gastrins has been researched along with Neoplasms* in 68 studies
26 review(s) available for gastrins and Neoplasms
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The Influence of Different Spacers on Biological Profile of Peptide Radiopharmaceuticals for Diagnosis and Therapy of Human Cancers.
Cancer is the leading cause of death worldwide. Early detection can reduce the disadvantageous effects of diseases and the mortality in cancer. Nuclear medicine is a powerful tool that has the ability to diagnose malignancy without harming normal tissues. In recent years, radiolabeled peptides have been investigated as potent agents for cancer detection. Therefore, it is necessary to modify radiopeptides in order to achieve more effective agents.. This review describes modifications in the structure of radioconjugates with spacers who have improved the specificity and sensitivity of the peptides that are used in oncologic diagnosis and therapy.. To improve the biological activity, researchers have conjugated these peptide analogs to different spacers and bifunctional chelators. Many spacers of different kinds, such as hydrocarbon chain, amino acid sequence, and poly (ethyleneglycol) were introduced in order to modify the pharmacokinetic properties of these biomolecules.. Different spacers have been applied to develop radiolabeled peptides as potential tracers in nuclear medicine. Spacers with different charge and hydrophilicity affect the characteristics of peptide conjugate. For example, the complex with uncharged and hydrophobic spacers leads to increased liver uptake, while the composition with positively charged spacers results in high kidney retention. Therefore, the pharmacokinetics of radio complexes correlates to the structure and total charge of the conjugates.. Radio imaging technology has been successfully applied to detect a tumor in the earliest stage. For this purpose, the assessment of useful agents to diagnose the lesion is necessary. Developing peptide radiopharmaceuticals using spacers can improve in vitro and in vivo behavior of radiotracers leading to better noninvasive detection and monitoring of tumor growth. Topics: Animals; Bombesin; Gastrins; Humans; Melanocyte-Stimulating Hormones; Neoplasms; Neurotensin; Oligopeptides; Peptides; Radiopharmaceuticals; Somatostatin | 2020 |
Radiolabeled gastrin/CCK analogs in tumor diagnosis: towards higher stability and improved tumor targeting.
Cholecystokinin subtype 2 receptors (CCK2R) are overexpressed in several human cancers, including medullary thyroid carcinoma. Gastrin and cholecystokinin (CCK) peptides that bind with high affinity and specificity to CCK2R can be used as carriers of radioactivity to CCK2R-expressing tumor sites. Several gastrin and CCK related peptides have been proposed for diagnostic imaging and radionuclide therapy of primary and metastatic CCK2R-positive human tumors. Their clinical application has been restricted to a great extent by their fast in vivo degradation that eventually compromises tumor uptake. This problem has been addressed by structural modifications of gastrin and CCK motifs, which, however, often lead to suboptimal pharmacokinetic profiles. A major enzyme implicated in the catabolism of gastrin and CCK based peptides is neutral endopeptidase (NEP), which is widely distributed in the body. Coinjection of the NEP inhibitor phosphoramidon (PA) with radiolabeled gastrin and other peptide analogs has been recently proposed as a new promising strategy to increase bioavailability and tumor-localization of radiopeptides in tumor sites. Specifically, co-administration of PA with the truncated gastrin analog [(111)In-DOTA]MG11 ([((111)In-DOTA)DGlu(10)]gastrin(10-17)) impressively enhanced the levels of intact radiopeptide in mouse circulation and has led to an 8-fold increase of CCK2R-positive tumor uptake in SCID mice. This increased tumor uptake, visualized also by SPECT/CT imaging, is expected to eventually translate into higher diagnostic sensitivity and improved therapeutic efficacy of radiolabeled gastrin analogs in CCK2R-expressing cancer patients. Topics: Animals; Carcinoma, Neuroendocrine; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Glycopeptides; Humans; Kidney; Kidney Neoplasms; Ligands; Mice; Mice, SCID; Models, Chemical; Neoplasm Transplantation; Neoplasms; Neprilysin; Peptides; Radiopharmaceuticals; Receptor, Cholecystokinin B; Thyroid Neoplasms; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed | 2015 |
Radiolabeled CCK/gastrin peptides for imaging and therapy of CCK2 receptor-expressing tumors.
Cholecystokinin (CCK) receptors are overexpressed in numerous human cancers, like medullary thyroid carcinomas, small cell lung cancers and stromal ovarian cancers. The specific receptor-binding property of the endogenous ligands for these receptors can be exploited by labeling peptides with a radionuclide and using these as carriers to guide the radioactivity to the tissues that express the receptors. In this way, tumors can be visualized using positron emission tomography and single photon emission computed tomography imaging. A variety of radiolabeled CCK/gastrin-related peptides has been synthesized and characterized for imaging. All peptides have the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-Phe-NH(2) in common or derivatives thereof. This review focuses on the development and application of radiolabeled CCK/gastrin peptides for radionuclide imaging and radionuclide therapy of tumors expressing CCK receptors. We discuss both preclinical studies as well as clinical studies with CCK and gastrin peptides. Topics: Animals; Cholecystokinin; Gastrins; Humans; Isotope Labeling; Neoplasms; Radioisotopes; Radionuclide Imaging; Receptor, Cholecystokinin B | 2011 |
Cell-specific precursor processing.
The singular gene for a peptide hormone is expressed not only in a specific endocrine cell type but also in other endocrine cells as well as in entirely different cells such as neurons, adipocytes, myocytes, immune cells, and cells of the sex-glands. The cellular expression pattern for each gene varies with development, time and species. Endocrine regulation is, however, based on the release of a given hormone from an endocrine cell to the general circulation from whose cappilaries the hormone reaches the specific target cell elsewhere in the body. The widespread expression of hormone genes in different cells and tissues therefore requires control of biogenesis and secretion in order to avoid interference with the function of a specific hormonal peptide from a particular endocrine cell. Several mechanisms are involved in such control, one of them being cell-specific processing of prohormones. The following pages present four examples of such cell-specific processing and the implications of the phenomenon for the use of peptide hormones as markers of diseases. Notably, sick cells - not least the neoplastic cells - often process prohormones in a manner different from that of the normal endocrine cells. Topics: Animals; Cholecystokinin; Endocrine System; Gastrins; Gene Expression Regulation; Hormones; Humans; Models, Biological; Neoplasms; Neurotensin; Peptides; Proglucagon; Protein Precursors; Signal Transduction | 2010 |
Rho GTPases and p21-activated kinase in the regulation of proliferation and apoptosis by gastrins.
Gastrins, including amidated gastrin (Gamide) and glycine-extended gastrin (Ggly), accelerate the growth of gastrointestinal cancer cells by stimulation of proliferation and inhibition of apoptosis. Gamide and Ggly activate different G proteins of the Rho family of small GTPases. For example, Gamide signals Rac/Cdc42 to activate p21-activated kinase 1 while Ggly signals Rho to activate Rho-activated kinase. p21-activated kinase 1 and Rho-activated kinase induce changes in phosphorylation or expression, respectively, of proteins of the Bcl-2 family, which then affect the caspase cascade with consequent inhibition of apoptosis. In addition, interaction of p21-activated kinase 1 with beta-catenin results in phosphorylation of beta-catenin, which enhances its translocation in to the nucleus, activation of TCF4-dependent transcription, and proliferation and migration. The central role of the beta-catenin pathway in carcinogenesis suggests that specific inhibitors of p21-activated kinase 1 may in the future provide novel therapies for gastrointestinal malignancies. Topics: Animals; Apoptosis; Cell Proliferation; Gastrins; Humans; Neoplasms; p21-Activated Kinases; rho GTP-Binding Proteins | 2008 |
Gastrin and cancer: a review.
In 1905, a Cambridge physiologist, John Sydney Edkins, initially identified a hormone responsible of gastric acid secretion, which he called gastric secretin, or gastrin. While gastrin's role in acid secretion is now well defined, more recent studies have implicated the various isoforms of gastrin in cancer. Important advances in the last decade have included the recognition of biological activity for processing intermediates such as progastrin and the glycine-extended gastrin. Here, we give an overview of the roles of these peptides in cancer, highlighted by molecular, cellular and integrated studies on animal models for progastrin-derived peptides and their receptors. Topics: Animals; Gastrins; Hormones; Humans; Neoplasms; Protein Isoforms; Protein Precursors; Signal Transduction | 2006 |
Gastrin, CCK, signaling, and cancer.
