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J C Reubi

Publications and source records attributed to J C Reubi.

At least 199 records · Page 11Linked to original sources
PubMed1987

Distinct topographical localisation of two somatostatin receptor subpopulations in the human cortex.

The use of two different radioligands, [125I]Leu8, D-Tryp22,Tyr25-somatostatin-28 and the stable somatostatin octapeptide analog [125I]204-090, D-Phe-Cys[125I]Tyr-D-Trp-Lys-Thr-Cys-Thr(ol), allowed to differentiate between two somatostatin receptor subpopulations in the human cortex. In homogenates, octapeptide somatostatin analogs displaced only part of the somatostatin-28 radioligand with high affinity. Autoradiography showed that the receptor subpopulation labelled with [125I]204-090, which we named SS1, was preferentially localized in layers V and VI, whereas the subpopulation having low affinity for somatostatin octapeptides (named SS2), measured with somatostatin-28 radioligand, was concentrated in the superficial cortical layers (I-IV) and particularly enriched in parts of lamina IV.

Aged↗
PubMed1987

Somatostatin receptors in human endocrine tumors.

A selection of 90 mainly endocrine but nonpituitary tumors have been tested for their content of specific somatostatin receptors using receptor autoradiography. Somatostatin receptors were detected in the following tumors: in all 5 meningiomas tested; in 3 of 39 malignant breast tumors; and in 3 growth hormone releasing factor-producing tumors, i.e., one mediastinal carcinoid, one intestinal carcinoma, and its liver metastasis. Receptor density varied greatly among individual tumors. Some of the positive tumors were biochemically characterized using in vitro binding assay and were shown to have saturable and high affinity receptors with pharmacological specificity for somatostatin. The following tumors did not contain somatostatin receptors: prostate carcinomas (n = 17); prostate hyperplasia (n = 2); ovarian carcinomas (n = 6); endometrial carcinomas (n = 4); primary liver cell carcinomas (n = 3); pheochromocytomas (n = 3); aldosteronomas (n = 2); medullary thyroid carcinomas (n = 2); one adrenocorticotropic hormone-secreting pulmonary carcinoid; one astrocytoma; one neurofibroma; one lung tumor; and one bladder tumor. Somatostatin receptors can be found in benign or malignant tumors, originating in part from tissue not primarily known as a somatostatin target. The biological function of such receptors is, therefore, partly unknown. If they can mediate antiproliferative properties, as has been suggested to be the case for somatostatin receptors in selected endocrine tumors in rats and humans, the present data could be of potential therapeutic interest.

Autoradiography↗
PubMed1987

Specific luteinizing-hormone-releasing hormone receptor binding sites in hippocampus and pituitary: an autoradiographical study.

Using the iodinated luteinizing-hormone-releasing hormone analogue [D-Ala6, N alpha MeLeu7, Pro9 NEt]-luteinizing-hormone-releasing hormone as radioligand, specific binding sites have been visualized in the rat both in the pituitary and the hippocampal formation of the brain. In the hippocampus, the CA1, CA2 and particularly CA3 regions were heavily labelled. These hippocampal sites have a pharmacological specificity resembling that of luteinizing-hormone-releasing hormone receptors in pituitary homogenates and could therefore represent true luteinizing-hormone-releasing hormone receptors. The luteinizing-hormone-releasing hormone superagonist [D-Ala6, Pro9 NEt]-luteinizing-hormone-releasing hormone and the potent antagonist [D-pGlu1, D-Phe2, D-Trp3,6]-luteinizing-hormone-releasing hormone were highly potent in displacing the iodinated luteinizing-hormone-releasing hormone analogue. The weak agonist [Gln8]-luteinizing-hormone-releasing hormone, however, was at least two orders of magnitude less potent. Somatostatin was inactive. Hippocampal luteinizing-hormone-releasing hormone receptors were species-specific, being present in the rat but not in the mouse, guinea-pig, hamster, rabbit and human brains. In order to identify the cellular location of these hippocampal receptors, various lesions were performed. Electrolytic lesions of the septal afferents did not reveal any receptor density change. Colchicine as well as kainic acid injections did, however, reduce considerably the number of hippocampal receptors. Interestingly, in the electrolytically and kainic-acid-lesioned animals, the appearance of non-displaceable luteinizing-hormone-releasing hormone binding sites within a well-defined area corresponding to the lesioned, gliosis-rich area was observed. The present results suggest the presence of pharmacologically specific, species-dependent, luteinizing-hormone-releasing hormone receptors located, at least partly, on intrinsic hippocampal neurons, in particular granule and pyramidal cells.

