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M de Jong

Publications and source records attributed to M de Jong.

At least 19 recordsLinked to original sources
PubMed1999

Evaluation of radiolabelled bombesin analogues for receptor-targeted scintigraphy and radiotherapy.

The 14-aminoacid peptide bombesin (BN) has a high affinity for the gastrin-releasing peptide receptor which is expressed by a variety of tumours. Thus, radiometal-labelled DTPA-BN derivatives are potentially useful radioligands for receptor-targeted scintigraphy and radiotherapy of BN receptor-expressing tumours. A number of such DTPA-BN analogues, [DTPA-D-Tyr6]BN(6-13)NHEt (Et=ethyl), [DTPA-Tyr5,D-Phe6]BN(5-13)NHEt, [DTPA-D-Phe6,Leu13psiPhe14]BN(6-14), [DTPA-Tyr5,D-Phe6,Leu13psiPhe14]BN(5-14), [DTPA-Pro1,Tyr4]BN and [DTPA-Pro1,Tyr4,Nle14]BN, were synthesized and studied for their binding characteristics to the BN receptor on 7315b rat pituitary tumour cell membranes in competition with [125I-Tyr4]BN. The effects of the BN analogues were determined on basal and BN-stimulated prolactin secretion by 7315b cells to distinguish between their agonistic and antagonistic characteristics. Internalization of selected (111)In-labelled BN analogues was studied using the BN receptor-positive 7315b pituitary tumour and the CA20948 and AR42J exocrine pancreas tumour cell lines. The tissue distribution of these (111)In-labelled BN analogues was investigated in 7315b tumour-bearing rats. Two DTPA-conjugated analogues, the antagonist [DTPA-Tyr5,D-Phe6]BN(5-13)NHEt and the agonist [DTPA-Pro1,Tyr4]BN showed the highest affinity for the BN receptor on 7315b cell membranes. Despite similar affinity for the BN receptor, the (111)In-labelled agonist, but not the antagonist, was internalized by the BN receptor-positive tumour cells. Consonant with this observation, the agonist [(111)In-DTPA-Pro1,Tyr4]BN showed much higher specific uptake in BN receptor-positive tissues and tumour than the antagonist [(111)In-DTPA-Tyr5,D-Phe6]BN(5-13)NHEt, with concordant target to background ratios. We conclude that [(111)In-DTPA-Pro1,Tyr4]BN has promising characteristics for applications in nuclear medicine.

Amino Acid Sequence↗
PubMed1999

Tumour uptake of the radiolabelled somatostatin analogue [DOTA0, TYR3]octreotide is dependent on the peptide amount.

Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin analogue [Tyr3]octreotide (D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelator DOTA (tetra-azacyclododecane-tetra-acetic acid), enabling stable radiolabelling with both the high-energy beta particle-emitter yttrium-90 and the Auger electron-emitter indium-111. The thus produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in vitro and in vivo (rat) experiments with these radiolabelled compounds showed favourable binding and biodistribution characteristics with high uptake and retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization of radiolabelled [DOTA0,Tyr3]octreotide in somatostatin receptor subtype 2 (sst2)-positive rat pancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of injected peptide on tissue distribution of 111In-labelled [DOTA0, Tyr3]octreotide in normal, i.e. non-tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find the amount of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide therapy while simultaneously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled [DOTA0,Tyr3]octreotide in sst2-positive organs showed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals), 0.05-0. 1 (pituitary and stomach) and 0.25 (pancreas) microg. Uptake in the tumour was highest at 0.5 microg injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for [111In-DTPA0]octreotide ((D-Phe-c(Cys-Phe-D-Trp-Lys-Thr-Cys)-Thr(ol), DTPA = diethylene-triamine-penta-acetic acid), consistent with the higher receptor affinity of the first compound. Our observations of mass-dependent differences in uptake of radiolabelled [DOTA0, Tyr3]octreotide, being the resultant of a positive effect of increasing amounts of peptide on, for example, receptor clustering and a negative effect of receptor saturation, are of consequence for rat radionuclide therapy studies with radiolabelled peptides and may also be of consequence for human radionuclide therapy studies with this compound.

Animals↗
PubMed1999

Radiolabelled somatostatin analogue(s) for peptide receptor scintigraphy and radionuclide therapy.

