Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Gastrin-secreting tumors have been identified in ectopic locations including the ovary; the mechanisms regulating gastrin gene expression, its distribution, and signaling pathways in these ectopic tissues are not known. The purpose of our present study was to determine: (1) whether the gastrin gene and peptide could be detected in ovarian cancer cell lines, (2) if functional gastrin releasing peptide receptors (GRP-R) are present, and (3) whether gastrin gene expression is altered by GRP. Five ovarian cancer cell lines (SW626, OVCA 420, OVCA 429, OVCA 432, and OVCA 433) were analyzed. We identified gastrin gene and peptide expression in the SW626 cell line but not in the OVCA lines. SW626 cells express a functional GRP-R that is correctly coupled to the Ca2+ signaling pathway. Treatment of SW626 cells with bombesin, the amphibian equivalent of GRP, inhibited expression of the gastrin gene in a time- and dose-dependent fashion. The SW626 ovarian cancer cell line will provide a useful model to further define regulation and expression of both the gastrin gene and peptide in ectopic (nongastrointestinal) tissues.
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PMID:Novel expression and regulation of gastrin gene in human ovarian cancer cell line, SW626. 969 Mar 80

Rat fetal pancreas development and maturation were investigated in vitro and in vivo, and the informations available on their controls do not agree. Our main objective was to reinvestigate fetal pancreas growth in vivo through treatments of the dams during their entire pregnancy. Pregnant rats were thus implanted subcutaneously with Alzet minipumps and received cerulein (0.25 microg kg-1 h-1), gastrin-releasing peptide (GRP; 0.18 microg kg-1 h-1), GRP antagonist (12 microg kg-1 h-1), pentagastrin (2.38 microg kg-1 h-1), L-365,260, a cholecystokinin B (CCKB) receptor antagonist (120 microg kg-1 h-1), and hydrocortisone (417 or 833 microg kg-1 h-1). After sacrifice at the end of pregnancy, the pancreata of the dams and those of their fetuses were excised for weight, protein, RNA, DNA, and digestive enzyme determinations. In the fetus, pancreas growth defined as hyperplasia was observed only in response to hydrocortisone, while aplasia occurred in response to cerulein. Gastrin and the GRP antagonist were the most effective hypertrophic agents, and the effect of the CCKB receptor antagonist was atrophic. In conclusion, hydrocortisone caused proliferation of the fetal rat pancreas, whereas gastrin induced its differentiation and maturation probably through CCKB receptor occupation.
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PMID:Hormonal control of rat fetal pancreas development. 1009 47

BACKGROUND: gastric abnormalities are a common feature in patients with primary antibody deficiency. The most important problem is the high incidence of stomach cancer found in these patients. Chronic atrophic gastritis with pernicious anemia is also a common finding that predisposes to gastric adenocarcinoma. The aim of the present study was to identify factors predictive of high risk for developing gastric cancer in patients with primary antibody deficiency. PATIENTS AND METHODS: we studied gastric hormones (gastrin, somatostatin and gastrin-releasing peptide, GRP) in 47 patients (23 children and 24 adults) with primary antibody deficiency. In accordance with the World Health Organization (WHO) classification, patients were diagnosed as having X-linked agammaglobulinemia (Bruton disease) in 13 cases, common variable immunodeficiency in 28, and hypogammaglobulinemia with hyperIgM in 6. Gastric biopsy was performed in 22 patients (16 children and 6 adults). Hormone determinations were carried out by radioimmunoassay. RESULTS: baseline serum gastrin levels were normal or increased compared with controls, but the response to stimulation with a hyperproteic diet was delayed in 18 patients and lower than in controls in 7. In 4 adult patients, all with pernicious anemia, gastric biopsy revealed chronic atrophic gastritis involving the stomach corpus and antrum (type B gastritis). The absence of a normal response of gastrin secretion to stimulation with a hyperproteic diet may be explained by this finding. Serum somatostatin and GRP levels were higher than in controls. No correlations were found between these findings and patient age, type of immunodeficiency or duration of clinical manifestations.
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PMID:Study of gastrointestinal polypeptides controlling gastric acid secretion in patients with primary antibody deficiency. 1021 2

