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)

Small cell lung cancers (SCLC) synthesize and secrete bombesin/gastrin releasing peptide (BN/GRP). The autocrine growth cycle of BN/GRP in SCLC can be disrupted by BN/GRP receptor antagonists such as [Psi13,14]BN. Here several BN analogues were solid-phase synthesized and incubated with intact SCLC cells at 37 degrees C in RPMI medium in a time-course fashion (0-1080 minutes) to determine enzymatic stability. The proteolytic stability of the compounds was determined by subsequent HPLC analysis. The metabolic half-life ranged from 154 minutes to 1388 minutes for the six analogues studied. [Psi13,14]BN was found to be very stable to metabolic enzymes (T1/2 = 646 mm) and also inhibited SCLC xenograft formation in vivo in a dose-dependent manner. When [Psi13,14]BN was incubated with NCI-H345 cells, it inhibited 125I-GRP binding with an IC50 value of 30 nM. These data suggest that BN/GRP receptor antagonists such as [Psi13,14]BN may be useful for the treatment of SCLC.
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PMID:Metabolic stability and tumor inhibition of bombesin/GRP receptor antagonists. 132 46

Several bombesin-receptor antagonists are available that inhibit secretory and growth effects of bombesin, in vitro. In the present study, we examined the effects of a new class of bombesin receptor antagonists (modified GRP(15-27) peptides, with D-Pro26 and D-Ala24 moieties), on bombesin mediated effects, in vivo and in vitro. Of the 10 different compounds tested, BW-10 or 2258U89 ([de-NH2)Phe19,D-Ala24,D-Pro26 psi(CH2NH)Phe27]-GRP(19-27)) was most potent towards inhibiting bombesin binding to rat pancreatic acinar cancer cells with an ID50 of 0.5 nM. BW-10 (1 and 10 nM) significantly inhibited the gastrin response to 1 nM bombesin, from isolated rat stomach, in vitro, in a dose-dependent fashion. BW-10 (10-100 nmol/kg) was equally effective at significantly inhibiting bombesin evoked gastrin release in anesthetized rats, in vivo. [D-Phe6]Bombesin(6-13)-propylamide (BIM), a member of another class of antagonists, reported previously to be the most potent antagonist, in vitro, on the other hand, enhanced bombesin provoked gastrin release in rats. The antagonistic effects of BIM, in vivo, may thus be more selective. Intravenous infusion of BW-10 (10 nmol/kg/h) partially depressed gastrin and pancreatic polypeptide and completely abolished insulin released in response to bombesin, in conscious dogs. These results suggest that BW-10 functions as one of the most potent bombesin receptor antagonists, in vitro and in vivo, which could potentially be used as a therapeutic compound in treatment of some human diseases.
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PMID:A novel bombesin receptor antagonist (2258U89), potently inhibits bombesin evoked release of gastrointestinal hormones from rats and dogs, in vitro and in vivo. 133 39

This article describes studies with four peptides, epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), gastrin-releasing peptide/bombesin (GRP), and gastrin. The mitogenic and anti-secretory activities of EGF/TGF alpha appear to be mediated by a single class of high-affinity membrane receptors but may involve different signal transducing mechanisms. Biological activity of EGF resides in the N-terminal 42 amino acid fragment with the C-terminal undecapeptide determining binding affinity. A parenteral depot formulation of an EGF-related peptide or a small molecule agonist of the EGF receptor could have utility in treating various ulcerative disorders of the gut. Although antagonism of EGF (and thus TGF alpha) receptors and/or transducing mechanisms is frequently cited as a potential therapeutic approach to hyperproliferative diseases, blocking the action of TGF alpha, GRP, or gastrin with neutralizing antibodies or receptor antagonists did not influence the growth of a wide range of solid tumors in nude mice. These findings suggest that, unless tumor growth displays absolute dependency on one particular mitogen, antagonism of a specific growth factor is unlikely to have great effect in cancer therapy.
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PMID:Therapeutic potential of growth factors and their antagonists. 134 Oct 74

The mechanism by which partly digested protein (peptone) stimulates gastrin secretion was examined in isolated antral tissues with intact intramural innervation. In the isolated vascularly perfused rat stomach, luminal perfusion with 0.5% peptone increased gastrin (62 +/- 14 pg/min; P less than 0.01) and decreased somatostatin (74 +/- 19; P less than 0.01) secretion. The axonal blocker tetrodotoxin (TTX) abolished the gastrin and somatostatin responses indicating that the responses were neurally mediated. Atropine partly inhibited the gastrin response (50%) and converted the somatostatin response to an increase above basal level. The selective bombesin/gastrin-releasing peptide (GRP) antagonist [Leu13-psi(CH2NH)-Leu14]-bombesin partly inhibited the gastrin response (65%) and caused a further decrease in somatostatin secretion. A combination of atropine and the bombesin/GRP antagonist, like TTX, abolished the gastrin and somatostatin responses. The pattern of response to peptone in superfused antral segments was identical to that in the vascularly perfused stomach. In fundic segments that do not secrete gastrin, the somatostatin response to peptone alone and with various antagonists was identical to that in antral segments. The results indicate that peptone stimulates gastrin secretion by activating stimulatory cholinergic and bombesin/GRP neurons. Cholinergic neurons stimulate gastrin directly as well as indirectly by eliminating the inhibitory paracrine influence of somatostatin.
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PMID:Peptone stimulates gastrin secretion from the stomach by activating bombesin/GRP and cholinergic neurons. 134 6