BACKGROUND: Peptide receptor scintigraphy with the radioactive somatostatin analogue, [111In-DTPA0]octreotide, is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumours. AIM: With this technique primary tumours and metastases of neuroendocrine cancers as well as of many other cancer-types can be localised. This technique is currently used to assess the possibility of peptide receptor radionuclide therapy (PRRT) with repeated administrations of high doses of [111In-DTPA0)octreotide. 111In emits Auger and conversion electrons having a tissue penetration of 0.02-10 microns and 200 to 500 microns, respectively. PATIENTS AND METHODS: Thirty end-stage patients with mostly neuroendocrine progressing tumours were treated with [111In-DTPA0]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase I trial. RESULTS: There were no major clinical side effects after up to two years treatment, except that in a few patients a transient decline in platelets counts and lymphocyte subsets occurred. Promising beneficial effects on clinical symptoms, hormone production and tumour proliferation were found. Of the 21 patients who received a cumulative dose of more than 20 GBq, eight patients showed stabilisation of disease and six other patients a reduction in size of tumours. There is a tendency towards better results in patients whose tumours have a higher accumulation of the radioligand. CONCLUSIONS: PRRT is feasible, also with 111In as radionuclide. Depending on the homogeneity of distribution of tumour cells expressing peptide receptors and the size of the tumour, beta-emitting radionuclides, e.g., 90Y, labelled to DOTA-chelated peptides, are also attractive candidates for PRRT. The first PRRT trials with [90Y-DOTA0,Tyr3]octreotide started recently.

Animals↗
PubMed1999

Somatostatin receptor imaging and therapy of pancreatic endocrine tumors.

Somatostatin receptors (SS-Rs) have been found on a variety of neuroendocrine tumors like carcinoids, paragangliomas, as well as on brain and breast tumors. SS-Rs are also present on most pancreatic endocrine tumors, while previous in vitro studies indicate the absence of these receptors on pancreatic duct cancers. Somatostatin receptor scintigraphy with a radionuclide labeled somatostatin analogue, [111In-DTPA0]-octreotide, is a sensitive and specific technique to visualize in vivo the presence of SS-Rs on various tumors. The purpose of this article is to review the somatostatin receptor imaging of pancreatic endocrine tumors and to illustrate the impact of SS-R expression for therapeutic strategies.

Apudoma↗
PubMed1998

Comparison of (111)In-labeled somatostatin analogues for tumor scintigraphy and radionuclide therapy.

We evaluated the following (111)In-labeled somatostatin (SS) analogues (diethylenetriaminepentaacetic acid, DTPA; tetraazacyclododecanetetraacetic acid, DOTA): [DTPA0]octreotide, [DTPA0,Tyr3]octreotide, [DTPA0,D-Tyr1]octreotide, [DTPA0,Tyr3]octreotate [Thr(ol) in octreotide replaced with Thr], and [DOTA0,Tyr3]octreotide, in vitro and in vivo. In vitro, all compounds showed high and specific binding to SS receptors in mouse pituitary AtT20 tumor cell membranes, and IC50s were in the nanomolar range. Furthermore, all compounds showed specific internalization in rat pancreatic tumor cells; uptake of [(111)In-DTPA0,Tyr3]octreotate was the highest of the compounds tested, and that of [(111)In-DTPA0,D-Tyr1]octreotide was the lowest. Biodistribution experiments in rats showed that, 4, 24, and 48 h after injection of [(111)In-DTPA0,Tyr3]octreotide, [(111)In-DTPA0,Tyr3]octreotate, and [(111)In-DOTA0,Tyr3]octreotide, radioactivity in the octreotide-binding, receptor-expressing tissues and tumor-to-blood ratios were significantly higher than those after injection of [(111)In-DTPA0]octreotide. Uptake of [(111)In-DTPA0,Tyr3]octreotate in the target organs was also, in vivo, the highest of the radiolabeled peptides tested, whereas that of [(111)In-DTPA0,D-Tyr1]octreotide was the lowest. Uptake of [(111)In-DTPA0,Tyr3]octreotide, [(111)In-DTPA0,Tyr3]octreotate, and [(111)In-DOTA0,Tyr3]octreotide in target tissues was blocked by >90% by 0.5 mg of unlabeled octreotide, indicating specific binding to the octreotide receptors. Blockade of [(111)In-DTPA0,D-Tyr1]octreotide was >70%. In conclusion, radiolabeled [DTPA0,Tyr3]octreotide and, especially, [DTPA0,Tyr3]octreotate and their DOTA-coupled counterparts are most promising for scintigraphy and radionuclide therapy of SS receptor-positive tumors in humans.