Gastrin, produced by G cells in the gastric antrum, has been identified as the circulating hormone responsible for stimulation of acid secretion from the parietal cell. Gastrin also acts as a potent cell-growth factor that has been implicated in a variety of normal and abnormal biological processes including maintenance of the gastric mucosa, proliferation of enterochromaffin-like cells, and neoplastic transformation. Here, we review the models used to study the effects of gastrin on cell proliferation in vivo and in vitro with respect to mechanisms by which this hormone might influence normal and cancerous cell growth. Specifically, human and animal models of hypergastrinemia and hypogastrinemia have been described in vivo, and several cells that express cholecystokinin (CCK)B/gastrin receptors have been used for analysis of intracellular signaling pathways initiated by biologically active amidated gastrins. The binding of gastrin or CCK to their common cognate receptor triggers the activation of multiple signal transduction pathways that relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades, including mitogen-activated protein kinase, is an important early response to these signaling peptides. Gastrin and CCK also induce rapid Rho-dependent actin remodeling and coordinate tyrosine phosphorylation of cellular proteins including the non-receptor tyrosine kinases p125fak and Src and the adaptor proteins p130cas and paxillin. This article reviews recent advances in defining the role of gastrin and CCK in the control of cell proliferation in normal and cancer cells and in dissecting the signal transduction pathways that mediate the proliferative responses induced by these hormonal GI peptides in a variety of normal and cancer cell model systems. Topics: Animals; Cholecystokinin; Gastrins; Humans; Neoplasms; Signal Transduction | 2001 |
[Safety profile of pariet clinical use (a literature review)].
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Aged; Benzimidazoles; Drug Interactions; Enzyme Inhibitors; Gastric Mucosa; Gastrins; Humans; Neoplasms; Omeprazole; Proton-Translocating ATPases; Rabeprazole | 2001 |
The cholecystokinin--gastrin family of peptides and their receptors.
Topics: Amino Acid Sequence; Cholecystokinin; Gastrins; Gastrointestinal Diseases; Mental Disorders; Molecular Sequence Data; Neoplasms; Receptors, Cholecystokinin; Structure-Activity Relationship | 1999 |
Gastrocystoplasty: is there a consensus?
The problems encountered with ileal and colocystoplasty have led to the use of the stomach for bladder augmentation, termed gastrocystoplasty. The advantages of gastrocystoplasty over intestinal segment augmentation include reduced chloride reabsorption, decreased mucus production, decreased urinary infection in the presence of acid urine, extremely low incidence of stones, and avoidance of complications from short bowel syndrome. The gastric patch provides comparable improvements in bladder volume, pressure, and continence. The thick muscular wall of the stomach facilitates ureteric reimplantation as compared with the small intestine, but the rate of stenosis and reflux may not be superior. The disadvantages of the gastric patch include complications of severe systemic alkalosis, which is usually manifest in dehydrated, renal compromised patients, and the hematuria-dysuria syndrome (HDS), which is more prevalent in patients with renal insufficiency, normal pelvic sensation, and urinary incontinence. The postoperative complication rate of gastrocystoplasty is comparable with that of other augmentation procedures and similarly warrants proper selection and close follow-up of patients. In this report we review the literature and present the results, including a discussion of the technique and the pathophysiology of its complications. Topics: Bacteriuria; Child; Gastrins; Hematuria; Humans; Neoplasms; Postoperative Complications; Stomach; Urinary Bladder; Urinary Diversion; Urinary Reservoirs, Continent; Urodynamics | 1998 |
The tumor biology of gastrin and cholecystokinin.
Topics: Amino Acid Sequence; Animals; Cholecystokinin; Gastrins; Humans; Molecular Sequence Data; Neoplasms; Protein Processing, Post-Translational; Receptors, Cholecystokinin | 1994 |
Gastrin and cancer.
Topics: Amino Acid Sequence; Animals; Gastrins; Growth Substances; Humans; Molecular Sequence Data; Neoplasms | 1992 |
Neuropeptide growth factors and cancer.
Topics: Animals; Gastrin-Releasing Peptide; Gastrins; Growth Substances; Humans; Kinins; Neoplasms; Neuropeptides; Neurotensin; Peptides; Vasoactive Intestinal Peptide; Vasopressins | 1991 |
Posttranslational attenuation of peptide gene expression.
Studies of the cell-specific processing of neuroendocrine peptides have shown that neuroendocrine cells occasionally fail to mature the biosynthetic precursors to bioactive peptides, or that they do so to a negligible extent only. Instead, inactive precursors and processing intermediates accumulate in the cells. Thus, the expression of genes encoding hormonal peptides is in certain cells and under certain conditions attenuated at the postranslational level. The exact molecular mechanisms of posttranslational attenuation are still largely unknown. The review emphasizes that posttranslational attenuation may play a significant role during normal cell differentiation and in the carcinogenic transformation of cells. The existence of postal attenuation may play a significant role during normal cell differentiation and in the carcinogenic transformation of cells. The existence of post-translational attenuation has significant biological and clinical implications. Topics: Age Factors; Amino Acid Sequence; Animals; Cholecystokinin; Gastrins; Gene Expression Regulation; Molecular Sequence Data; Neoplasms; Neuropeptides; Protein Processing, Post-Translational | 1990 |
Growth factors in cancer and their relationship to oncogenes.
Topics: Bombesin; Cell Line; Cell Transformation, Neoplastic; Epidermal Growth Factor; ErbB Receptors; Gastrins; Growth Substances; Humans; Neoplasms; Nerve Growth Factors; Oncogenes; Platelet-Derived Growth Factor; Receptors, Cell Surface; Somatomedins; Transferrin | 1986 |
Fruit flies, yeasts, and onc genes: developmental biology and cancer research come together.
Topics: Animals; Antigens, Polyomavirus Transforming; Antigens, Viral, Tumor; Base Sequence; Cell Differentiation; Cell Division; Cell Line; Cell Transformation, Neoplastic; Chromosome Mapping; Cytopathogenic Effect, Viral; DNA, Neoplasm; DNA, Viral; Drosophila; Gastrins; Gene Expression Regulation; Genetic Complementation Test; Humans; Models, Biological; Models, Genetic; Neoplasms; Oncogenes; Oncogenic Viruses; Phenotype; Platelet-Derived Growth Factor; Translocation, Genetic; Viral Proteins | 1984 |
Gastrointestinal hormones in clinical medicine.
Information concerning GEP hormones has progressively advanced since the initial discovery of a GEP hormone, secretin, in 1902. Studies in this area flourished with the advent of radioimmunoassay, and have provided an understanding of the secretion, regulation, metabolic actions, and role in certain diseases of major GEP hormones. Measurement of GEP hormones has achieved importance in clinical medicine and allowed understanding of the pathophysiology of several clinical disorders. The decade to come should witness additional advances in this rapidly expanding field. Topics: Chemical Phenomena; Chemistry; Cholecystokinin; Diabetes Mellitus; Diarrhea; Endocrine System Diseases; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Hypoglycemia; Motilin; Neoplasms; Neurotensin; Pancreatic Polypeptide; Peptic Ulcer; Secretin; Skin Diseases; Somatostatin; Substance P; Vasoactive Intestinal Peptide | 1982 |
Recent advances in the immunodiagnosis of cancer.
Topics: Acid Phosphatase; alpha-Fetoproteins; Calcitonin; Carcinoembryonic Antigen; Gastrins; Humans; Insulin; Male; Neoplasms; Parathyroid Hormone; Prostate; Thyroglobulin | 1979 |
Clinical aspects of gastrointestinal hormones.
Topics: Adenoma, Islet Cell; Cholecystokinin; Gastric Juice; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Neoplasms; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptides; Precancerous Conditions; Secretin; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome | 1978 |
Clinical implications of growth hormone release inhibiting hormone (GH-RIH).
