Thyroid hormone uptake by rat hepatocytes in primary culture

Iodide is taken up by the thyroid follicular cell, oxydized and bound to thyroglobulin at the apical membrane facing the colloid in the follicular lumen. Iodinated colloid is subsequently engulfed by the follicular cell and hydrolysed, liberating thyroxine and triiodothyronine from their peptide linkage to thyroglobulin. Iodothyronines are then secreted into the blood stream. These and other steps in the synthesis and secretion of thyroid hormones are conditioned by the extent of thyroid stimulation by pituitary thyrotropin. The synthesis and release of thyrotropin is stimulated by the hypothalamic thyrotropinreleasing hormone, while thyroid hormone inhibits these processes (Larsen, 1982). In this way, a negative feedback mechanism is formed between the thyroid and pituitary. The main product secreted by the human thyroid is thyroxine (mean 115 nmol/day per 70 kg body weight). Other products are triiodothyronine (mean 9 nrnol/day, which accounts for 20% of the total daily production) and reverse triiodothyronine (mean 2 nmol/day; 6%) (Chopra, 1976; Chopra et al., 1978a; Visser, 1980). From these figures it will be clear that synthesis of the latter iodothyronines occurs mainly outside the thyroid gland by monodeiodination of thyroxine, the so-called peripheral production. In pathophysiological conditions, like iodine deficiency and Graves' disease, thyroidal secretion of triiodothyronine is increased relative to that of thyroxine (Izumi and Larsen, 1977). The relative contribution of different tissues to the daily production of triiodothyronine and reverse triiodothyronine is at present unknown. However, deiodination has been observed in vitro in almost all tissues studied (see review by Visser, 1980). Based on circumstantial evidence, it is generally believed that the liver is the main site of triiodothyronine synthesise For instance, in liver cirrhosis triiodothyronine production is decreased, while apparent reverse triiodothyronine synthesis is unaltered (Chopra, 1976). The latter finding is in favour of extra-hepatic thyroxine_.reverse triiodothyronine conversion. The low serum reverse triiodothyronine levels in patients with severe, chronic renal failure may suggest that substantial amounts of reverse triiodothyronine are produced in the kidneys (Chopra et al., 1975; Weissel et al., 1977; Weissel and Stummvoll, 1981)

Somatostatin receptor scintigraphy in patients with carcinoid tumors

In 80% to 90% of patients with carcinoids, tumor sites can be detected with [111In-DTPA-D-Phe1]-octreotide scintigraphy. Unexpected, additional localizations are reported in one-third to two-thirds of patients. In a group of 52 patients, we analyzed the results of various combinations of octreotide scintigraphy and conventional imaging. Octreotide scintigraphy, alone or in combination with other imaging modalities, led to the detection of more tumor sites than any combination of conventional imaging techniques. The combination of octreotide scintigraphy, chest radiography, and ultrasonography of the upper abdomen led to the detection of lesions in all patients in whom they could be demonstrated by any imaging means, with a sensitivity of 87% in terms of the number of detected lesions. The calculated cost for this imaging regimen was higher than for the combination of conventional imaging as applied in our group. However, the benefit was the detection of at least one lesion in 11% of patients in whom with conventional imaging no abnormalities were found. Moreover, if the results from our patient group were extrapolated to a group of 100 patients, the advantage in terms of the number of extra lesions detected would be 65 extra lesions per 100 patients. The detection of more tumor sites in patients who are known to have one tumor localization with conventional imaging may be essential when deciding whether to perform surgery. Octreotide scintigraphy can be used to localize tumors, direct the choice of medical therapy, and (expected in the near future) select patients for radiotherapy. The impact on patient management is fourfold: Octreotide scintigraphy may detect resectable tumors that would be unrecognized with conventional imaging techniques; it may prevent surgery in patients whose tumors have metastasized to a greater extent than can be detected with conventional imaging; it may direct the choice of therapy in patients with inoperable tumors; and in the future it may be used to select patients for radionuclide therapy

To serve and protect: Enzyme inhibitors as radiopeptide escorts promote tumor targeting

Radiolabeled octreotide analogs are most successfully being applied today in clinical cancer imaging and treatment. Propagation of this paradigm to other radiopeptide families has been greatly hampered by the inherent poor metabolic stability of systemically administered peptide analogs. We hypothesized that the in vivo coadministration of specific enzyme inhibitors would improve peptide bioavailability and hence tumor uptake. Through single coinjection of the neutral endopeptidase inhibitor phosphoramidon (PA), we were able to provoke remarkable rises in the percentages of circulating intact somatostatin, gastrin, and bombesin radiopeptides in mouse models, resulting in a remarkable increase in uptake in tumor xenografts in mice. Methods: The peptide conjugates [DOTA-Ala1]SS14 (DOTA-Ala-Gly-c[Cys-Lys- Asn-Phe-Phe-Trp-Lys-Thr-Phe- Thr-Ser-Cys]-OH), PanSB1 (DOTAPEG2- DTyr-Gln-Trp-Ala-Val-βAla- His-Phe-Nle-NH2), and DOTA-MG11 (DOTA-DGlu-Al

Considerations concerning a tailored, individualized therapeutic management of patients with (neuro)endocrine tumours of the gastrointestinal tract a