Ninety patients suffering from peptic ulcer and 25 healthy subjects were examined for the content of gastrin, bombesin and somatostatin in blood and gastric juice. Among patients with duodenal ulcer, 2 groups were distinguished: group I included patients in whom peptic ulcer occurred before 30 years; the majority of the patients manifested blood hypergastrinemia, a decrease of bombesin concentration and normal somatostatin concentration; gastric juice was characterized by a lowering of somatostatin concentration and unchanged gastrin concentration; group II was made up of patients who developed peptic ulcer after 30: in the majority of the patients, gastrin concentration was reduced under basal conditions, after loading it was unchanged; in part of the patients, blood somatostatin concentration was elevated, in 16 in exacerbation and in 19 in remission; in the remainder, it was unchanged. The concentration of bombesin in blood remained unchanged. In gastric juice, gastrin concentration was increased only after histamine administration, somatostatin concentration was unchanged whatever the disease stage. In patients with gastric ulcer, gastrin concentration in blood was elevated only under basal conditions, being unchanged in gastric juice irrespective of the disease stage. Meanwhile, the concentration of bombesin was lowered both under basal conditions and after insulin administration, the concentration of somatostatin was decreased both in blood and gastric juice whatever the disease stage.
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PMID:[The content of gastrin, bombesin and somatostatin in the blood and gastric juice of patients with duodenal and gastric peptic ulcer]. 135 94

Physiological stimuli from inside and outside the stomach coverage on gastric effector neurons that are the primary regulators of acid secretion. The effector neurons comprise cholinergic neurons and two types of non-cholinergic neurons: bombesin/GRP and VIP neurons. The neurons act directly on target cells or indirectly by regulating release of the hormone, gastrin, the stimulatory paracrine amine, histamine, and the inhibitory paracrine peptide, somatostatin. In the antrum, cholinergic and bombesin/GRP neurons activated by intraluminal proteins stimulate gastrin secretion directly and, in the case of cholinergic neurons, indirectly by eliminating the inhibitory influence of somatostatin (disinhibition). In turn, gastrin acts on adjacent somatostatin cells to restore the secretion of somatostatin. The dual paracrine circuit activated by antral neurons determines the magnitude of gastrin secretion. Low-level distention of the antrum activates, preferentially, VIP neurons that stimulate somatostatin secretion and thus inhibit gastrin secretion. Higher levels of distention activate predominantly cholinergic neurons that suppress antral somatostatin secretion and thus stimulate gastrin secretion. In the fundus, cholinergic neurons activated by distention or proteins stimulate acid secretion directly and indirectly by eliminating the inhibitory influence of somatostatin. The same stimuli activate bombesin/GRP and VIP neurons that stimulate somatostatin secretion and thus attenuate acid secretion. In addition, gastrin and fundic somatostatin influence acid secretion directly and indirectly by regulating histamine release. Acid in the lumen stimulates somatostatin secretion, which attenuates acid secretion in the fundus and gastrin secretion in the antrum.
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PMID:Neural, hormonal, and paracrine regulation of gastrin and acid secretion. 136 24

With the aim of disclosing a possibility for gastrin and bombesin to participate in the postprandial regulation of the renal hemodynamic response, 10 healthy males were studied before and after a meat meal (2 g/kg BW of proteins as cooked red meat). We evaluated the time course changes of glomerular filtration rate (GFR) renal plasma flow (RPF), and the plasma concentrations of gastrin, bombesin, glucagon, and total amino acids. After the meat meal a significant increase in GFR and RPF was seen, within 30 min, along with an increase in plasma gastrin and glucagon. Bombesin and amino acid concentrations increased at a later time. The data suggest but cannot demonstrate a causal role for gastrin and glucagon in the genesis of the hyperfiltration response to acute protein administration.
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PMID:Brain-gut peptides and the renal hemodynamic response to an oral protein load: a study of gastrin, bombesin, and glucagon in man. 137 48