Animals↗
PubMed1987

Immunocytochemistry of pituitary tumors.

Pituitary tumors from 376 patients were investigated, using immunocytochemical techniques at the light and electron microscopic level, and autoradiography combined with immunocytochemistry for localizing somatostatin (SRIH) receptors. Prolactinomas, growth hormone-secreting adenomas causing acromegaly, and hormonally inactive adenomas were most frequently observed (153, 86, and 90 tumors, respectively). Among the latter, we could distinguish "alpha-only adenomas," many of which were oncocytomas. At the light and electron microscopic levels, cells containing (and presumably producing) simultaneously both prolactin and growth hormone, and cells containing exclusively either prolactin or growth hormone, could be demonstrated. In addition, a highly variable number and distribution of SRIH receptors could be shown in tumors secreting prolactin, growth hormone, and in tumors not associated with symptoms caused by inappropriate hormone secretion. The systematic combination of clinical, radiological, and biological techniques has currently brought great progress in the behavior and therapeutic concepts of pituitary lesions, and promises new achievements in the near future.

Adenoma↗
PubMed1987

Visualization of somatostatin receptors and correlation with immunoreactive growth hormone and prolactin in human pituitary adenomas: evidence for different tumor subclasses.

Using combined autoradiographic and immunohistochemical techniques, specific somatostatin (SRIH) receptors were measured in 31 human pituitary tumors. SRIH receptor distribution was compared with that of immunoreactive GH and PRL in the same tissue sections. Among the 10 tumors from acromegalic patients, 7 contained a high or medium density of SRIH receptors, whereas only a low density of such receptors was present in the remaining 3 tumors despite a comparably high concentration of immunoreactive GH in all 10 tumors. No correlation between plasma GH levels and SRIH receptors was found. One corticotroph tumor was SRIH receptor negative. Among the 5 prolactinomas tested, only 1 contained a significant density of SRIH receptors, the distribution of which did not correlate with that of immunoreactive PRL cells. Interestingly, among the 15 endocrine-inactive adenomas investigated, 6 had a measurable, sometimes high, density of SRIH receptors despite undetectable GH, PRL, or TSH immunoreactivity. These results suggest that based on their SRIH receptor content, there may be subclasses of GH-producing pituitary adenomas. The difference in SRIH receptor density may be an explanation for the clinically described differential responsiveness of acromegalic patients to SRIH. The results also suggest that subclasses of endocrine-inactive pituitary adenomas may exist; some of them contain significant amounts of SRIH receptors, which may be responsive to SRIH treatment.

Adenoma↗
PubMed1987

Hormone-producing gastrointestinal tumors contain a high density of somatostatin receptors.

Fourteen hormone-producing gastrointestinal tract tumors were tested for their content of somatostatin (SRIH) receptors, using receptor autoradiography and in vitro binding assay with tumor homogenates. All four gastrinomas tested had high levels of SRIH receptors, as did two of five insulinomas and four of five vasoactive intestinal peptide-producing tumors. Receptor visualization was obtained with two different radioligands, either a SRIH-28 analog, [125I]-[Leu8,D-Trp22,Tyr25]SRIH-28, or a SRIH octapeptide, the [125I]Tyr3 derivative of SMS 201-995 [H-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr(ol)], [125I]204-090. In both cases receptors were localized over the tumor cell area only. Biochemical and pharmacological analyses of one insulinoma and two vipomas revealed saturable, high affinity binding sites with pharmacological specificity for SRIH. However, differences in receptor affinity of selected SRIH analogs, in particular SRIH-28 and SRIH octapeptides, were found between the insulinomas and the two other tumor types, vipoma and gastrinoma. The presence of SRIH receptors on various hormone-producing gastrointestinal tumors suggests that at least part of the beneficial effects of chronic therapy with SRIH analogs may be mediated through such membrane-bound receptors located on the tumor itself. SRIH receptor measurement may be of prognostic value in assessment of the therapeutic efficacy of SRIH analogs. They may also be of diagnostic value, if used as in vivo markers for the localization of small hormone-producing gastrointestinal tumors or their metastases.