Topics: Acromegaly; Adenoma, Islet Cell; Adrenocorticotropic Hormone; Bronchial Neoplasms; Diabetes Mellitus; Gastrins; Glucagon; Growth Hormone; Humans; Hypoglycemia; Neoplasms; Pancreatic Neoplasms; Somatostatin; Thyrotropin; Zollinger-Ellison Syndrome | 1976 |
Ectopic hormone production.
Topics: Adrenocorticotropic Hormone; Calcitonin; Child; Erythropoietin; Gastrins; Glucagon; Gonadotropins; Growth Hormone; Hormones, Ectopic; Humans; Insulin; Male; Melanocyte-Stimulating Hormones; Neoplasms; Parathyroid Hormone; Prostaglandins; Secretin; Serotonin; Thyrotropin; Vasopressins | 1975 |
[Paraneoplastic syndrome].
Topics: Adrenocorticotropic Hormone; Chorionic Gonadotropin; Erythropoietin; Gastrins; Genetic Code; Gonadotropins, Pituitary; Hormones; Humans; Insulin; Insulin Secretion; Melanocyte-Stimulating Hormones; Neoplasms; Serotonin; Skin; Skin Neoplasms; Syndrome | 1972 |
[Ectopic hormone synthesis].
Topics: 5-Hydroxytryptophan; Adrenocorticotropic Hormone; Chorionic Gonadotropin; Gastrins; Hormones, Ectopic; Humans; Hypercalcemia; Hypoglycemia; Neoplasms; Parathyroid Hormone; Precancerous Conditions; Thyrotropin; Vasopressins | 1971 |
Clinical and laboratory studies of ectopic humoral syndromes.
Topics: Adrenocorticotropic Hormone; Erythropoietin; Female; Gastrins; Gonadotropins; Hormones, Ectopic; Humans; Insulin; Male; Melanocyte-Stimulating Hormones; Neoplasms; Parathyroid Hormone; Thyrotropin; Vasopressins | 1969 |
Preliminary characterization of some ectopic hormones.
Topics: Adrenocorticotropic Hormone; Animals; Chemical Phenomena; Chemistry; Erythropoietin; Gastrins; Gonadotropins; Hormones, Ectopic; Humans; Immunochemistry; Melanocyte-Stimulating Hormones; Neoplasms; Parathyroid Hormone; Thyrotropin; Vasopressins | 1968 |
[Ectopic endocrine syndromes].
Topics: Adrenocorticotropic Hormone; Calcitonin; Chorionic Gonadotropin; Endocrine System Diseases; Erythropoietin; Gastrins; Hormones, Ectopic; Humans; Insulin; Lung Neoplasms; Neoplasms; Serotonin; Thyrotropin; Vasopressins | 1968 |
1 trial(s) available for gastrins and Neoplasms
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A phase I trial of the bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC3095 in patients with advanced solid malignancies.
Bombesin/gastrin-releasing peptides (BN/GRP) were shown to bind selectively to cell surface receptors, stimulating the growth of various types of malignancies in murine and human models. The novel BN/GRP synthetic receptor antagonist, RC-3095, was able to produce long-lasting tumor regressions in murine and human tumor models in vitro and in vivo. Animal toxicology studies showed no detectable organ toxicity apart from local irritation at the injection site. The purpose of this study was to determine the safety and feasibility of the administration of RC-3095 by daily subcutaneous injections in patients with advanced and refractory solid malignancies. Twenty-five patients received RC-3095 once or twice-daily at doses ranging from 8 to 96 ug/kg. Dose was escalated in groups of 3-5 patients per dose level. The only toxicity observed was local discomfort in the injection site at the highest doses. A single dose administration of RC-3095 at the highest dose level (96 ug/kg) was tested in a clearly hypergastrinemic individual with the Zollingen-Ellison syndrome and produced a decrease in plasma gastrin down to 50% of basal levels in 6 h. There was no objective tumor responses in patients included in the study. A short-lasting minor tumor response was observed in a patient with a GRP-expressing progressive medullary carcinoma of the thyroid. Due to problems with the analytical method, plasma pharmacokinetic data was obtained only from two patients included at the highest dose level. In these patients, RC-3095 reached plasma concentrations >100 ng/mL for about 8 h, which were within therapeutic levels on the basis of prior data obtained in mice and rats. The plasma elimination half-life was between 8.6-10.9 h. Due to the occurrence of local toxicity at the injection site, the dose escalation procedure could not be fully evaluated up to a maximum tolerated dose. Thus, a recommended dose of RC-3095 for Phase II trials could not be clearly established. Considering the novelty of its mechanism of action and impressive preclinical anti-tumor activity, further studies exploiting new formulations of RC-3095 for human use, such as slow-release preparations, and analogues with a more favorable pharmacokinetics are warranted. Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bombesin; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Injections, Subcutaneous; Male; Middle Aged; Neoplasms; Pain; Peptide Fragments; Skin | 2006 |
41 other study(ies) available for gastrins and Neoplasms
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A novel method to detect hPG
hPG Topics: Gastrins; Humans; Neoplasms; Protein Precursors | 2021 |
The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients.
In colorectal cancer, hPG80 (progastrin) is released from tumor cells, promotes cancer stem cells (CSC) self-renewal and is detected in the blood of patients. Because the gene GAST that encodes hPG80 is a target gene of oncogenic pathways that are activated in many tumor types, we hypothesized that hPG80 could be expressed by tumors from various origins other than colorectal cancers, be a drug target and be detectable in the blood of these patients.. hPG80 expression was monitored by fluorescent immunohistochemistry and mRNA expression in tumors from various origins. Cancer cell lines were used in sphere forming assay to analyze CSC self-renewal. Blood samples were obtained from 1546 patients with 11 different cancer origins and from two retrospective kinetic studies in patients with peritoneal carcinomatosis or hepatocellular carcinomas. These patients were regularly sampled during treatments and assayed for hPG80.. We showed that hPG80 was present in the 11 tumor types tested. In cell lines originating from these tumor types, hPG80 neutralization decreased significantly CSC self-renewal by 28 to 54%. hPG80 was detected in the blood of patients at significantly higher concentration than in healthy blood donors (median hPG80: 4.88 pM versus 1.05 pM; p < 0.0001) and shown to be correlated to GAST mRNA levels in the matched tumor (i.e., lung cancers, Spearman r = 0.8; p = 0.0023). Furthermore, we showed a strong association between longitudinal hPG80 concentration changes and anti-cancer treatment efficacy in two independent retrospective studies. In the peritoneal carcinomatosis cohort, median hPG80 from inclusion to the post-operative period decreased from 5.36 to 3.00 pM (p < 0.0001, n = 62) and in the hepatocellular carcinoma cohort, median hPG80 from inclusion to remission decreased from 11.54 pM to 1.99 pM (p < 0.0001, n = 63).. Because oncogenic hPG80 is expressed in tumor cells from different origins and because circulating hPG80 in the blood is related to the burden/activity of the tumor, it is a promising cancer target for therapy and for disease monitoring.. ECS-Progastrin. Topics: Adult; Aged; Aged, 80 and over; Antibodies, Neoplasm; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cohort Studies; Female; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Kinetics; Male; Middle Aged; Neoplasms; Oncogenes; Organ Specificity; Protein Precursors; RNA, Messenger; Spheroids, Cellular; Young Adult | 2020 |
Design of Radiolabeled Analogs of Minigastrin by Multiple Amide-to-Triazole Substitutions.
The insertion of single 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Gastrins; Humans; Lutetium; Mice; Neoplasms; Peptidomimetics; Protein Binding; Radioisotopes; Radiopharmaceuticals; Receptor, Cholecystokinin B; Triazoles | 2020 |
Expression, purification and characterization of recombinant toxins consisting of truncated gastrin 17 and pseudomonas exotoxin.