Animals↗
PubMed1998

Altered [Ca2+] homeostasis in PC12 cells after nerve growth factor deprivation.

[Ca2+]i homeostasis in individual PC12 cells after elevated [K+]o was studied by ratiometric microscopy, during nerve growth factor (NGF) deprivation. A significantly lower number of cells responded with an increased [Ca2+]i in the NGF deprived condition. Moreover, the responding cells were more deficient in regulating their [Ca2+]i back to control levels, after the transient peak. This suggests that differentiated neurons do not traverse the apoptotic program homogeneously with regard to their [Ca2+]i regulation and that NGF deprived PC12 cells have more difficulties to reduce their [Ca2+]i after influx of [Ca2+]o.

Animals↗
PubMed1998

99mTc-MIBI, 99mTc-tetrofosmin and 99mTc-Q12 in vitro and in vivo.

The aim of this study was to compare uptake of 99mTc-MIBI, 99mTc-tetrofosmin and 99mTc-Q12 in vitro and biodistribution in vivo in rats. In vitro, uptake decreased in the order MIBI-->tetrofosmin-->Q12. Uptake of MIBI and tetrofosmin, but not of Q12, in cultured tumor cells was dependent on the plasma membrane and mitochondrial potential. In vivo, heart uptake of all three compounds was high and stable. Tumor uptake decreased in the order MIBI-->Q12-->tetrofosmin and the tumor/blood ratio in the order MIBI-->tetrofosmin-->Q12.

Animals↗
PubMed1998

Okadaic acid-induced apoptosis in neuronal cells: evidence for an abortive mitotic attempt.

There is increasing evidence that apoptosis in postmitotic neurons is associated with a frustrated attempt to reenter the mitotic cycle. Okadaic acid, a specific protein phosphatase inhibitor, is currently used in models of Alzheimer's research to increase the degree of phosphorylation of various proteins, such as the microtubule-associated protein tau. Okadaic acid induces programmed cell death in the human neuroblastoma cell lines TR14 and NT2-N, as evidenced by fragmentation of DNA and attenuation of this process by protein synthesis inhibitors. In differentiated TR14 cells, okadaic acid increases the fraction of cells in the S phase, induces the appearance of cyclin B1 and cyclin D1 markers of the cell cycle, and triggers a time-dependent increase in DNA fragmentation after release of a thymidine block. Fully differentiated NT2-N cells are forced to enter the mitotic cycle as shown by DNA staining. Chromatin condensation and chromosome formation are initiated, but the cells fail to complete their mitotic cycle. These data suggest that okadaic acid forces differentiated neuronal cells into the mitotic cycle. This pattern of cyclin up-regulation and cell cycle shift is compared with apoptosis induced by neurotrophic factor deprivation in differentiated rat pheochromocytoma PC12 cells.

Anaphase↗
PubMed1997

Aberrant tau phosphorylation and neurite retraction during NGF deprivation in PC12 cells.

Recently apoptotic markers have been found in Alzheimer's Disease (AD) brain. To investigate the relation between tau phosphorylation and apoptosis, immunocytochemistry of AT8 (indicating the degree of phosphorylation at the tau Ser202/Thr205 site) was quantitatively determined the degree of tau phosphorylation at the Ser202 site was monitored during neuronal apoptosis in differentiated PC12 cells after nerve growth factor (NGF) deprivation. During this programmed cell death a prominent retraction of neurites took place that was associated with a clear increase in the level of AT8 signalaberrant phosphorylated tau at the Ser202 site. The broad spectrum kinase inhibitor staurosporine attenuated both this increase in tau phosphorylation, neurite retraction, and apoptosis. We suggest that at some point during programmed cell death, kinases with tau as substrate become activated and that the resulting loss of cytoskeletal integrity leads to neurite instability.

Animals↗
PubMed1997

Yttrium-90 and indium-111 labelling, receptor binding and biodistribution of [DOTA0,d-Phe1,Tyr3]octreotide, a promising somatostatin analogue for radionuclide therapy.