Adult↗
PubMed1986

Somatostatin binding sites in human leptomeninx.

Specific binding sites for somatostatin (SRIF) have been visualized in the human leptomeninx by means of autoradiographical techniques using the stable SRIF octapeptide analog 125I-204-090 as radioligand. The binding sites are specific for SRIF since only biologically active SRIF analogs compete with the radioligand. The density of the binding sites is comparable to that of the adjacent cortical structure. The presence of SRIF binding sites in the human leptomeninx, together with the recent demonstration of SRIF binding sites in human meningiomas, strongly suggest that this peptide may play a role in the physiology of the leptomeninx.

Arachnoid↗
PubMed1986

Somatostatin receptors in rat hippocampus: localization to intrinsic neurons.

The effect of neurotoxic chemical and electrolytical lesions on somatostatin (SS) receptor binding in the septo-hippocampal afferents, pyramidal and granule cells of the rat hippocampus was examined by autoradiography using the stable SS analogue 125I-204-090 as radioligand. Electrolytical lesions of the septum did not result in modification of SS binding in the hippocampus. In contrast, both granule cell lesion with colchicine and pyramidal or pyramidal and granule cell lesions with increasing kainic acid doses did result in a specific decrease of binding in the dentate gyrus and hippocampus (CA1 and CA3). These results suggest that SS receptors in the hippocampus are probably associated with elements from intrinsic neurons.

Animals↗
PubMed1986

Distribution and coregulation of three peptide receptors in adrenals.

Receptors sites for angiotensin II and atrial natriuretic factor were concentrated in the zone glomerulosa of the adrenal cortex in the rat, mouse, hamster, rhesus monkey, guinea-pig and the cow. Angiotensin Ii receptor sites were also accumulated in adrenal medullary tissue of the rat, mouse and the hamster. With exception of the cow the zonae fasciculata and reticulata of the adrenal cortex were not labelled with the angiotensin II ligand, but showed a moderate density of atrial natriuretic factor receptor sites in all species except the rhesus monkey. In comparison, somatostatin receptors were even more heterogeneously distributed in all species mentioned above. In the rat, the increased growth of zona glomerulosa cells found after three weeks of sodium deprivation was accompanied by a similar increase in number of receptor sites for angiotensin II, atrial natriuretic factor and somatostatin. This shows that all three peptide receptors are regulated simultaneously by a single metabolic disturbance, suggesting that they might be localized on the same cell type in the adrenal cortex.

Adrenal Glands↗
PubMed1986

Somatostatin and Alzheimer's disease: a hypothesis.

Recent data suggest a disturbance of some brain somatostatin neurons in Alzheimer's disease. Moreover, some endocrine activities known to be regulated by somatostatin, such as growth hormone, thyroid-stimulating-hormone, somatomedins, as well as insulin and glucose metabolism, also seem to be affected in some patients. It is speculated that these changes are due to a global CNS and endocrine somatostatin defect in Alzheimer's disease and that the described endocrine imbalance may indirectly be responsible for at least part of the CNS pathology.

Alzheimer Disease↗
PubMed1986

Different ionic requirements for somatostatin receptor subpopulations in the brain.

Two populations of brain somatostatin (SS) receptors, one with high affinity for the somatostatin octapeptide analogue SMS 201-995 (SS1 type) and one poorly sensitive to this analogue (SS2 type) have been characterised in regard to their ionic requirements using two radioligands, the iodinated Tyr3 derivative of the octapeptide SS analog SMS 201-995 and the iodinated [Tyr11]-SS. Specific binding of 125I-[Tyr11]-SS to rat cortex membrane homogenates can be increased by approximately 180% in presence of 5 mM Mg2+. The increase in number of binding sites seen by Mg2+ is not accompanied by a marked increase in affinity for SS but for SMS 201-995: the low affinity binding for SMS 201-995 seen in absence of Mg2+ is replaced in part by higher affinity binding in presence of these ions. SMS 201-995 sensitive SS1 receptor subpopulation measured with 125I-204-090, a specific ligand for SS1 subpopulation, is massively increased in presence of Mg2+. However, SMS 201-995 insensitive SS2 receptor population measured with 125I-[Tyr11]-SS in presence of excess SMS 201-995 is unchanged in presence of Mg2+. The Mg2+-dependency can also be observed with autoradiography for extra cortical, i.e. hippocampal, brain SS receptors. 120 mM Na+ does not affect the total brain SS receptor population, but reduces the specific binding of SS1 receptors and increases that of SS2 receptors. Therefore, the rat brain, in particular the cortex, possesses a SMS 201-995-sensitive, Mg2+-dependent SS receptor subpopulation (SS1) as well as a SMS 201-995-insensitive, Mg2+-independent SS population (SS2).