Gastric cancer is a major cause of mortality and morbidity around world. However the effectiveness of the current approaches to the diagnosis and treatment of gastric cancer is limited. Recombinant targeted toxins may represent a novel direction of cancer therapy. In this study, we aimed to explore whether recombinant toxins fused with the truncated forms of G17 could target to kill cancer cells by recognizing CCK2R. Four recombinant Pseudomonas toxins PE38 fused with the forward or reverse truncated forms of G17 (G14 and G13) were successfully constructed, expressed, and purified. Their characteristics were further analyzed by SDS-PAGE, western blot and indirect immunofluorescence assay. The cytotoxicity assay demonstrated that only reversely fused recombinant toxins rG14PE38 and rG13PE38 exhibited certain toxicity on several cancer cell lines, and a competition assay indicated that the binding of the reverse gastrin-endotoxin to CCK2R (+) cells may be mediated by interaction between gastrin/gastrin-like and CCK2R. Topics: Blotting, Western; Cell Survival; DNA Primers; Electrophoresis, Polyacrylamide Gel; Exotoxins; Fluorescent Antibody Technique, Indirect; Gastrins; Humans; Neoplasms; Polymerase Chain Reaction; Pseudomonas; Receptor, Cholecystokinin B; Recombinant Proteins; Toxins, Biological; Tumor Cells, Cultured | 2015 |
Stereochemistry of amino acid spacers determines the pharmacokinetics of (111)In-DOTA-minigastrin analogues for targeting the CCK2/gastrin receptor.
The metabolic instability and high kidney retention of minigastrin (MG) analogues hamper their suitability for use in peptide-receptor radionuclide therapy of CCK2/gastrin receptor-expressing tumors. High kidney retention has been related to N-terminal glutamic acids and can be substantially reduced by coinjection of polyglutamic acids or gelofusine. The aim of the present study was to investigate the influence of the stereochemistry of the N-terminal amino acid spacer on the enzymatic stability and pharmacokinetics of (111)In-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-D) and (111)In-DOTA-(l-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-L). Using circular dichroism measurements, we demonstrate the important role of secondary structure on the pharmacokinetics of the two MG analogues. The higher in vitro serum stability together with the improved tumor-to-kidney ratio of the (d-Glu)6 congener indicates that this MG analogue might be a good candidate for further clinical study. Topics: Amino Acid Sequence; Animals; Gastrins; Heterocyclic Compounds, 1-Ring; Humans; Indium Radioisotopes; Male; Neoplasms; Positron-Emission Tomography; Rats, Inbred Lew; Receptor, Cholecystokinin B | 2015 |
"To serve and protect": enzyme inhibitors as radiopeptide escorts promote tumor targeting.
Radiolabeled octreotide analogs are most successfully being applied today in clinical cancer imaging and treatment. Propagation of this paradigm to other radiopeptide families has been greatly hampered by the inherent poor metabolic stability of systemically administered peptide analogs. We hypothesized that the in vivo coadministration of specific enzyme inhibitors would improve peptide bioavailability and hence tumor uptake. Through single coinjection of the neutral endopeptidase inhibitor phosphoramidon (PA), we were able to provoke remarkable rises in the percentages of circulating intact somatostatin, gastrin, and bombesin radiopeptides in mouse models, resulting in a remarkable increase in uptake in tumor xenografts in mice.. The peptide conjugates [DOTA-Ala(1)]SS14 (DOTA-Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-OH), PanSB1 (DOTA-PEG2-dTyr-Gln-Trp-Ala-Val-βAla-His-Phe-Nle-NH2), and DOTA-MG11 (DOTA-dGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) were labeled with (111)In by 20 min of heating at an acidic pH. Metabolic stability was studied with high-performance liquid chromatography analysis of blood samples collected 5 min after the injection of the test radiopeptide alone or with PA into mice. Biodistribution was studied after injection of each (111)In-labeled radiopeptide alone or after coinjection of PA in tumor-bearing severe combined immunodeficient (SCID) mice.. The amount of intact [(111)In-DOTA-Ala(1)]SS14 detected in the mouse circulation at 5 min after the injection of PA increased impressively-from less than 2% to 86%-whereas the uptake in AR4-2J xenografts rose from less than 1 percentage injected dose per gram of tissue (%ID/g) to 14 %ID/g at 4 h after injection. Likewise, the coadministration of PA resulted in a marked increase in the amount of circulating intact (111)In-PanSB1-from 12% to 80%-at 5 min after injection, and radioligand uptake in human PC-3 xenografts in SCID mice escalated from less than 4 %ID/g to greater than 21 %ID/g at 4 h after injection. In a similar manner, the coadministration of PA resulted in an equally impressive increase in intact [(111)In-DOTA]MG11 levels in the mouse bloodstream-from less than 5% to 70%-at 5 min after injection, leading to a remarkable increase in radiotracer uptake-from 2 %ID/g to greater than 15 %ID/g-in both AR4-2J tumors and A431(CCKR+) tumors (i.e., tumors induced by A431 cells transfected to stably express the human cholecystokinin subtype 2 receptor) in mice at 4 h after injection. This effect was well visualized by SPECT/CT imaging of AR4-2J tumor-bearing mice at 4 h after injection.. The results of this study clearly demonstrate that the coadministration of key enzyme inhibitors can effectively prolong the survival of radiolabeled peptides in the circulation, securing their safe transit to the target. This strategy clearly provoked an unprecedented increase in radiolabel accumulation in tumor xenografts in mice; this increase might translate into higher diagnostic sensitivity or improved therapeutic efficacy of radiopeptide drugs in cancer patients. Hence, our findings provide exciting new opportunities for the application of biodegradable (radio)peptide drugs of either natural or synthetic origin as well as for the rationale design of analogs that are stable in vivo. Topics: Animals; Bombesin; Chromatography, High Pressure Liquid; Enzyme Inhibitors; Female; Gastrins; Glycopeptides; Humans; Indium Radioisotopes; Male; Mice; Mice, SCID; Neoplasm Transplantation; Neoplasms; Peptides; Protein Binding; Radiopharmaceuticals; Somatostatin; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed | 2014 |
Gastrin receptor pharmacology.
C-terminally amidated gastrins act at cholecystokinin-2 receptors (CCK2R), which are normally expressed by gastric parietal and enterochromaffin-like (ECL) cells and smooth muscle; there is also extensive expression in the CNS where the main endogenous ligand is cholecystokinin. A variety of neoplasms express CCK2R, or splice variants, including neuroendocrine, pancreatic, medullary thyroid and lung cancers. Other products of the gastrin gene (progastrin, the Gly-gastrins) may stimulate cell proliferation but are not CCK2R ligands. Depending on the cell type, stimulation of CCK2R evokes secretion, increases proliferation and cell migration, inhibits apoptosis, and controls the expression of various genes. These effects are mediated by increased intracellular calcium and activation of protein kinase C, MAPkinase and other protein kinase cascades. There has been recent progress in developing CCK2R ligands that can be used for imaging tumours expressing the receptor. New antagonists have also been developed, and there is scope for using these for suppression of gastric acid and for treatment of neuroendocrine and other CCK2R-expressing tumours. Topics: Antineoplastic Agents; Gastrins; Humans; Ligands; Neoplasms; Receptor, Cholecystokinin B; Signal Transduction | 2012 |
[Adverse events associated with long-term use of proton pump inhibitors].
Proton pump inhibitors (PPI) remain the leading therapy for acid-related disorders. Long-term PPI use increases the risk of pneumonia and enteric bacterial infections and of nosocomial Clostridium difficile-associated diarrhoea. PPIs do not lead to vitamin B12 or iron deficiencies and do not induce malignancies or increase the risk of major birth defects. Prolonged PPI use may be a weak risk factor for certain fractures and results in hypergastrinaemia and parietal cell hyperplasia leading to rebound acid hypersecretion, which may induce symptoms on withdrawal of therapy. Topics: Anti-Ulcer Agents; Bacterial Infections; Congenital Abnormalities; Dyspepsia; Fractures, Bone; Gastrins; Gastroenteritis; Gastroesophageal Reflux; Heartburn; Humans; Neoplasms; Omeprazole; Pneumonia; Proton Pump Inhibitors; Risk Factors; Time Factors; Vitamin B 12 Deficiency | 2012 |
Optical imaging of CCK₂/gastrin receptor-positive tumors with a minigastrin near-infrared probe.