In vitro octreotide receptor binding of [111In-DOTA0,d-Phe1, Tyr3]octreotide (111In-DOTATOC) and the in vivo metabolism of 90Y- or 111In-labelled DOTATOC were investigated in rats in comparison with [111In-DTPA0]octreotide [111In-DTPAOC). 111In-DOTATOC was found to have an affinity similar to octreotide itself for the octreotide receptor in rat cerebral cortex microsomes. Twenty-four hours after injection of 90Y- or 111In-labelled DOTATOC, uptake of radioactivity in the octreotide receptor-expressing tissues pancreas, pituitary, adrenals and tumour was a factor of 2-6 that after injection of 111In-DTPAOC. Uptake of labelled DOTATOC in pituitary, pancreas, adrenals and tumour was almost completely blocked by pretreatment with 0.5 mg unlabelled octreotide, indicating specific binding to the octreotide receptors. These findings strongly indicate that 90Y-DOTATOC is a promising radiopharmaceutical for radiotherapy and that 111In-DOTATOC is of potential value for diagnosis of patients with octreotide receptor-positive lesions, such as most neuroendocrine tumours.

Animals↗
PubMed1997

Computer simulation to support policy making in the control of pseudorabies.

A further integration of international markets makes a coordinated policy against contagious animal infections increasingly important. In the future, stricter demands are to be expected concerning the control and eradication of such infections. To anticipate these demands, a computer simulation model is created in which scenarios can be evaluated with respect to epidemiological and economic effects of the infections and control strategies. In this paper, the simulation model is described for Pseudorabies in swine. In the model, the population of herds is subdivided into two main herd types: breeding and finishing. Each herd is in one of 24 states per herd type. The states are based on (1) the reproduction ratio R which is the number of secondary cases caused by one infectious herd, (2) the prevalence for each value of R and (3) the expected number of infectious animals in an infectious herd within each prevalence range and for each R. The different values of R are based on experiments and field data in which different vaccination strategies were used. The transition matrix with the probabilities of every transition from one state to another is calculated on a weekly base. With this matrix the distribution of herds over states from week to week is derived. To include a dynamic element in the transition probabilities, the number of newly infectious herds per week is a function of animal and other contacts, including aerial, material and personal contacts. Calculations show that the infection in the Dutch swine population will not disappear without vaccination. With a vaccination scheme in which sows are vaccinated 3 times per year and fattening pigs 1 time per cycle the infection will ultimately be eradicated, but 2 vaccinations per cycle for fattening pigs are needed to eradicate the infection within an acceptable timespan (i.e. 2 to 3 years). The latter strategy will become compulsory in the Netherlands from October 1st 1995.

Animals↗
PubMed1997

Effects of ligand priming and multiple-dose injection on tissue uptake of 111In-pentetreotide in rats.

In patients undergoing somatostatin receptor scintigraphy, treatment with octreotide (Sandostatin) is usually discontinued 24-48 h before and after injection with the radioligand 111In-pentetreotide ([111In-DTPA(O)]octreotide) (Octreoscan) because octreotide competes with radioligand for the same receptors. However, Dörr et al. and Soresi et al. reported improved visualization of carcinoid and small cell lung cancer lesions, respectively, during continued octreotide treatment. We found that intravenous administration of unlabeled octreotide to rats inhibited the binding of an optimal dose (0.5 microg) of 111In-pentetreotide to somatostatin receptors in pancreas and adrenals in a mass- and time-dependent way. Pretreatment with unlabeled octreotide never increased receptor binding of 111In-pentetreotide. Administration of 100 microg of octreotide decreased receptor-bound radioactivity if given simultaneously with or 10 or 20 min after injection of the radioligand, but had no effect if given 30 min after the radioligand. These findings indicate rapid processing of receptor-bound octreotide and suggest that octreotide treatment of patients undergoing 111In-pentetreotide scintigraphy may be reinitiated as soon as 1 h after radioligand administration.

Animals↗
PubMed1997

D-lysine reduction of indium-111 octreotide and yttrium-90 octreotide renal uptake.