Pulmonary neuroendocrine cells function as hypoxia-sensitive chemoreceptors, and they release peptides and biogenic amines that are important mediators of pulmonary neonatal adaptation. Some of these products additionally act as autocrine growth factors. Increased numbers of pulmonary neuroendocrine cells have been observed in several smoking-associated pediatric lung disorders such as bronchopulmonary dysplasia, cystic fibrosis, sudden infant death syndrome, and asthma. Disturbed pulmonary neuroendocrine function has been implicated in the etiology of this disease complex. One of the most common smoking-associated lung cancer types, small cell lung carcinoma, expresses phenotypic and functional features of pulmonary neuroendocrine cells. We, as well as others, have shown that the release of the autocrine growth factors 5-hydroxytryptamine (5-HT, serotonin) and mammalian bombesin/gastrin releasing peptide (MB/GRP) by cell lines derived from human small cell lung carcinoma or fetal hamster pulmonary neuroendocrine cells are regulated by a neuronal nicotinic acetylcholine receptor comprised of alpha(7) subunits. In radio-receptor assays, nicotine and the nicotine-derived carcinogenic nitrosamines NNNN. Binding of nicotine or NNK to the alpha(7) receptor resulted in calcium influx and overexpression and activation of the serine-threonine protein kinase Raf-1. In turn, this event lead to overexpression and activation of the mitogen activated (MAP) kinases extracellular signal regulated kinase 1 (ERK1) and extracellular signal regulated kinase 2 (ERK2) and stimulation of DNA synthesis accompanied by an increase in cell numbers in fetal pulmonary neuroendocrine cells and small cell carcinoma cells. Exposure of fetal pulmonary neuroendocrine cells for 6 days to NNK caused a prominant up-regulation of Raf-1. Our findings suggest that chronic exposure to nicotine and NNK in pregnant women who smoke may up-regulate the alpha(7) nicotinic receptor as well as components of its associated mitogenic signal transduction pathway, thus increasing the susceptibilities of the infants for the development of pediatric lung disorders. Similarly, up-regulation of one or several components of this nicotinic receptor pathway in smokers may be an important factor for the development of small cell lung carcinoma.
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PMID:Interaction of tobacco-specific toxicants with the neuronal alpha(7) nicotinic acetylcholine receptor and its associated mitogenic signal transduction pathway: potential role in lung carcinogenesis and pediatric lung disorders. 1077 Oct 23

The effects of some oncogenes, growth factors and neuropeptides are mediated by tyrosine phosphorylation of focal adhesion kinase (p125(FAK)) and paxillin cytoskeletal proteins. In this study the ability of bombesin/gastrin releasing peptide (BB/GRP) to stimulate tyrosine phosphorylation of p125(FAK) and paxillin in non-small cell lung cancer (NSCLC) H1299 cells was investigated. BB, 100 nM caused increased p125(FAK) and paxillin tyrosine phosphorylation maximally after 1 min. The effect of BB on p125(FAK) and paxillin tyrosine phosphorylation was concentration-dependent, being half maximal at 4-8 nM. Also, 100 nM GRP, GRP(14-27) but not GRP(1-16) increased p125(FAK) and paxillin tyrosine phosphorylation indicating that the C-terminal of GRP is essential. BW2258U89, a GRP receptor antagonist, caused a dose-dependent inhibition of BB-stimulated p125(FAK) and paxillin tyrosine phosphorylation with an IC50 value of 3 microM. Cytochalasin D (0.3 microM), which inhibits actin polymerization, reduced the ability of BB to stimulate tyrosine phosphorylation of p125(FAK) and paxillin. Genistein (50 microM) and H-7 (50 microM), which are kinase inhibitors, reduced the tyrosine phosphorylation of p125(FAK) and paxillin stimulated by BB. Also, treatment of NCI-H1299 cells with FAK antisense resulted in decreased FAK tyrosine kinase activity and proliferation. These results suggest that p125(FAK) is an important enzyme for NSCLC proliferation.
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PMID:Bombesin and gastrin releasing peptide increase tyrosine phosphorylation of focal adhesion kinase and paxillin in non-small cell lung cancer cells. 1112 66