Recently synthesized highly specific and potent bombesin receptor antagonists permit study of the role of endogenous bombesin-like peptides in the physiological regulation of pancreatic secretion. We now tested the action of three novel pseudononapeptide bombesin/gastrin releasing peptide (GRP) antagonists (RC-3095, RC-3100 and RC-3120) on amylase release in vitro from isolated rat pancreatic acini and on protein secretion in vivo in chronic pancreatic fistula rats. In isolated pancreatic acini, all three bombesin receptor antagonists inhibited the amylase secretion induced by bombesin by shifting to the right the amylase response to bombesin without altering the maximal response. These antagonists alos reduced concentration dependently the near-maximal amylase response to bombesin, the concentration required for 50% reduction (IC50) being about 10(-7) M for RC-3095 and RC-3100 and 10(-6) M for RC-3120. None of the bombesin/GRP antagonists used affected the amylase response to CCK, pentagastrin or urecholine. In conscious rats with a chronic pancreatic fistula, all three bombesin antagonists shifted to the right the pancreatic protein response to graded doses of bombesin without changing the maximal response. These antagonists inhibited the protein response to constant background stimulation with bombesin in a dose-dependent manner, the ID50 being about 20 nmol/kg per h for RC-3095 and RC-3100 and about 160 nmol/kg per h for RC-3120. None of the antagonists significantly affected basal pancreatic secretion or secretion induced by sham-feeding, ordinary feeding or the diversion of pancreatic juice from the duodenum. These results indicate that exogenous bombesin is a potent direct stimulant of pancreatic enzyme secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Actions of novel bombesin receptor antagonists on pancreatic secretion in rats. 138 17

The effect of the specific cholecystokinin-receptor antagonist loxiglumide on basal and bombesin-, and gastrin 17-I-stimulated gastric acid secretion and serum gastrin levels was studied in 12 healthy subjects. Loxiglumide (10 mg.kg-1.h-1) significantly augmented basal gastric acid output from 1.8 +/- 0.3 to 3.9 +/- 0.6 mmol H+/h (P less than 0.005) but did not significantly influence integrated basal serum gastrin concentrations (2 +/- 21 vs. 32 +/- 21 pmol L-1.h-1). Both gastric acid secretion and integrated serum gastrin concentrations stimulated by bombesin infusion (92.6 pmol.kg-1.h-1) were significantly augmented by loxiglumide [from 4.0 +/- 0.3 to 10.0 +/- 1.3 mmol H+/h (P less than 0.005) and from 1251 +/- 93 to 2558 +/- 206 pmol.L-1.h-1 (P less than 0.005), respectively]. Gastric acid output and serum gastrin concentrations during infusion of 5 pmol.kg-1.h-1 of synthetic human gastrin 17-I (9.6 +/- 2.9 mmol H+/h and 1045 +/- 177 pmol.L-1.h-1) and during infusion of 15 pmol.kg-1.h-1 of gastrin 17-I (14.5 +/- 3.1 mmol H+/h and 2412 +/- 312 pmol.L-1.h-1) were not significantly influenced by loxiglumide (10.3 +/- 2.3 mmol H+/h and 1291 +/- 257 pmol.L-1.h-1 for the 5-pmol.kg-1.h-1 gastrin 17-I infusion dose with loxiglumide and 13.6 +/- 3.4 mmol H+/h and 2611 +/- 305 pmol.L-1.h-1 for the 15-pmol.kg-1.h-1 gastrin 17-I infusion dose with loxiglumide). These data indicate that endogenous cholecystokinin inhibits gastric acid secretion under basal conditions and gastrin release and gastric acid secretion during infusion of bombesin in humans and suggest that the augmented effect of loxiglumide on bombesin-stimulated gastric acid secretion may be explained largely by enhanced gastrin release.
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PMID:Effect of loxiglumide on basal and gastrin- and bombesin-stimulated gastric acid and serum gastrin levels. 139 78

1. This study was designed to determine the involvement of cholecystokinin (CCK) in the gastric secretory responses to exogenous and endogenous secretagogues in conscious dogs with chronic gastric fistulae (GF), pancreatic fistulae (PF) and Heidenhain pouches (HP). 2. A meal of meat or intragastric application of peptone (300 mosM) increased secretion of HCl from the HP and pancreatic secretion of protein and plasma levels of gastrin, CCK and somatostatin. 3. The CCK receptor antagonist L-364,718 caused a further increase in the postprandial HCl secretion from the HP and in the plasma levels of gastrin and CCK but pancreatic output of protein and plasma concentration of somatostatin were significantly reduced. 4. Addition to intragastric peptone of 10% oleate or its acidification to pH 3.0 profoundly inhibited the HP secretion and gastrin release but significantly increased pancreatic secretion of protein and plasma levels of CCK and somatostatin. Administration of L-364,718 reversed the fall in the HP secretion and plasma gastrin while significantly attenuating pancreatic protein secretion and plasma somatostatin levels. 5. Intragastric administration of hyperosmolar (1200 mosM) peptone also inhibited HCl secretion from the HP but this was not affected by L-364,718. 6. Exogenous CCK and bombesin (but not gastrin) caused a small increase in HCl secretion from the HP and marked stimulation of pancreatic protein secretion accompanied by a significant rise in plasma levels of gastrin, CCK and somatostatin. Administration of L-364,718 resulted in a further increase in the HCl response of HP to bombesin and in plasma levels of gastrin and CCK but caused a reduction in plasma levels of somatostatin. 7. We conclude that CCK released by a meal of meat, intragastric peptone, oleate or acidified peptone and intravenous bombesin exerts tonic inhibitory influences on gastric acid secretion and that this effect is mediated, at least in part, by somatostatin.
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PMID:Role of cholecystokinin in the inhibition of gastric acid secretion in dogs. 140 19


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