uptake decreased whereas the T/S was relatively constant. However, at this higher range of concentrations no unambiguous interpretation of the effect of thiocyanate could be made because of the lack of information about the distribution of radioiodide in the internal compartments of the thyroid. A comparison was made also of the effect of thiocyanate on the T/S when the iodination process was permitted with the effect on the T/S when iodination was blocked.

The effect of electrical aulation of the nuclei habenulae, pineal body and subcommissural organ on endocrine function, with special reference to thyroid function.

Although it has been proposed that the habenular nuclei may be a primary center in the control of thyrotropin secretion by the pituitary, in the present study it was found that animals with extensive damage including the habenula, pineal body and subcommissural organ developed thyroid enlargement approximately equal to that of untreated controls when fed propylthiouracil. Thyroidal radioiodine accumulation and testis and adrenal weights were not consistently affected by any of the lesions. There was no persistent change in either serum sodium and potassium concentration or water intake postoperatively.

Studies on the effect of thyrotropin on human thyroid function.

ABSTRACT Time-response and dose-response relationships between a single intramuscular injection of thyroid-stimulating hormone (TSH) and its effect on thyroid function were studied in human subjects without thyroid disease. The effect of TSH on thyroidal accumulation of radioiodine was demonstrable after a latent period of eight to ten hours. It reached its maximum after eighteen to twenty-four hours, decreased to pre-TSH values after five to six days, fell to levels significantly below the pre-TSH values from the eighth to eighteenth days after injection of TSH, and then returned to the original level. The rate of release of thyroid hormone had already started to increase within the first ninety minutes after injection of TSH, and did not return to the pre-TSH rate for at least twenty-four hours. The effect of TSH on the radioiodineaccumulating capacity of the thyroid increased continuously with mounting doses from 0.003 to 0.025 USP unit per Kg. of body weight, but no additional rise was obtained after ...

The thyroidal accumulation of radioiodine as a clinical test for hyperthyroidism.

Eight radio-iodine uptake tests have been compared. The neck/thigh ratio at two hours and the 8–24-hour excretion fraction are shown to be simple and effective tests and suitable for routine clinical use.

Thyroidal accumulation of radioiodine in children.

Although a large volume of information on the radioiodine uptake by the thyroid of the adult is available, there is relatively little such information concerning the infant and child. For the most part, published data for the child or infant relate to the normal or hypothyroid person and pertain to the period between 24 and 96 hours following the administration of the radioiodine test dose. The present study concerns the thyroid uptake of radioiodine as a function of the status of the thyroid gland, the age of the patient, and the time after the administration of the test dose. It provides data on the effect of the thyroid-stimulating hormone (TSH) on thyroidal accumulation of radioiodine in the euthyroid, the primary hypothyroid, and the pituitary hypothyroid child. In a recent paper by Martmer, Corrigan, Charbeneau, and Sosin,1the 24-hour radioiodine uptake in 65 premature infants was reported as being within

Influence of iodoalphionic acid priodax, with and without thyrotropin, on thyroidal I 131 uptake in euthyroid patients.

THE ingestion or administration of iodine-containing solutions is known to suppress thyroidal radioactive iodine uptake in euthyroid individuals. Werner et al. (1) state that a low uptake may persist up to twelve weeks after administration of stable iodine. Keating et al. (2) observed that the ingestion of Priodax (an organic iodine-containing compound used in cholecystography) resulted in low thyroidal radioiodine accumulation for periods ranging from a few weeks to many months. Drummy (3) reported reduction of the radioiodine uptake to less than 15 per cent for at least six months in a majority of 29 euthyroid patients after the ingestion of Priodax. Our experience in the Isotope Clinic at Letterman Army Hospital suggested that the inhibiting effect of Priodax is of shorter duration. Many patients who undergo thyroid function studies have had recent cholecystography with Priodax. Because of this, we felt it important to attempt a more accurate determination of the length of the period during which thyro...

Effect of diethylstilbestrol on the binding of thyroxine in serum.

An apparent paradox in thyroidal economy is presented by the normally pregnant woman. Thus, there occurs during pregnancy thyroidal hyperplasia, augmentation of the thyroidal accumulation of radioiodine, and an increase in the concentration of circulating thyroid hormone (1–5). These changes, ordinarily associated with the thyrotoxic state, are not accompanied during pregancy by symptomatic stigmata of thyrotoxicity nor by increases in basal oxygen consumption beyond those which have been attributed to fetal needs (6).

Increased uptake of iodine-131 by the thyroid gland after administration of hesperidine methyl chalcone.

Scott(1) has shown that the rat's thyroid takes up 50 to 200% more radioiodine under the influence of hesperidine methyl chalcone (H.M.C.). It was therefore decided to try this drug in human beings in order to determine its effect upon thyroidal accumulation of radioiodine. This drug is known to suppress the output of I131 through the kidney; probably I131 stays in the body in circulation a long enough time to favor increased uptake by the gland. Method. Nineteen patients having the diagnoses shown in Table I were studied. All of these were considered to be euthyroid except K.E. and O.C. who were judged to be hyper-and hypothyroid respectively . Two periods of tests were done on each patient. These were the first or the patient's control period before the administration of H.M.C. and the second or his testing period following the administration of H.M.C. At the start of the control period, 20 μc I131 was given orally. Thyroid gland uptake measurements were done at 24-hour intervals for 96 hours. After a rest period of three days, the same patient's thyroid uptake was again measured for residual I131 then 1.0 g of H.M.C. mixture in water was ingested. After an hour lapse to allow for effective absorption of the drug the patient ingested 80 μc I131. At 24-hour intervals, for 96 hours, his thyroid gland uptake was measured and due correction for decay and effective half-life was made for the residual I131 uptake from the control period. The tracer dose of 80 μ I131 was large enough to be readily measurable in the presence of residual I131 and thus also to minimize statistical differences between the measurements of the two periods. Results. Studies on the nineteen patients summarized in Table I show that the oral administration of one gram of H.M.C. significantly increases the thyroidal accumulation of I131.

Alteration of thyroid function by ACTH and cortisone.

RECENT observations have indicated that both ACTH and cortisone produce an alteration in the function of the normal thyroid gland. Hill, Reis, Forsham and Thorn (1) have noted a decrease in the radioiodine accumulation gradient, a depression of the basal metabolic rate and a decrease in the serum protein-bound iodine concentration during ACTH therapy. Hardy, Riegel and Erisman (2) also noted a decrease in the level of the serum protein-bound iodine. Money et al. (3) observed a decrease in thyroid weight and thyroidal radioiodine accumulation in rats. Wolfson et al. (4) have confirmed the results reported by Hill, Reiss, Forsham and Thorn and used the term “corticogenic hypothyroidism” to designate these changes. In an attempt to evaluate further the changes in thyroid function during ACTH or cortisone therapy, we have determined the 48-hour radioiodine excretion, the basal metabolic rate, and the levels of total and free serum cholesterol, before, during and after ACTH and cortisone administration.