RT-PCR-based amplification of transcripts expressed in cancer but not in normal non-neoplastic cells is increasingly used for the sensitive detection of rare disseminated or exfoliated cancer cells to improve cancer staging and early detection protocols. However, these assays are frequently hampered by false-positive test results due to low-level transcription of the marker genes in normal cells. To overcome these limitations, target transcripts have to be identified that are tightly suppressed in normal non-neoplastic tissues, whereas they should be actively transcribed in the respective cancer cells. Here, we tested RT-PCR assays for 7 neuroendocrine marker transcripts including NCAM, PGP 9.5, gastrin, gastrin receptor, synaptophysin, preprogastrin-releasing peptide (preproGRP) and GRP-receptor to detect rare exfoliated tumor cells in peripheral venous blood and sputum samples from patients with lung cancer. Among these preproGRP RT-PCR was the only assay with which illegitimate transcription in blood or sputum samples from healthy donors or patients with unrelated diseases did not interfere. However, it reproducibly detected up to 10 small-cell lung cancer cells diluted in either 10 ml blood or 5 ml sputum samples. Single blood and sputum samples were collected directly before diagnostic bronchoscopy from 175 patients suspected to have lung cancer. Twenty-six of these had small-cell lung cancer (SCLC). Thereof, 13 patients (50%) tested positive in the blood sample and 5 of 23 patients (22%) tested positive in the sputum sample. Moreover, among 92 patients with non-small-cell lung cancer (NSCLC) 25 patients (27%) had disseminated cancer cells in peripheral blood. Amplification of preproGRP transcripts from clinical samples is a sensitive and specific assay to detect disseminated or exfoliated lung cancer cells either in peripheral blood or sputum samples.
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PMID:Sensitive detection of rare cancer cells in sputum and peripheral blood samples of patients with lung cancer by preproGRP-specific RT-PCR. 1127 99

A new radiolabeled bombesin analogue, [99mTc(I)-PADA-AVA]bombesin (7-14), was synthesized and in vitro and in vivo characterized. High affinity and rapid internalization were obtained in binding assays. A specific binding towards gastrin releasing peptide receptors-positive tissues, pancreas and tumor, was observed in CD-1 nu/nu mice bearing PC-3 prostate adenocarcinoma xenografts. We therefore conclude that [99mTc(I)-PADA-AVA]bombesin (7-14) might have promising characteristics for applications in nuclear medicine, namely for diagnosis of GRP receptor overexpressing tumors.
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PMID:In vitro and in vivo evaluation of a 99mTc(I)-labeled bombesin analogue for imaging of gastrin releasing peptide receptor-positive tumors. 1208 25

Gastrin-releasing-peptide(1-27) (GRP) has been implicated in the regulation of satiety and appetite in numerous paradigms. However, the specific site and mode of action of this gut-brain peptide has not been elucidated. The following experiment examined the effects of GRP on taste responses to sucrose in the behaving rat. A brief-exposure, multi-bottle gustometer was used to provide rats with momentary access to six different concentrations of sucrose in a single test session. This procedure has been used previously, resulting in monotonically increased licking behavior as concentrations of sucrose increase. Differing injection procedures were employed such that rats were tested immediately after i.p. injection or 5 min after i.p. injection of 5 nmol/kg body wt of GRP. Results indicate that GRP does reduce the oral reinforcing properties of sucrose, but the effect is transient, diminishing significantly within 5 min after injection.
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PMID:Effects of gastrin-releasing peptide 1-27 on taste responses in the rat. 1250 19

