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

Somatostatin (SRIF) is a cyclic tetradecapeptide hormone initially isolated from ovine hypothalami. It inhibits endocrine and exocrine secretion, as well as tumor cell growth, by binding to specific cell surface receptors. Its potent inhibitory activity, however, is limited by its rapid enzymatic degradation and the consequent short plasma half-life. Octreotide is a short SRIF analog with increased duration of action compared to SRIF. Octreotide is approved for the treatment of acromegaly, amine precursor uptake and decarboxylation-omas, complications of pancreatic surgery and severe forms of diarrhea. Preclinical studies have focussed on the anticancer effects of octreotide and the related SRIF analogs BIM 23014 and RC-160. In vitro at nanomolar concentrations, these analogs inhibit the growth of tumor cells that express high affinity SRIF receptors. Accordingly, SRIF analogs, such as octreotide, potently inhibit the growth of SRIF receptor-positive tumors in various rodent models, and, in particular, xenotransplanted human tumors in nude mice. The range of cancers susceptible to octreotide and related SRIF analogs includes mammary, pancreatic, colorectal and lung malignancies. Moreover, an indirect antiproliferative effect of SRIF analogs is achievable in SRIF receptor-negative tumors, whose growth is driven by factors (gastrin, insulin-like growth factor-1, etc.) that are downregulated by SRIF. The use of radiolabeled somatostatin analogs represents a new diagnostic approach. [111In-DTPA]octreotide was developed for gamma camera imaging of SRIF receptor-positive malignancies, such as gasteroenteropancreatic tumors. Visualization of SRIF receptor-positive tumors in humans is emerging as an important methodology, both in tumor staging and predicting therapeutic response to octreotide. Recently, five SRIF receptor subtypes (SSTR1-5) have been cloned, all of which bind SRIF with high affinity. In contrast, SRIF receptor subtypes 1-5 have different binding profiles for short SRIF analogs. Octreotide, SSTR5, show moderate affinity for SSTR3 and fail to bind with high affinity to the other subtypes (SSTR1 and 4). Accordingly, the oncological profile of these three analogs is apparently similar. In conclusion, somatostatin analogs are a promising class of compounds for diagnosis and treatment of cancer. Current work is focussed on the identification of further SRIF receptor subtype-selective analogs with potential in oncology.
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PMID:Somatostatin analogs for diagnosis and treatment of cancer. 791 34

Five somatostatin receptor subtypes (SSTR) have been cloned and characterized in various tissues, including the gastrointestinal tract. This study examined which receptor subtypes mediate the inhibitory actions of somatostatin on gastric acid secretion and gastrin release in conscious dogs. Peptide agonists with relatively high specificity for SSTR1-5 (somatostatin-14), SSTR2 (MK-678), SSTR3 (L-362823), and SSTR5 (L-362855) were infused i.v. after nutrient-stimulated gastric acid secretion and gastrin release with intraduodenal perfusions of 8% peptone and after secretagogue-stimulated acid secretion with gastrin (75 pmol kg-1 h-1) or histamine (20 micrograms kg-1 h-1). At 1000 pmol kg-1 h-1, the SSTR2 agonist inhibited peptone-stimulated acid output to baseline (P < 0.001), whereas the SSTR3 agonist decreased acid output by 58 +/- 6% (P < 0.01): the SSTR5 agonist was without effect. The SSTR2 agonist at 100 pmol kg-1 h-1 also abolished the rise of plasma gastrin. At 50 pmol kg-1 h-1 i.v. infusions of S-14, to simulate circulating S-14 rises after nutrients, decreased peptone-stimulated acid secretion by 58 +/- 8% (P < 0.01), whereas the SSTR2 agonist inhibited gastric acid by 96 +/- 2% (P < 0.001); the SSTR3 agonist was without effect. S-14 or the agonists at 50 pmol kg-1 h-1 did not alter elevations of plasma gastrin. S-14 and the SSTR2 agonist at 50 pmol kg-1 h-1 decreased gastrin-stimulated acid secretion by 42 +/- 8% (P < 0.01) and 78 +/- 4% (P < 0.001), respectively but the SSTR3 and SSTR5 agonists were without effect. In contrast, histamine-stimulated acid secretion was not altered by 1000 pmol kg-1 h-1 S-14 or the agonists. These results in conscious dogs suggest that the inhibitory actions of circulating S-14 on nutrient and gastrin-stimulated acid secretion include activation of the SSTR-2 subtype. Regulation of gastrin release by S-14 may also occur via SSTR-2, but not through an endocrine mechanism. Factors in addition to gastrin and histamine modulate intestinal protein-stimulated acid secretion yet include peripheral S-14 inhibition via SSTR2 activation.
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PMID:Characterization of somatostatin receptor subtypes mediating inhibition of nutrient-stimulated gastric acid and gastrin in dogs. 910 Feb 87