UNLABELLED: Indium-111-DTPA-octreotide (111In-DTPAOC) is used successfully for imaging somatostatin receptor-positive lesions. A new and promising application is its use in peptide-receptor radionuclide therapy (PRRT). For the latter purpose, [DOTA0,D-Phe1,Tyr3]octreotide (DOTATOC), which is suitable for stable radiolabeling with 90Y, is probably even more promising. Significant renal uptake of these octreotide analogs exists, however, reducing the scintigraphic sensitivity for detection of small tumors in the perirenal region and limiting the possibilities for PRRT. We showed that the renal uptake of 111In-DTPAOC could be reduced to about 50% of control by L-lysine administration in vivo in rats. This study compares the effects of several doses and different methods of administration of D- and L-lysine, in addition to time-related effects of D-lysine, on kidney uptake of 111In-DTPAOC and 90Y-DOTATOC. METHODS: Male Wistar rats (200-250 g) were given 111In-DTPAOC (0.2 MBq, 0.5 microg-0.5 mg intravenously, intraperitoneally or orally) in the presence or absence of D- or L-lysine. At 1, 4 or 24 hr, the rats were killed, and the organs were isolated and counted for radioactivity. In different experiments, male Wistar rats (200-250 g) were given 90Y-DOTATOC (1 MBq, 0.5 microg intravenously) in the presence or absence of D-lysine. At 24 hr, the rats were killed, and the organs were isolated and counted for radioactivity. RESULTS: Administration of D- or L-lysine in a single intravenous dose of 400 mg/kg, resulted in more than 50% inhibition of kidney uptake of 111In-DTPAOC at all time points tested, independently of the mass of 111In-DTPAOC used. Higher or repeated doses of lysine did not give a significantly higher percentage inhibition. D-lysine, given orally in a dose of 400 mg/kg at 30 or 15 min before 111In-DTPAOC injection, resulted in 30% and 20% inhibition of kidney uptake, respectively. L-lysine, given orally 30 min before 111In-DTPAOC administration, resulted in 30% inhibition as well. Inhibition of kidney uptake of 111In-DTPAOC by L-lysine after intraperitoneal administration was 40%. After L-lysine administration, 111In-DTPAOC was decreased in the kidneys and in somatostatin receptor-positive organs such as the pancreas and adrenal glands. In contrast, D-lysine did not have a significant effect on uptake in octreotide receptor-positive organs. Renal uptake of 90Y-DOTATOC was reduced by 65% by intravenous D-lysine, whereas radioactivity in blood, pancreas and adrenal glands was not affected. CONCLUSION: D-lysine may be preferred to L-lysine for reduction of renal uptake of radioactivity during scintigraphy and PRRT because of its lower toxicity and because it should not interfere with the natural amino acid metabolic balance.

Animals↗
PubMed1996

Iodine-131 labelled octreotide: not an option for somatostatin receptor therapy.

Gamma-emitting radiopeptides are useful for scintigraphy of tumours on the basis of receptor binding. Likewise, beta-emitting radiopeptides may be used in radionuclide therapy of such tumours. As iodine-131 suggested to be suitable for this purpose, experiments were performed using three somatostatin analogues, in which the effects of coupling of a therapeutic dose of 131I to such peptides were investigated. This study deals with the radioiodination of very small amounts of peptide on a therapeutic scale, the required purification procedures after radioiodination, and the influence of high beta fluxes from 131I on a peptide during radioiodination and purification. Based on the regularly used therapeutic doses of 131I in cancer treatment and our previous experience with [111In-DTPA-D-Phe1]-octreotide, it was assumed that a minimal effective therapeutic dose of 3.7 GBq 131I has to be coupled to a maximum of approximately 100 microg peptide, representing only a slight excess of peptide over 131I. This contrasts with non-peptide radiopharmaceuticals in which high compound to radionuclide ratios are usually used. Labelling at low peptide to radionuclide ratios (low labelling yields) results in the formation of di-iodinated compounds, whereas at high peptide to radionuclide ratios (high labelling yields) mono-iodinated products of low specific activity are formed. Thus, after radioiodination the desired mono-iodinated peptide has to be separated from unreacted iodide, and from di-iodinated and unreacted peptide, as both compounds compete for the receptors. Possible radiolysis of the peptide during labelling and separation steps were investigated by irradiating 30 microgram unlabelled peptide with 370 MBq 131I in a small volume. The peptide composition of the incubation mixtures was investigated by high-performance liquid chromatography after irradiation for 30 min to 24 h. The results showed that the peptide was degraded with a half-life of less than 1 h. During the preparation of a real therapeutic dose (at much higher beta-flux) the peptide will be degraded even faster during the various steps required. In conclusion, intact mono-iodinated 131I-labelled somatostatin analogues for peptide receptor therapy will be difficult to obtain.

