Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatostatin [somatotropin release-inhibiting factor (SRIF)] is a cyclic tetradecapeptide that is a potent inhibitor of growth hormone (GH) secretion from the anterior pituitary. In addition to the inhibitory effects on GH-release, SRIF-14 and SRIF-28, a 28-amino acid form of SRIF extended from the N-terminal end, inhibit the release of a variety of other peptides including glucagon, insulin, and gastrin, and both peptides act as neurotransmitters and neuromodulators in the central nervous system and the periphery. SRIF exerts its potent inhibitory effects following binding to high affinity SRIF receptors (ssts) that have been identified on target tissues. The recent cloning of five ssts has confirmed that the effects of SRIF are mediated by a family of G protein-coupled receptors (sst1-5). Based on structural and pharmacological properties sst2, sst3, and sst5 belong to the SRIF1 receptor subclass, and the sst1 and sst4 subtypes comprise the SRIF2 subclass. The major difference between these two subclasses is that SRIF1 receptors bind octapeptide and hexapeptide SRIF-14 analogs with high affinity, while SRIF2 receptors bind these analogs with drastically reduced affinity. A screening program was initiated to identify a lead nonpeptide with affinity for sst1-5 receptors. The search focused on a scaffold with the following attachments: (1) a heteroaromatic nucleus to mimic the Trp8 residue, (2) a nonheteroaromatic nucleus to mimic Phe7, and (3) a primary amine or other basic group to mimic the Lys9 residue of SRIF-14. Using these criteria, a novel thiourea (NNC 26-9100, 17) was discovered as a structural lead. The key fragments in this compound are a heteroaromatic moiety (pyridine), an aromatic group, and a basic imidazole group connected through a thiourea scaffold. Compound 17 exhibited a Ki = 6 nM at sst4 receptors with a 100-fold sst4/sst2 selectivity and was shown to be a full agonist at this receptor subtype. This article will review the literature on the design and development of nonpeptide somatostatin receptor ligands and the therapeutic potential of these agents. Furthermore, our work on the development of 2-pyridylthioureas as sst4 receptor agonists will be described.
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PMID:2-pyridylthioureas: novel nonpeptide somatostatin agonists with SST4 selectivity. 1010 Dec 24

Regulatory peptides are small, readily diffusable and potent natural substances with a wide spectrum of receptor-mediated actions in humans. High affinity receptors for these peptides are (over-) expressed in many neoplasms, and these receptors may represent, therefore, new molecular targets for cancer diagnosis and therapy. This review intends to give an overview of the peptide-based radiopharmaceuticals which are presently already commercially available or which are in advanced stages of their clinical testing so that their broader availability is anticipated soon. Physiologically, these peptides bind to and act through G protein-coupled receptors in the cell membrane. Historically, somatostatin analogs are the first class of receptor binding peptides having gained clinical application. 111In-DTPA-[D-Phe1]-octreotide is the first and only radiopeptide which has obtained regulatory approval in Europe and the United States to date. Extensive clinical studies involving several thousands of patients have shown that the major clinical application of somatostatin receptor scintigraphy is the detection and the staging of gastroenteropancreatic neuroendocrine tumors (carcinoids). In these tumors, octreotide scintigraphy is superior to any other staging method. However, its sensitivity and accuracy in other, more frequent neoplasms is limited. Radiolabeled vasoactive intestinal peptide (VIP) has been shown to visualize the majority of gastrointestinal adenocarcinomas, as well as some neuroendocrine tumors, including insulinomas (the latter being often missed by somatostatin receptor scintigraphy). Due to the outstanding diagnostic accuracy of the pentagastrin test in detecting the presence, persistence, or recurrence of medullary thyroid cancer (MTC), we postulated the expression of the corresponding [i.e., cholecystokinin (CCK-)-B] receptor type in human MTC. This receptor is also widely expressed on human small-cell lung cancer. Indeed, 111In-labeled DTPA derivatives of gastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and patients. A variety of further peptide-based radioligands is currently under development. Summarizing, radiolabeled regulatory peptides have opened new horizons in nuclear oncology for diagnosis (and potential internal radionuclide therapy). Further work will probably reveal a multitude of novel potentially clinically useful peptide-based radioligands.
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PMID:Diagnostic applications of radiolabeled peptides in nuclear endocrinology. 1056 42