Animals↗
PubMed1986

Somatostatin receptors in the adrenal.

Somatostatin receptors have been visualized in the adrenal by autoradiography using the iodinated Tyr3 derivative of the somatostatin octapeptide analog SMS 201-995 (H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol), Sandostatin*). In the rat adrenal gland somatostatin receptors are not exclusively restricted to the glomerulosa cell layer, but can also be found in the adrenal medulla, particularly after in vitro incubation. The receptor sites in the adrenal are saturable and have affinity constants of 0.42 nM in the adrenal cortical and 0.15 nM in medullary membranes. The distribution of somatostatin receptors in the adrenal visualized in vitro is strongly species specific. Whereas only the adrenal medulla is labelled in the hamster, mouse and rhesus monkey, solely the glomerulosa layer shows somatostatin receptor sites in the cow and the guinea pig. The rat is the only species with a high density of somatostatin receptor sites in both the glomerulosa cell layer and the adrenal medulla.

Adrenal Cortex↗
PubMed1986

Distribution of somatostatin receptors in the human brain: an autoradiographic study.

High affinity somatostatin receptors have been measured in postmortem brains from 18 neurologically asymptomatic patients (mean age: 67 years) using the stable somatostatin analog 125I-204-090, DPhe-Cys-Tyr-DTrp-Lys-Thr-Cys-Thr(ol), as radioligand. In homogenates from human frontal cortex, high affinity (Kd = 0.52 nM; Bmax = 557 fmol/mg protein) receptors with pharmacological specificity for somatostatin, [D-Trp8]somatostatin and somatostatin-28 were found. The CNS distribution of these receptors was studied by autoradiography. Somatostatin receptors were distributed in varying densities throughout the whole brain. High concentrations are found in all cortical layers, the deeper layers (V-VI) being usually more dense than the superficial layers (I-III). The limbic system is heavily labeled, in particular hippocampus (CA1, dentate gyrus), most of the nuclei of the amygdala, and the habenula. Also parts of the basal ganglia are very rich in somatostatin receptors: the nucleus caudatus as well as the nucleus accumbens are very dense, whereas the globus pallidus is virtually unlabeled. Interestingly, significant amounts of somatostatin receptors are found in the human cerebellum, which is devoid of endogenous somatostatin. Other discrete areas of the CNS are enriched with somatostatin receptors: locus coeruleus, tuberal nuclei of the hypothalamus, claustum, tuberculum olfactorium as well as spinal trigeminal nucleus and substantia gelatinosa of the spinal cord. The substantia innominata is poor in somatostatin receptors. In general there is a good correlation in the distribution of somatostatin receptors in the human and rat brain and there is a reasonable correlation with endogenous somatostatin levels in human brain tissue, particularly in the larger structures. The very high density and the specific localization of somatostatin receptors in strategic key points in the CNS such as cortex, basal ganglia, limbic system and substantia gelatinosa suggests an important role of somatostatin in cognitive, sensory and extrapyramidal motor functions. The significance of somatostatin receptors in the human cerebellum remains to be elucidated.

Aged↗
PubMed1986

Studies on the mechanism of action of the inhibitory effect of the somatostatin analog SMS 201-995 on the growth of the prolactin/adrenocorticotropin-secreting pituitary tumor 7315a.