A variety of tumors in different organs with good accessibility to near-infrared light express the cholecystokinin-2 (CCK₂)/gastrin receptor. Therefore, the applicability of fluorescence optical imaging was assessed using a novel peptide probe.. This study was approved by the regional animal committee. Our optical peptide probe (DY-minigastrin) was synthesized by coupling a hemicyanine dye to a gastrin derivative peptide (minigastrin). In vitro CCK₂/gastrin receptor identification was performed in receptor-positive HT-29 and negative A-375 cells using flow cytometry, laser scanning microscopy, and macroscopic near-infrared fluorescent (NIRF) imaging. For in vivo studies, tumor cells were implanted into mice, and DY-minigastrin in presence or absence of nonlabeled minigastrin (control of signaling specificity) was applied intravenously. Fluorescence signals in tumors and organs were recorded and statistically analyzed.. Flow cytometry, laser scanning microscopy, and in vitro macroscopic imaging of cell pellets revealed a distinct accumulation of our minigastrin probe in HT-29 cells, showing distinct probe internalization. In vivo NIRF whole-body animal imaging, again, demonstrated a clear depiction of HT-29 tumors, which was reversed by blocking with nonlabeled minigastrin. Semi-quantitative fluorescence analysis and histologic observations were in agreement with these observations. A distinct probe organ distribution was observed.. Our observations indicate that DY-minigastrin-based NIRF optical imaging of CCK₂/gastrin receptor protein is feasible. Because of its widespread occurrence in different tumor types, endoscopic, laparoscopic, and tomographic receptor imaging could be accomplished in the near future. Topics: Animals; Disease Models, Animal; Feasibility Studies; Flow Cytometry; Gastrins; HT29 Cells; Humans; Mice; Mice, Inbred BALB C; Neoplasms; Receptor, Cholecystokinin B; RNA, Messenger | 2011 |
Preclinical evaluation of 68Ga-DOTA-minigastrin for the detection of cholecystokinin-2/gastrin receptor-positive tumors.
In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK2)/gastrin receptor-positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET-computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK2/gastrin receptor-mediated uptake (p = .0005). The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor-positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor-positive tumors in humans. Topics: Animals; Binding, Competitive; Cell Line, Tumor; Cholecystokinin; Chromatography, High Pressure Liquid; Coordination Complexes; Drug Screening Assays, Antitumor; Gastrins; Inhibitory Concentration 50; Male; Mice; Mice, Nude; Neoplasms; Peritoneal Neoplasms; Positron-Emission Tomography; Rats; Receptor, Cholecystokinin B; Subcutaneous Tissue; Tissue Distribution | 2011 |
Targeting of CCK-2 receptor-expressing tumors using a radiolabeled divalent gastrin peptide.
Gastrin/cholecystokinin subtype 2 receptors (CCK-2Rs) are overexpressed in several tumor types and are, thus, a potential target for peptide receptor radionuclide therapy (PRRT) of cancer. To improve the in vivo performance of CCK-2R binding peptides, we have previously synthesized and screened a series of divalent gastrin peptides for improved biochemical and biologic characteristics. In this study, we explore in more detail the most promising of these compounds and compare its performance with a previously described monomeric peptide.. From six (111)In-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-conjugated divalent gastrin peptides based on the C-terminal sequence of minigastrin, the maleimide-linked compound DOTA-GSC(succinimidopropionyl-EAYGWNleDF-NH(2))-EAYGWNleDF-NH(2) (MGD5) was selected. The in vitro stability, receptor binding, and internalization of (111)In-MGD5 were studied and compared with those of monomer compound (111)In-APH070. In vivo biodistribution and imaging using a SPECT/CT camera were also performed.. More than 90% of the labeled divalent peptide remained intact after 20 h of incubation in plasma. The inhibitory concentration of 50% of the divalent peptide was 1.0 versus 5.6 nM for the monomer, and the dissociation constant was 0.7 versus 2.9 nM. The rate of internalization of the divalent peptide was twice that of the monomer. Tumor uptake of the divalent peptide in vivo was about 6 times that of the monomer. The rate of washout of the divalent peptide from the tumor was lower than that of the monomer.. Dimerization of the CCK-2R binding site results in an increase in binding affinity and an increase in tumor uptake both in vitro and in vivo. It is likely that these increases would result in improved tumor-targeting efficiency in patients with CCK-2R-positive tumors. Topics: Amino Acid Sequence; Animals; Cell Line, Tumor; Female; Gastrins; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 1-Ring; Isotope Labeling; Mice; Neoplasms; Protein Stability; Protein Transport; Rats; Receptor, Cholecystokinin B; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed | 2009 |
99mTc-labelled HYNIC-minigastrin with reduced kidney uptake for targeting of CCK-2 receptor-positive tumours.
Different attempts have been made to develop a suitable radioligand for targeting CCK-2 receptors in vivo, for staging of medullary thyroid carcinoma (MTC) and other receptor-expressing tumours. After initial successful clinical studies with [DTPA(0),D: Glu(1)]minigastrin (DTPA-MG0) radiolabelled with (111)In and (90)Y, our group developed a (99m)Tc-labelled radioligand, based on HYNIC-MG0. A major drawback observed with these derivatives is their high uptake by the kidneys. In this study we describe the preclinical evaluation of the optimised shortened peptide analogue, [HYNIC(0),D: Glu(1),desGlu(2-6)]minigastrin (HYNIC-MG11).. (99m)Tc labelling of HYNIC-MG11 was performed using tricine and EDDA as coligands. Stability experiments were carried out by reversed phase HPLC analysis in PBS, PBS/cysteine and plasma as well as rat liver and kidney homogenates. Receptor binding and cell uptake experiments were performed using AR4-2J rat pancreatic tumour cells. Animal biodistribution was studied in AR4-2J tumour-bearing nude mice.. Radiolabelling was performed at high specific activities and radiochemical purity was >90%. (99m)Tc-EDDA-HYNIC-MG11 showed high affinity for the CCK-2 receptor and cell internalisation comparable to that of (99m)Tc-EDDA-HYNIC-MG0. Despite high stability in solution, a low metabolic stability in rat tissue homogenates was found. In a nude mouse tumour model, very low unspecific retention in most organs, rapid renal excretion with reduced renal retention and high tumour uptake were observed.. (99m)Tc-EDDA-HYNIC-MG11 shows advantages over (99m)Tc-EDDA-HYNIC-MG0 in terms of lower kidney retention with unchanged uptake in tumours and CCK-2 receptor-positive tissue. However, the lower metabolic stability and impurities formed in the labelling process still leave room for further improvement. Topics: Animals; Carcinoma, Medullary; Cysteine; Edetic Acid; Gastrins; Gene Expression Regulation, Neoplastic; Glycine; Humans; Kidney; Liver; Neoplasms; Organotechnetium Compounds; Radionuclide Imaging; Rats; Receptor, Cholecystokinin B; Technetium; Thyroid Neoplasms; Tissue Distribution | 2007 |
Selection of radiolabeled gastrin analogs for peptide receptor-targeted radionuclide therapy.