Somatostatin is a cyclic tetradecapeptide hormone. It was initially isolated from bovine hypothalami. Somatostatin inhibits endocrine and exocrine secretion, as well as tumor cell growth, by binding to specific cell-surface receptors. Its potent inhibitory activity is limited, however, by its rapid enzymatic degradation and the consequently short plasma half-life. Octreotide is a short somatostatin analogue with increased duration of action compared with somatostatin. Preclinical studies have focused on the anticancer effects of octreotide and the related somatostatin analogues. In vitro, at nanomolar concentrations, these analogues inhibit the growth of tumor cells that express high-affinity somatostatin receptors. Accordingly, such analogues potently inhibit the growth of somatostatin receptor-positive tumors in various rodent models. The range of cancers susceptible to octreotide and related somatostatin analogues includes mammary, pancreatic, gastric, colorectal, prostate, thyroid, and lung carcinomas. Moreover, an indirect antiproliferative effect of somatostatin analogues is achievable in somatostatin receptor-negative tumors whose growth is driven by factors (e.g., gastrin, insulin-like growth factor-1) that become down-regulated by somatostatin. The clinical effect of somatostatin analogues in terms of tumor response in cancer patients is a subject of controversy, however. Most responses have been seen in patients with pancreatic cancers.
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PMID:The significance of somatostatin analogues in the antiproliferative treatment of carcinomas. 1062 87

Gastrinomas are uncommon tumors which are difficult to locate. They are often located in the head of the pancreas. About two-thirds of them are malignant, their growth is slow and they usually metastasize in the liver. In about 25% of cases, the Zollinger-Ellison (Z-E) syndrome is included in the multiple endocrine neoplasm type 1 syndrome (MEN 1).A 14-year old male patient presenting an episode of abdominal perforation which required emergency surgery is reported. The abdominal ultrasonography, CT scan and magnetic resonance revealed a single lesion in the left liver lobe, suggesting metastasis. Significantly increased levels of serum gastrin suggested a diagnosis of Z-E syndrome. A study with 111In-octreotide was required to locate the primary tumor and evaluate its extent. The scintigraphy showed only one abnormal uptake focus in the left liver lobe. Post-surgery scintigraphy studies revealed the presence of metastatic adenopathies which were removed after a second surgery. No pathologic findings were observed in the last nuclear medicine study. The somatostatin receptor scintigraphy is the most sensitive method to locate primary gastrinomas and to assess the tumoral dissemination in patients with Z-E Syndrome.
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PMID:[Scintigraphy with 111In-octreotide in a case of primary hepatic gastrinoma]. 1147 73