Antineoplastic Agents↗
PubMed1996

Comparison of uptake of 99mTc-MIBI, 99mTc-tetrofosmin and 99mTc-Q12 into human breast cancer cell lines.

Technetium-99m hexakis-2-methoxyisobutylisonitrile (MIBI), 99mTc-tetrofosmin and 99mTc-Q12 were all introduced for myocardial imaging but found additional applications as they are taken up by different tumours, enabling imaging of these lesions in patients. The aim of this study was to compare the uptake characteristics of these compounds in vitro in the human adenocarcinoma breast cell lines MCF-7 and ZR-75. It was shown that 99mTc-MIBI had the highest cellular uptake (15.9%+/-0.5% dose/mg protein after 60 min in MCF-7, and 14.2%+/-0.4% dose/mg protein in ZR-75), followed by 99mTc-tetrofosmin (6.8%+/-0.6% dose/mg protein in MCF-7, and 8. 2%+/-0.2% dose/mg protein in ZR-75) and 99mTc-Q12 (3.2%+/-0.1% dose/mg protein in MCF-7, and 3.5%+/-0.3% dose/mg protein in ZR-75 cells). For all three compounds tenfold differences in specific activity did not influence total cell-associated radioactivity. Uptake of 99mTc-MIBI and 99mTc-tetrofosmin was obviously lower at 4 degrees C than at 37 degrees C, whereas 99mTc-Q12 uptake showed only slight temperature dependence. When uptake was compared in cells grown to different cell densities (1 mg/ml cellular protein versus 0.3 mg/ml), no differences in uptake were detected when uptake was corrected for the amount of cellular protein present in the dishes. Furthermore, for all compounds it was shown that cellular radioactivity decreased rapidly after washing. Apart from the differences in cellular uptake of the three compounds after 60 min, no differences in residual cellular radioactivity after washing were found between the different compounds when expressed as a percentage of their 60-min uptake, suggesting that the efflux process of the radiolabelled compounds was similar. The differences in cell-associated activity after 60 min were thus presumably caused by differences in uptake. It was concluded that of the Tc-labelled compounds tested, 99mTc-MIBI had the highest cellular retention in both human breast tumour cell lines. However, for imaging in vivo not only radioactivity in the target organ is important, but also the ratio of radioactivity in the target versus that in the background. Therefore, further studies in vivo need to be performed to investigate which compound is the optimal imaging agent.

Adenocarcinoma↗
PubMed1996

Different regulation of thyroid hormone transport in liver and pituitary: its possible role in the maintenance of low T3 production during nonthyroidal illness and fasting in man.

Nonthyroidal illness (NTI) and fasting in man are characterized by a low serum concentration of T3 and an increased serum concentration of rT3. Since the serum level of T3 is one of the most important factors that determine the metabolic rate, the low serum T3 during NTI or fasting results in reduction of the energy consumption of the body. This can be regarded as an adaptive mechanism to save energy, and thus to conserve protein and to protect organ function. The low serum T3 concentration should preferentially be maintained until recovery from illness or adequate calorie supply. This implies that the low serum T3 should not result in a rise in serum TSH. We postulate that different regulation of thyroid hormone transport into the relevant tissues, i.e., liver and pituitary, may play a role in maintenance of the low T3 production during NTI and fasting. This hypothesis is further elaborated in this paper by comparing (i) the properties of the thyroid hormone uptake mechanism in rat and human hepatocytes, perfused rat liver, and rat anterior pituitary cells, and (ii) the effects of fasting and conditions that mimic NTI on thyroid hormone transport in the same preparations. In addition, the consequences of changes in thyroid hormone transport and peripheral thyroid hormone metabolism during fasting and NTI for the serum level of rT3 and for TSH secretion are discussed. The data are compatible with the existence of different transport systems for thyroid hormone in liver and pituitary. We suggest that these different thyroid hormone carriers allow tissue-specific regulation of the intracellular availability of T3.

Animals↗