The gastrin/cholecystokinin-2 (CCK-2) receptor has been identified as a possible target for peptide receptor radionuclide imaging and therapy. Several radiolabeled peptides binding to this receptor have been explored in animal models and clinical trials but either low tumor uptake or high renal retention has been found. The aim of this study was to identify a peptide with improved tumor-to-kidney pharmacodynamics when compared with current candidates.. A small peptide-chelator library of 34 compounds based on the C-terminal sequences of CCK-8 or minigastrin was constructed. The peptides were radiolabeled with (111)In with high labeling efficiency (>90%), as determined by high-performance liquid chromatographic analysis. The labeled peptides were screened by assessing tumor and kidney uptake in pancreatic xenograft nude mouse models, including AR42J. An extensive biodistribution analysis was performed on the lead candidate from the library.. Minigastrin analogs containing a pentaglutamate sequence showed the highest tumor uptake but very high renal retention. CCK analogs showed the lowest tumor and renal uptake. Deletion of the pentaglutamate sequence in the gastrin analogs lowered the tumor uptake by a factor of 3 but decreased the kidney uptake by a factor of 20. Insertion of histidine residues in the sequence reduced kidney uptake by a further factor of almost 2-fold. In AR42J tumor-bearing mice, the peptide with the sequence DOTA-HHEAYGWMDF-NH(2) (DOTA is tetraazacyclododecane tetraacetic acid) showed the highest tumor-to-kidney ratio of all peptides studied, with saturable uptake in target organs and low uptake by nontarget tissues other than the kidney.. This peptide is a worthwhile candidate for clinical studies to determine whether it is suitable for use in peptide receptor-targeted radionuclide therapy. Topics: Amino Acid Sequence; Animals; Cell Line, Tumor; Gastrins; Humans; Kidney; Male; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Transplantation; Neoplasms; Rats; Receptor, Cholecystokinin B; Receptors, Peptide | 2007 |
Effects of erythromycin on plasma gastrin, somatostatin, and motilin levels in healthy volunteers and postoperative cancer patients.
Erythromycin, an antibiotic agent, is known to be a motilin receptor agonist. Motilin is a peptide hormone that regulates gastric motility. One of the gastrointestinal motility regulatory factors has been assumed to be the induction of changes in the levels of peptides (gastrin, somatostatin and motilin) in plasma. We have elucidated the effects of erythromycin by examining changes in the plasma levels of gastroinitestinal peptides. In this study, we investigated the effects of erythromycin on the plasma levels of gastrointestinal peptides (somatostatin, motilin, and gastrin) in healthy volunteers and patients with delayed gastric emptying (DGE). After a single oral administration, erythromycin caused a significant increase in plasma gastrin-like immunoreactive substance (IS) levels at 60 min. But the agent did not alter the levels of somatostatin- and motilin-IS. DGE is the most frequent postoperative complication after pylorus-preserving pancreatoduodenectomy. Molitin is assumed to be one important factor that influences DGE. We also examined the effects of erythromycin on the plasma motilin-IS levels of postoperative patients. The plasma motilin-IS levels were increased after 1 week of oral administration of erythromycin compared with preadministration. These results suggest that the pharmacologic effects of erythromycin in promoting gastric emptying are closely related to changes in plasma motilin-IS levels. Topics: Adult; Aged; Anti-Bacterial Agents; Case-Control Studies; Erythromycin; Gastric Emptying; Gastrins; Humans; Immunoenzyme Techniques; Male; Middle Aged; Motilin; Neoplasms; Postoperative Period; Somatostatin | 2005 |
The role of electrogastrography and gastrointestinal hormones in chemotherapy-related dyspeptic symptoms.
The aim of this study was to investigate the relationship among motility disorders, dyspeptic symptoms, and plasma levels of gastrointestinal hormones in cancer patients who were well controlled for post-chemotherapy emesis.. Twenty-five cancer patients treated with standard dosages of antiemetics and chemotherapies completed the study. Gastrointestinal symptoms were investigated by detailed questionnaire and visual analog score. Motility was investigated by cutaneous electrogastrography, and by blood levels of gastrin, serotonin, vasopressin, and substance P, before and 7 days after chemotherapy.. Before chemotherapy, no patient complained of dyspeptic symptoms, and no differences in electrogastrography (EGG) or in circulating peptide levels were found between patients who developed dyspepsia and those who did not. After chemotherapy, 13 patients suffered from dysmotility-like symptoms (total symptom score, 11.5 [2.5-37.9]; median value and 5th-95th percentiles), with susceptibility to nausea, early satiety, and postprandial fullness being the major complaints. As regards EGG parameters, a significant reduction (P = 0.04; Mann-Whitney test) in the normal slow-wave percentage and significantly increased tachygastria percentage were found in dyspeptic patients compared with symptom-free patients. The tachygastria percentage was significantly associated with susceptibility to nausea score, in a non-linear fashion (R2 = 0.37). Dyspeptic patients showed lower levels of substance P and gastrin than patients who were not dyspeptic, but this difference had no clinical significance for dyspepsia.. Chemotherapy may induce upper gastrointestinal symptoms suggestive of motility disorders. These dyspeptic symptoms were associated with EGG alterations, but not with variations in circulating peptides. Other hormones or pathophysiological factors, not considered in the present work, could be actively involved in these dyspeptic symptoms. Topics: Aged; Antineoplastic Agents; Dyspepsia; Electrophysiology; Female; Gastrins; Gastrointestinal Hormones; Gastrointestinal Motility; Humans; Male; Neoplasms; Serotonin; Stomach; Substance P; Vasopressins | 2005 |
Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors.
Cholecystokinin (CCK)-A and CCK-B/gastrin receptors were evaluated with in vitro receptor autoradiography in 406 human tumors of various origins using a sulfated 125I-labeled CCK decapeptide analogue 125I-(D-Tyr-Gly, Nle28,3l)-CCK 26-33 and 125I-labeled Leu15-gastrin as radioligands. CCK-B/gastrin receptors were found frequently in medullary thyroid carcinomas (92%), in small cell lung cancers (57%), in astrocytomas (65%), and in stromal ovarian cancers (100%). They were found occasionally in gastroenteropancreatic tumors, breast, endometrial, and ovarian adenocarcinomas. They were either not expressed or rarely expressed in colorectal cancers, differentiated thyroid cancers, non-small cell lung cancers, meningiomas, neuroblastomas, schwannomas, glioblastomas, lymphomas, renal cell cancers, prostate carcinomas, and the remaining neuroendocrine tumors (i.e., pituitary adenomas, pheochromocytomas, paragangliomas, and parathyroid adenomas). CCK-A receptors were expressed rarely in tumors except in gastroenteropancreatic tumors (38%), meningiomas (30%), and some neuroblastomas (19%). The identified CCK-A and CCK-B receptors were specific and of high affinity in the subnanomolar range. The rank order of potency of various CCK analogues was: sulfated CCK-8 = L-364,718 >> nonsulfated CCK-8 = L-365,260 > or = gastrin for CCK-A receptors and sulfated CCK-8 > gastrin = nonsulfated CCK-8 > L-365,260 > L-364,718 for CCK-B receptors. CCK-B receptors could also be selectively and specifically labeled with a newly designed nonsulfated 125I-(D-Tyr-Gly, Nle28,31)-CCK 26-33. Gastrin mRNA measured by in situ hybridization was present in most CCK-B receptor-positive small cell lung cancers, breast tumors, and ovarian tumors, representing the molecular basis of a possible autocrine growth regulation of these tumors. Gastrin and CCK mRNAs were lacking in medullary thyroid cancers. Thus, these results may have pathogenic, diagnostic, differential diagnostic, and therapeutic implications. Topics: Autoradiography; Breast Neoplasms; Carcinoma, Small Cell; Cholecystokinin; Female; Gastrins; Humans; Lung Neoplasms; Neoplasms; Neuroendocrine Tumors; Ovarian Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Thyroid Neoplasms | 1997 |
Production of immunoreactive corticotropin-releasing hormone in various neuroendocrine tumors.