Regulatory peptides are small, readily diffusable and potent natural substances with a wide spectrum of receptor-mediated actions in humans. High affinity receptors for these peptides are (over-) expressed in many neoplasms, and these receptors may represent, therefore, new molecular targets for cancer diagnosis and therapy. This review aims to give an overview of the peptide-based radiopharmaceuticals which are presently already commercially available or which are in advanced stages of their clinical testing so that their broader availability is anticipated soon. Physiologically, these peptides bind to and act through G protein-coupled receptors in the cell membrane. Historically, somatostatin analogs are the first class of receptor binding peptides having gained clinical application. 111In-DTPA-[D-Phe1]-octreotide is the first and only radiopeptide which has obtained regulatory approval in Europe and the United States to date. Extensive clinical studies involving several thousands of patients have shown that the major clinical application of somatostatin receptor scintigraphy is the detection and the staging of gastroenteropancreatic neuroendocrine tumors (carcinoids). In these tumors, octreotide scintigraphy is superior to any other staging method. However, its sensitivity and accuracy in other, more frequent neoplasms is limited. Radiolabeled vasoactive intestinal peptide (VIP) has been shown to visualize the majority of gastrointestinal adenocarcinomas, as well as some neuroendocrine tumors, including insulinomas (the latter being often missed by somatostatin receptor scintigraphy). Due to the outstanding diagnostic accuracy of the pentagastrin test in detecting the presence, persistence, or recurrence of medullary thyroid cancer (MTC), we postulated the expression of the corresponding (ie. cholecystokinin [CCK-] -B) receptor type in human MTC. This receptor is also widely expressed on human small-cell lung cancer. Indeed, 111In-labeled DTPA derivatives of gastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and patients. A variety of further peptide-based radioligands, e.g. among many others, gastrin-releasing peptide/bombesin, neurotensin, substance-P, pan-somatostatin (somatostatin derivatives which bind to all five receptor subtypes) or glucagon-like peptide-1 (glp-1) analogs (the latter for the specific detection of insulinomas), is currently under development. Summarizing, radiolabeled regulatory peptides have opened new horizons in nuclear oncology for diagnosis (and potential internal radionuclide therapy). Future work will probably reveal a multitude of novel potentially clinically useful peptide-based radioligands.
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PMID:Imaging tumors with peptide-based radioligands. 1147 70

Somatostatin is a hypothalamic peptide hormone that inhibits the secretion of growth hormone, glucagon, insulin, gastrin and secretin, and also plays a role in neural transmission. Because of its wide range of possible clinical applications hundreds of somatostatin analogs have been synthesized and bioassayed to date. This review gives a historical perspective, summarizing approximately 30 years of research on somatostatin. The main focus is on the structure-activity relationships and conformational studies of the last generation of somatostatin agonists and their selectivity for five somatostatin receptor subtypes. Achievements in the synthesis of nonpeptide somatostatin analogs, as well as the first somatostatin antagonists, are also discussed. Finally, the use of a cyclic somatostatin scaffold to design ligands for other G-protein-coupled receptors, such as opioid and melanocortin receptors, is mentioned.
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PMID:Somatostatin analogs. 1153 69

Gastroenteropancreatic (GEP) neoplasms originate from any of the various cell types belonging to the neuroendocrine system. A general characteristic of GEP endocrine tumours is that the vast majority produce and secrete a multitude of peptide hormones and amines. Many patients with malignant metastasising tumours present clinical symptoms related to hormone hyperproduction. These include the so-called carcinoid syndrome, characterised by flushing, diarrhoea, wheezing and right heart disease, which is predominantly associated with the serotonin- and tachykinins-producing carcinoids of the midgut. Several types of syndrome associated with GEP endocrine tumors are caused by overproduction of a specific hormone. For instance, the well-known Zollinger-Ellison syndrome is gastrin-mediated. The so-called 'insulinoma syndrome' depends on excessive production of insulin and proinsulin, resulting in hypoglycemia. The 'glucagonoma syndrome' is characterised by necrolytic migratory erythema, diabetes and diarrhoea. The Verner-Morrison syndrome, which is brought about by high circulating levels of vasointestinal peptide (VIP). produces severe secretory diarrhoea. Finally the 'somatostatinoma syndrome' involves gallbladder dysfunction and gallstones, diarrhoea with or without steatorrhea, and impaired glucose tolerance. The biochemical diagnosis of endocrine digestive tumors is based on general and specific markers. The best general markers are chromogranin A (CgA) and pancreatic polypeptide (PP). Specific markers for endocrine tumors include insulin, gastrin, glucagon, vaso intestinal polypeptide (VIP), somatostatin and the primary cathabolic product of serotonin, 5-hydroxyndoleacetic acid (5-HIAA). Localisation procedures commonly applied, in the diagnosis of endocrine tumours include ultrasound (US), computed tomography (CT) and somatostatin receptor scintigraphy (SRS).
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PMID:Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumours. 1176 60