Endocrine tumours of the gastrointestinal tract and pancreas may present at different disease stages with either hormonal or hormone-related symptoms/syndromes, or without hormonal symptoms. They may occur either sporadically or as part of hereditary syndromes. In the therapeutic approach to a patient with these tumours, excessive hormonal secretion and/or its effects should always be controlled first. Tumour-related deficiencies or disorders should also be corrected. Subsequently, control should be aimed at the tumour growth. Surgery is generally considered as first-line therapy for patients with localized disease, as it can be curative. However, in patients with metastatic disease the role of first-line surgery is not clearly established and other therapies should be considered, such as non-surgical cytoreductive therapies, biotherapy (with somatostatin analogues or interferon-alpha), embolization and chemoembolization of liver metastases, chemotherapy (with single or multiple dose regimens) and peptide receptor-targeted radiotherapy. The delicate balance of the use of the different therapeutical options in patients with endocrine tumours of the gastrointestinal tract and pancreas emphasizes the importance of team approach and team expertise

Adaptive changes in transmembrane transport and metabolism of triiodothyronine in perfused livers of fed and fasted hypothyroid and hyperthyroid rats

The transport and subsequent metabolism of triiodothyronine (T3) were studied in isolated perfused livers of euthyroid, hypothyroid, and hyperthyroid rats, both fed and 48-hour-fasted. T3 kinetics (transport and metabolism) during perfusion were evaluated by a two-pool model, whereas the metabolism of T3 was also investigated by determination of T3 breakdown products by chromatography of medium and bile. For comparison of groups, metabolism was corrected for differences in transport. Transport parameters in fed hypothyroid livers were not significantly changed as compared with euthyroid livers, whereas metabolism was decreased. In fed hyperthyroid livers, fractional transfer rate constants for influx (k21) and efflux (k12) were decreased and metabolism, corrected for differences in intracellular mass transfer, was increased. Furthermore, for transport in hyperthyroid livers it was shown that only total mass transfer (TMT) into the metabolizing liver compartment (not into the nonmetabolizing liver compartment) was decreased. Transport and metabolic parameters in fasted hypothyroid livers were decreased as compared with euthyroid fed livers. In fasted hyperthyroid livers, transport and metabolism were not significantly different as compared with that in euthyroid fed livers, so transport was increased versus hyperthyroid fed livers. It appeared therefore that fasting normalized the effects of hyperthyroidism on both the transport and metabolic processes of T3 in the liver. The present study demonstrates normal transport and decreased metabolism in livers of hypothyroid fed rats and decreased transport and increased metabolism in livers of hyperthyroid fed rats. In livers of hypothyroid fasted rats transport and metabolism were decreased, whereas in livers of hyperthyroid fasted rats transport and metabolism were not significantly different from that in euthyroid fed livers. These changes might favor tissue euthyroidism despite the altered thyroid and nutritional state, and can therefore be seen as adaptation mechanisms to these altered states at the tissue level

Bone mineral density and body composition before and during treatment with gonadotropin-releasing hormone agonist in children with central precocious and early puberty

Major changes in bone mineral density (BMD) and body composition occur during puberty. In the present longitudinal study, we evaluated BMD and calculated volumetric BMD [bone mineral apparent density (BMAD)], bone metabolism, and body composition of children (32 girls and 2 boys) with central precocious and early puberty before and during treatment with GnRH agonist (GnRH). Patients were studied at baseline and during treatment for 6 months (n = 34), 1 yr (n = 33), and 2 yr (n = 16). Lumbar spine and total body BMD and body composition were measured with dual-energy x-ray absorptiometry. The variables were compared with age- and sex-matched reference values of the same population and expressed as SD score (SDS). Bone age was assessed. Serum calcium, phosphate, alkaline phosphatase, osteocalcin, the carboxyterminal propeptide of type I collagen (PICP), cross-linked telopeptide of collagen I (ICTP), 1,25 dihydroxyvitamin D and urinary hydroxyproline/creatinine, and calcium/ creatinine ratios were measured. Mean lumbar spine BMD SDS was significantly higher than zero at baseline (P < 0.02) and did not differ from normal, after 2 yr of treatment. Mean spinal BMAD SDS and total body BMD SDS were not significantly different from zero at baseline and had not changed significantly after 2 yr of treatment. During therapy, fat mass and percentage body fat SDS increased, whereas lean tissue mass SDS decreased. Mean lumbar spine BMD and BMAD and total body BMD SDS, calculated for bone age, were all lower than zero at baseline (BMD P < 0.001 and BMAD P < 0.05) and also after 2 yr treatment (respectively, P < 0.001, P < 0.05, and P < 0.01). Biochemical bone parameters were significantly higher than prepubertal values at baseline, and they decreased during treatment. In conclusion, patients with central precocious and early puberty had normal BMD for chronological age but low BMD for bone age, after 2 yr of treatment with GnRH. Bone turnover decreased during treatment. Changes in body composition resembled those seen in patients with GH deficiency

Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues

Prostate Cancer (PC) is a type of cancer that is often diagnosed at very early stages due to improved detection among man in the Western world. Current imaging techniques are not optimal to determine extent of minimal early stage PC even though this is of great clinical importance. Human PC and high-grade PIN have shown high Gastrin-Releasing Peptide Receptor (GRPR) expression, while normal prostate tissue and BPH revealed to be predominantly GRPR-negative. Radiolabelled Gastrin-Releasing Peptide (GRP) or bombesin (BN) analogues targeting the GRPR can be used as non-invasive tools to diagnose, monitor and potentially treat PC. These BN analogues have already proven to be able to image PC in both tumour-bearing mice and clinical patients showing no important side effects. It's desirable that new peptides require fast-track standardised comparative testing in relevant PC models to select the best performing BN analogues for further evaluation in patients. Although knowledge about GRPR expression and development of new BN analogues can be extended, it is time to study performance of BN analogues for peptide receptor based imaging in patients validating results of PC imaging using histopathology as a golden standard