The concentrations of immunoreactive (IR) corticotropin-releasing hormone (CRH) in 218 neuroendocrine tumors were determined by CRH radioimmunoassay. The tumors examined were 86 pancreatic endocrine tumors (PET), 22 neuroblastic tumors (NBT), 26 carcinoid tumors (CA), 24 pheochromocytomas (PHEO), 40 small cell lung carcinomas (SCLC) and 20 medullary thyroid carcinomas (MTC). IR-CRH was detectable in 21 neuroendocrine tumors (10 PET, four NBT, three CA, two PHEO and two SCLC) at levels of 10-2,700 ng/g wet weight (9.6%). The 21 patients with these CRH-producing tumors showed no clinical symptoms suggestive of Cushing's syndrome. The levels of plasma IR-CRH extracted by immunoaffinity chromatography were < 7.5 pg/ml in five normal subjects and a patient with a neuroblastic tumor containing 55 ng/g wet weight IR-CRH, but in a patient with a thymic carcinoid tumor containing 1,000 ng/g wet weight IR-CRH, the plasma level was elevated to 180 pg/ml. This patient did not have Cushing's syndrome nor an elevated plasma adrenocorticotropic hormone (ACTH) level. The concentrations of nine peptides (growth hormone-releasing hormone, somatostatin, ACTH, calcitonin, gastrin-releasing peptide, glucagon, vasoactive intestinal peptide, neuropeptide tyrosine and pancreatic polypeptide) were determined in extracts of the 21 IR-CRH-producing tumors. Some of these peptides were frequently found to be produced concomitantly with CRH. The results indicate IR-CRH to be produced by various neuroendocrine tumors, but Cushing's syndrome, due to the CRH, to be very rare. The results also show that CRH-producing tumors produce multiple hormones. Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Bombesin; Calcitonin; Carcinoid Tumor; Carcinoma, Small Cell; Chromatography, Gel; Corticotropin-Releasing Hormone; Gastrin-Releasing Peptide; Gastrins; Humans; Hypothalamus; Lung Neoplasms; Neoplasms; Neuroblastoma; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide | 1992 |
Intravenous administration of bombesin in man stimulates natural killer cell activity against tumour cells.
Peptides from both the nervous and endocrine system have been shown to influence immune functions. This study describes the stimulatory effect of bombesin on natural killer cell activity of peripheral blood mononuclear cells. The stimulation of cytotoxicity by bombesin in vivo was much higher than found in vitro. In vitro studies with bombesin and gastrin revealed that the stimulatory effect of bombesin in vivo can for a major part be attributed to other stimulatory mediators which are released by BBS. These results indicate that neuropeptide release might rapidly interfere, both directly and indirectly, with natural killer activity of peripheral blood mononuclear cells. Topics: Adult; Bombesin; Cytotoxicity, Immunologic; Female; Gastrins; Humans; Killer Cells, Natural; Leukemia, Erythroblastic, Acute; Leukocytes, Mononuclear; Male; Neoplasms; Tumor Cells, Cultured | 1991 |
Peptide and steroid hormones in subjects at different risk for diet-related diseases.
Populations eating low-fat or low-fat, high-fiber diets have lower mortality rates for many cancers and coronary heart disease. The importance of nutrient composition in the lumen on absorption and on function of the gastrointestinal tract as a factor in the development of these diseases has not been studied. We investigated the plasma levels of gut-CNS peptide hormones in lean and obese Dutch women fed a high-fat meal and administered cholecystokinin (CCK). After a high-fat meal the increase in plasma CCK was similar in lean and obese women. CCK administration significantly decreased insulin release in lean and obese women, decreased glucagon release in obese women, but caused a rapid increase in plasma glucagon in lean women. Although the CCK response was similar to a fat meal in lean and obese women, differences in the control of peptide hormone release occurred in response to fat meals and CCK administration. Topics: beta-Endorphin; Cholecystokinin; Cholesterol; Coronary Disease; Diet; Diet, Vegetarian; Dietary Fiber; Female; Gastrins; Glucagon; Humans; Insulin; Lipids; Middle Aged; Neoplasms; Obesity; Risk Factors | 1988 |
Binding of gastrin(17) to human gastric carcinoma cell lines.
The hormone gastrin stimulates acid secretion by gastric parietal cells and acts as a growth factor for the gastric mucosa. Gastrin receptors with dissociation constants of approximately 0.5 nM have been detected on isolated gastric parietal cells, and on some cell lines derived from colon carcinomas. We now report that gastrin is also bound by five cell lines derived from human gastric carcinomas, but that the affinities of these lines for gastrin range from 0.2 to 1.3 microM. Cholecystokinin8 binds to the cell line Okajima with an affinity similar to gastrin17, while shorter gastrin analogues bind with reduced affinity. Binding of gastrin is unaffected by acetylcholine, histamine, or a number of other hormones with the exception of insulin which inhibits binding with an IC50 value of 0.5 microM. The ability to bind gastrin with affinities in the microM range appears to be a property widespread among other tumor cell lines. Topics: Animals; Binding, Competitive; Cell Line; Dogs; Gastrins; Hormones; Humans; Kinetics; Neoplasms; Parietal Cells, Gastric; Receptors, Cholecystokinin; Stomach Neoplasms | 1988 |
Plasma GRP-like immunoreactivity in healthy and diseased subjects.
Gastrin releasing peptide(GRP)-like immunoreactivity in human plasma was measured using radioimmunoassay of neuromedin C (NMC) in 83 healthy and 58 diseased subjects. In the healthy group, the mean value of fasting GRP-like immunoreactivity was 2.1 +/- 1.4 (mean +/- SD) pmol/L. There was a slight positive correlation between the GRP-like immunoreactivity values and aging. Postprandial serial measurements demonstrated that GRP-like immunoreactivity showed no response to a significant elevation of serum gastrin concentration. The group with chronic renal failure on hemodialysis gave the highest value, 7.1 +/- 2.1 pmol/L (p less than 0.01). There were no statistical differences between the healthy controls and groups with peptic ulcer, liver cirrhosis, diabetes mellitus or carcinomas, although some cancer patients had a marked increase in GRP-like immunoreactivity value. Topics: Adult; Aged; Bombesin; Diabetes Mellitus; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Kidney Failure, Chronic; Liver Cirrhosis; Male; Middle Aged; Neoplasms; Peptic Ulcer; Peptide Fragments; Peptides; Radioimmunoassay | 1988 |
The requirement for gastrin measurements.
In order to evaluate the clinical requirement for gastrin measurements, we examined all gastrin measurements requested over 1.5 years in a homogeneous population of 5.1 million inhabitants. Gastrin was quantitated with a radioimmunoassay that measured bioactive gastrins with equimolar potency. We received 1392 serum samples from 931 patients. In 394 samples from 121 patients the gastrin concentration was above the limit of the reference interval (50 pmol/l). Of the 121 patients, 19 were known Zollinger-Ellison patients followed for control of the therapy. In 11 previously unknown patients the gastrin analysis suggested presence of gastrin-producing tumours. Of these, four had classical Zollinger-Ellison syndromes, three had mixed endocrine tumours without peptic ulcer, and four were awaiting final confirmation of gastrinomas. Two vitiligo patients were hypergastrinaemic suggesting latent pernicious anaemia. Upon second measurement the plasma gastrin concentrations were within the reference interval in 14 previously hypergastrinaemic ulcer patients. In the remaining 75 patients the hypergastrinaemia was secondary to other gastrointestinal diseases. The results indicate that diagnosis, localization, and therapeutic control of gastrinomas require 200 gastrin measurements per million inhabitants per year. We suggest that this number be used in planning gastrin-assay services. Topics: Blood Specimen Collection; Endocrine System Diseases; Gastrins; Gastrointestinal Diseases; Gastrointestinal Neoplasms; Humans; Neoplasms; Radioimmunoassay; Zollinger-Ellison Syndrome | 1986 |
Gastrin releasing peptide in human neuroendocrine tumours.
Neuroendocrine tumours of the lung and gut are known to possess bombesin-like immunoreactivity. The recent observation that gastrin releasing peptide (GRP), a 27 amino acid peptide isolated from the porcine intestine, may be the mammalian analogue of bombesin led us to look for this peptide in a variety of human neoplasms. Formalin-fixed tissues from 85 tumours were examined by the immunoperoxidase technique, using specific antisera to the GRP molecule (1-27) and the GRP fragment (1-16). Intense cytoplasmic GRP immunoreactivity was seen in thyroid medullary carcinomas (3/3), carcinoids of lung, pancreas, and intestine (22/36), and paragangliomas (2/3). Less frequent staining was present in pulmonary small cell (oat cell) carcinomas (1/8) and pituitary adenomas (1/6). Complete absence of immunoreactivity was observed in three phaeochromocytomas, five Merkel cell tumours, six neuroblastomas and 15 non-neuroendocrine tumours. Normal neuroendocrine cells of the thyroid (C-cells) and bronchial mucosa (Kulchitsky cells) exhibited GRP immunoreactivity; nerve fibres from all sites failed to demonstrate staining for GRP. In each positive case, the pattern of staining for GRP (1-27) and GRP (1-16) was identical, although the GRP (1-16) immunostaining was weaker. These findings indicate that bombesin immunoreactivity in human neuroendocrine cells and tumours is attributable to GRP-like molecules and that GRP is a useful marker of neuroendocrine differentiation in many tumours. Topics: Adenoma; Adrenal Gland Neoplasms; Amino Acid Sequence; Bombesin; Carcinoid Tumor; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Gastrins; Humans; Intestinal Neoplasms; Lung Neoplasms; Neoplasms; Neurosecretory Systems; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Pituitary Neoplasms; Thyroid Neoplasms | 1985 |
Localisation of C-terminal gastrin immunoreactivity in gastrinoma cells. An immunoelectron microscopy study on conventionally processed tissue.