Helicobacter pylori infection has been found to decrease the expression of antral somatostatin and to increase the release of the acid-stimulating hormone gastrin. The reversal of these changes in gut hormones by the eradication of H. pylori, and in-vivo and in-vitro studies in animals either infected with H. pylori or exposed to H. pylori-related materials may support the somatostatin-gastrin link theory in the pathophysiology of H. pylori infection. The following mechanisms have been proposed to explain the H. pylori infection-associated changes in gut hormones; (1) ammonia produced by H. pylori and monochloramine, (2) effect on somatostatin receptor subtype-2, (3) action of lipopolysaccharide from H. pylori on somatostatin receptor, (4) inflammatory cells and mediators, and (5) bacterial strain diversity. H. pylori infection can alter gastric acid secretion in both directions. The elevated acid secretion in patients with duodenal ulcer is decreased by H. pylori eradication, and is accompanied by the normalization of gut hormones in patients whose H. pylori-induced gastritis is limited to the antrum with hyperacidity. Corpus gastritis and the subsequent development of mucosal atrophy induced by H. pylori result in decreased acid secretion, although the mechanism underlying H. pylori-induced atrophy in some subjects remains unclear. Hypoacidity enhances corpus atrophy and increases gastrin secretion, mediated via a physiological suppression of somatostatin release, features that are also observed in H. pylori infection. Therefore, the capacity of acid secretion and distribution of gastritis or atrophy should be taken into consideration when we discuss the affect of H. pylori on gut hormones.
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PMID:Helicobacter pylori and gut hormones. 1187 70

A 55-year-old woman, known with multiple endocrine neoplasia (MEN) type 1, had rectal bleeding and later haematemesis but colonoscopy and gastroduodenoscopy revealed no abnormalities. Due to the normal results for serum gastrin concentration, gastroduodenoscopy and CT scanning of the pancreas, Zollinger-Ellison syndrome was considered to be less likely. Yet the diagnosis could be established on the basis of persistent symptoms and a positive somatostatin receptor scintigraphy. The patient was treated with high doses of a proton pump inhibitor and temporary tube feeding due to weight loss. Follow-up will take place at the endocrinology outpatients' department. Zollinger-Ellison syndrome is a relatively common feature of patients with MEN-1. The diagnosis and localisation of the gastrinoma can be difficult: serum gastrin concentrations can be normal and the sensitivity of CT scanning is low. The primary aim of treating gastrinoma is to control gastric acid hypersecretion by means of high doses of a proton pump inhibitor. The question as to whether surgery is indicated remains controversial.
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PMID:[Clinical thinking and decision making in practice. Unexplained rectal blood loss in a patient with multiple endocrine neoplasia type 1 syndrome]. 1198 Mar 71

In multiplex endocrine neoplasia type 1, hyperparathyroidism, pancreas tumor and pituitary tumor are generally combined. The authors report two patients with this syndrome, in whom overproduction of parathormone and gastrin was detected, and parathyroid adenomas were detected by parathyroid scintigraphy. Pancreatic adenomas were discovered with somatostatin receptor scintigraphy or magnetic resonance imaging. Hyperprolactinaemia without pituitary tumor in the first case, and prolactinoma in the second case, as well as nonfunctioning adrenal adenomas in both cases were also observed. After several unsuccessful surgical interventions a long-term octreotide (Sandostatin, Novartis) treatment was started; in the first patient subcutaneous injection was given for 6 months, then the treatment was continued with the long-acting intramuscular preparation (Sandostatin LAR, Novartis). The second patient received long-acting octreotide from the beginning of medical therapy. The authors intended to obtain data about the effects of this therapy on all overproduced hormones. In the first case, a 6-months treatment with subcutaneous octreotide surprisingly resulted not only in a decrease of serum gastrin, but also in that of parathormone level. In the second case, serum gastrin was normalized, but parathormone did not change. The levels of prolactin and adrenocortical hormones were not affected. At present, the two patients are without any symptoms of their disease.
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PMID:[Octreotide therapy in multiple endocrine neoplasia type-1]. 1206 65


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