The somatostatin analog SMS 201-995 (2 X 6 or 2 X 20 micrograms daily for 30 days) inhibited the growth of the PRL/ACTH-secreting pituitary tumor 7315a by 36% and 48%, respectively. A biphasic curve of the inhibitory effect of the SMS analog on tumor growth was recognized: the actual tumor growth inhibitory effect occurred during the first 15 days, after which the tumors grew in parallel with the control tumors despite SMS 201-995 treatment. At the end of the 30-day SMS 201-995 treatment, plasma GH and plasma somatomedin-C levels were similar to those in the control tumor-bearing rats. Separate experiments in normal rats showed that tachyphylaxis of the GH-secretion inhibitory effects of three different doses of SMS 201-995 occurred within 6-10 days. No specific somatostatin-14 or SMS 201-995 receptors were present on well grown, untreated 7315a pituitary tumors. However, PRL and ACTH secretion by cultured cells prepared from the 7315a tumor was inhibited by SMS 201-995. Pretreatment of the cultured cells with dexamethasone made PRL secretion by these tumor cells insensitive to SMS 201-995. These studies suggest that several factors played a role in the mechanism of action of the tumor growth-inhibitory actions of SMS 201-995. Twice daily administration of the somatostatin analog rapidly (within 6-10 days) induces tachyphylaxis of the GH-inhibitory effect. From 10 days after implantation the PRL/ACTH-secreting pituitary tumor causes adrenal hyperplasia and increased plasma corticosterone concentrations. Exposure of the 7315a tumor to high glucocorticosteroid levels probably decreases the number of somatostatin receptors, diminishing the possible direct antitumor effect of SMS 201-995.

Adrenocorticotropic Hormone↗
PubMed1986

High incidence of somatostatin receptors in human meningiomas: biochemical characterization.

Thirteen human meningiomas were tested for their content of specific somatostatin (SRIH) receptors using an in vitro binding assay with meningioma homogenates as well as receptor autoradiography. All tumors had measurable amounts of somatostatin receptors. Receptor density, however, greatly varied among the tumors, ranging from low levels to more than 400 fmol/mg protein. Seven tumors, biochemically characterized in detail, had saturable and high affinity receptors [mean Kd, 1.10 +/- 0.42 (+/- SEM) nM], with pharmacological specificity for SRIH resembling the noncentral nervous system type of SRIH receptor. There was no correlation between the density of SRIH receptors and the density of progestin receptors measured in parallel. The presence of SRIH receptors in meningiomas was completely unexpected, and their role unknown. If the receptors can mediate antiproliferative properties in meningiomas, as has been suggested to be the case for such receptors in other endocrine tumors, the present data could be of potential therapeutic interest.

Adult↗
PubMed1986

Chemistry and pharmacology of SMS 201-995, a long-acting octapeptide analogue of somatostatin.

Starting from a hypothetical conformation of natural somatostatin and a knowledge of the minimal fragment needed for biological activity, a process of rational design and lead optimization has led to the potent, selective, and long-acting analogue SMS 201-995, (formula: see text) which selectively inhibits growth hormone secretion in several animal species for up to 6 h after subcutaneous application. In the rat, SMS inhibits GH, insulin, and glucagon 70, 3, and 23 times more potently than SRIF, resulting in GH/insulin and GH/glucagon selectivities of 20 and 3, respectively. The compound has been shown to inhibit growth of transplantable insulinomas in hamsters and to label selectively a subset of somatostatin receptors in the rat cortex. A radioactively labelled analogue has been used to visualize somatostatin receptors in a GRF-secreting human tumour. The stability and duration of action of SMS 201-995 after subcutaneous injection enable for the first time extended investigations of the clinical utility of somatostatin in various diseases.

Animals↗
PubMed1985

New specific radioligand for one subpopulation of brain somatostatin receptors.

Cyclic octapeptide analogues of somatostatin (SS) like SMS 201-995 [H-(D) Phe-Cys-Phe-(D) Trp-Lys-Thr-Cys-Thr(ol)] or its Tyr3-derivative 204-090, displaced [125I-Tyr11]-SS 100% from pancreatic membranes but only 62-75% from brain membranes; the remaining sites were displaced by SS. These data indicate that some mini-somatostatins bind to a subpopulation of SS receptors in rat brain. The iodinated Tyr3-derivative (125I-204-090) can be considered a selective radioligand for one rat brain SS receptor subpopulation: It shows saturable and high affinity binding (KD = 0.29 nM; Bmax = 350 fmoles/mg protein) to rat cortex. The pharmacological properties of 125I-204-090 binding sites are similar to those of [125I-Tyr11]-SS sites. Distribution of these sites correspond to SS receptor-rich areas such as cortex, hippocampus, striatum, pituitary, pancreatic beta-cell. SS as well as SMS 201-995 bind to these sites with high affinity. The stability and high specific vs non-specific binding ratio makes 204-090 a radioligand of choice to measure this SS receptor subpopulation in CNS but also the SS receptors in pituitary and pancreas.

Animals↗