Nuclear medicine is engaged with the detection of pathological processes with the help of radionuclides. An interesting approach is to target antigens, symporters, or receptors with diagnostic and therapeutic radionuclides. Different peptide receptors like somatostatin, bombesin/GRP or VIP are (over)expressed on cancer cells, and are therefore an ideal target for the diagnosis and therapy in nuclear medicine with radiolabeled peptides. The somatostatin analogue OctreoScan [octreotide coupled with diethylene-triamine-pentaacetate (DTPA)] can be labeled with In-111 and is widely used in nuclear oncology for the staging of different tumors (e.g., carcinoids). Other peptides like neurotensin, bombesin/GRP, and VIP are under (pre)clinical investigations. The staging of metastatic medullary thyroid cancer (MTC) with the conventional radiological procedures is sometimes difficult. The high sensitivity of the pentagastrin stimulation test in detecting primary or metastatic MTC indicates the presence of tumor, but its localization is often not possible. This reaction of the tumor cells to the pentagastrin stimulation test suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in over 90% of MTCs, but in a high percentage of small cell lung cancers, stromal ovarian, and potentially a variety of other tumors, including gastrointestinal adenocarcinomas, neuroendocrine tumors, and malignant glioma. The aim of our recent work was to develop and systematically optimize suitable radioligands for targeting CCK-B receptors in vivo and to investigate their role in the staging and therapy of MTC and other CCK-B receptor expressing malignancies. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the C-terminal CCK receptor binding tetrapeptide sequence -Trp-Met-Asp-PheNH(2) or derivatives thereof, were investigated. They were members of the gastrin- or cholecystokinin families, or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family, due to their superior selectivity and affinity for the CCK-B receptor subtype. Radiometal-labeled derivatives of minigastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and healthy human volunteers. Preclinical therapy experiments in MTC-bearing animals showed significant antitumor efficacy. In a subsequent clinical study, 75 MTC patients with metastatic MTC were investigated; 43 suffered of known, 32 of occult disease. CCK-B receptor scintigraphy was performed with (111)In-DTPA-D-Glu(1)-minigastrin. The normal organ uptake was essentially confined to the stomach (and to a lower extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of CCK-B receptor specific binding, and to the kidneys as excretory organs. All tumor manifestations known from conventional imaging were visualized as early as 1 h p.i., with increasing tumor-to-background ratios over time; at least one lesion was detected in 29/32 patients with occult disease (patient-based sensitivity 91%). Among them were local recurrences, lymph node, pulmonary, hepatic, splenic, and bone (marrow) metastases. Eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a (90)Y-labeled minigastrin derivative at 4-6-weekly intervals (30-50 mCi/m(2) per injection for a maximum of four injections). Hematologic and renal were identified as the dose-limiting toxicities at the 40 and 50 mCi/m(2) levels. Two patients experienced partial remissions, 4 stabilization of their previously rapidly progressing disease. These data suggest that CCK-B receptor ligands may be a useful new class of receptor binding peptides for diagnosis and therapy of a variety of (CCK-B receptor expressing) tumor types. They allow for a sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved.
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PMID:Cholecystokinin-B (CCK-B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK-B receptor expressing malignancies. 1265 27

After the discovery of several specific peptide receptors in a variety of cancer types more than 10 years ago, radiolabeled peptide analogs with adequate stability, receptor binding properties, and biokinetic behavior were introduced for imaging of neuroendocrine tumors, several adenocarcinomas, lymphoma, and melanoma. Although initially 123I or 111In were used for labeling, recent efforts have also concentrated on 99mTc or PET-radionuclides (18F,68Ga), as they result in better image resolution with lower radiation dose to patients. Scintigraphy with labeled somatostatin analogs (99mTc, 111In,18F,68Ga), with 123I-labeled vasoactive intestinal peptide, and recently 99mTc-bombesin/GRP-or-111In gastrin analogs, have shown a mean sensitivity of greater than 85% to localize deposits of tumors, with appropriate receptor expression frequently scarcely visible with other imaging procedures. Moreover, these observations introduced peptide-targeted metabolic radiotherapy for metastatic cancers. This development has produced a considerable amount of preclinical studies to broaden the impact of labeled peptide ligands on the management of cancer.
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PMID:Peptide targeted imaging of cancer. 1462 17


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