Localisation of C-terminal gastrin immunoreactivity has been studied, using the immunogold staining procedure, on ultrathin sections of 6 human gastrinomas conventionally processed for electron microscopy. The specific labelling, whose density depended on the mean diameter of the gold marker, was restricted to endocrine secretory granules. However, in poorly differentiated cells from malignant tumours, a number of granules remained unreactive. The labelling pattern depended also on the functional state of each cell. The immunoreactive granules showed various morphological features. A moderate number of gold particles was demonstrated over the floccular content of the infrequent diagnostic G-type granules. Non-diagnostic round granules of varying size and electron density were prevalent in most cells; their usually strong immunostaining allowed immediate recognition of cell specificity. Dense granules which were large in size and angular in shape and present in one case, were also intensely labelled. In the same tumour, unequal labelling occurred over polymorphous, often elongated granules, of varying size. Granules of different types, including intermediate forms, could be found in the same cell, indicating a spectrum of granule maturation towards well-defined types of the fetal or adult normal tissues. The present methodology would help to identify gastrin-producing cells in prospective or retrospective electron microscopy studies of multi-hormonal endocrine tumours. Topics: Adult; Cytoplasmic Granules; Endocrine System Diseases; Female; Gastrins; Gold; Humans; Immunologic Techniques; Male; Microscopy, Electron; Middle Aged; Neoplasms; Zollinger-Ellison Syndrome | 1985 |
Prospective evaluation of some candidate tumor markers in the diagnosis of pancreatic cancer.
As part of a prospective diagnostic protocol, patients suspected of having pancreatic cancer had systemic and portal venous blood samples assayed, in coded batches, for peptide hormones and enzymes thought to be of potential value as tumor markers. An average of 111 patients were tested for each candidate marker. Results were analyzed by dividing patients into three groups according to the definitive diagnoses. These were pancreatic cancer (32% of patients), other cancers (27%), and benign diseases (41%). Although elevated mean levels of fasting plasma glucose and serum alkaline phosphatase were found in the pancreatic cancer group, there were no significant differences in the mean levels of any of the candidate markers studied in the three groups. The diagnostic values of normal and elevated levels of each candidate marker studied have been calculated. None has proven to be as useful as the serum level of pancreatic oncofetal antigen, fasting plasma glucose, or serum alkaline phosphatase in the diagnosis or exclusion of pancreatic cancer. Topics: Alkaline Phosphatase; C-Peptide; Calcitonin; Chorionic Gonadotropin; Clinical Enzyme Tests; Clinical Laboratory Techniques; Evaluation Studies as Topic; Gastrins; Glucagon; Hormones; Humans; Insulin; Neoplasms; Pancreatic Neoplasms; Parathyroid Hormone; Prospective Studies; Ribonucleases | 1980 |
Adrenergic mechanisms in selected diseases: arterial hypertension, duodenal ulcer, primary depressive illness, malignant tumors, and ketotic hypoglycemia.
The sympathetic nervous system is of major importance for the regulation of several physiologic functions. Drugs that inhibit the actions of catecholamines and adrenergic drugs are used in the treatment of many clinical disorders. The potential role of catecholamines in a number of human diseases has, however, until recent years been studied to a limited extent only due to lack of methods for quantitation of sympathetic nervous activity. After the development of enzymatic isotope-derivative assays, reliable measurements of noradrenaline and adrenaline became available. Studies in man have shown that plasma noradrenaline is an index of sympathetic nervous activity. The present survey deals with noradrenaline and adrenaline concentrations in blood, tissue, and cerebrospinal fluid in a number of clinical disorders viz. arterial hypertension, duodenal ulcer, malignant tumors, primary depressive illness, and ketotic hypoglycemia. Topics: Adult; Blood Pressure; Child; Clonidine; Depression; Duodenal Ulcer; Epinephrine; Female; Gastrins; Heart Rate; Humans; Hypertension; Hypoglycemia; Ketosis; Male; Middle Aged; Neoplasms; Norepinephrine; Sympathetic Nervous System | 1980 |
The 2nd International Symposium on Gastrointestinal Hormones. August 30th--September 2nd 1978 Beito Mountain Hospital, Valdres, Norway.
Topics: Animals; Congresses as Topic; Endocrine System Diseases; Gastric Inhibitory Polypeptide; Gastric Juice; Gastrins; Gastrointestinal Hormones; Gastrointestinal Motility; Glucagon-Like Peptides; Histamine; Humans; Insulin; Insulin Secretion; Motilin; Neoplasms; Neurotransmitter Agents; Pancreatic Hormones; Pancreatic Juice; Pancreatic Polypeptide; Secretin; Somatostatin; Vasoactive Intestinal Peptide | 1978 |
Hormone production by tumors.
Topics: Adrenocorticotropic Hormone; Chorionic Gonadotropin; Female; Gastrins; Growth Hormone; Hormones; Hormones, Ectopic; Humans; Male; Neoplasms; Prolactin | 1978 |
Effects of cancers of the endocrine and central nervous systems on nutritional status.
Topics: Brain Neoplasms; Calcitonin; Cholesterol; Diarrhea; Endocrine Glands; Gastrins; Gastrointestinal Hormones; Histamine Release; Humans; Hypercalcemia; Neoplasms; Nutrition Disorders; Pellagra; Peptides; Serum Albumin; Thyroid Hormones; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome | 1977 |
Gastrointestinal hormones and apudomas.
Topics: Animals; Anura; Bombesin; Cholecystokinin; Dogs; Gastrins; Gastrointestinal Hormones; Glucagon; Guinea Pigs; Humans; Neoplasms; Neurosecretory Systems; Secretin | 1977 |
Ectopic apudocarcinomas and associated endocrine hyperplasias of the foregut.
Foregut endocrine polypeptide-secreting APUD cells (Amine-Precursor-Uptake and Decarboxylation), in their embryologic migration from neural crest to foregut may become "arrested" in the mesoderm or in other ectopic locations. They may become hyperplastic, adenomatous or malignant. Eight illustrative patients are reported. One patient had "pancreatic hyperparathyroidism" with hypercalcemic crises, pancreatic apudocarcinoma, normal parathyroids, biologically active parathormone, but inert immunochemically to the usual parathyroid antisera. Two had gastrin-secreting malignancies in the mesoderm. Remission after excision, but eventual recurrence of the syndrome due to islet cell hyperplasia required total gastrectomy. One patient had a gastric corpus apudocarcinoma found prospectively with hypergastrinemia which required excision of the tumor. One patient had acromegaly with hypergastrinemia and antral gastrinosis treated by pituitary irradiation, One patient had the antral or intermediary type of the Zollinger-Ellison syndrome with moderate hypergastrinemia, duodenal ulcer and antral gastrinosis, treated by vagotomy and antrectomy. One patient had hyperparathyroidism with antral gastrinosis, treated by parathyroidectomy. One patient had malignant Zollinger-Ellison syndrome and developed associated thyroid parafollicular cell hyperplasia and parathyroid chief cell hyperplasia, treated by total gastrectomy and multiple endocrine excisions. These investigative observations demonstrate ectopic loci and associated hyperplasias which support the concept of migration and bizarre potentiality of polypeptide-secreting cells of the foregut. Topics: Adenoma; Adult; Aged; Amines; Child; Decarboxylation; Endocrine System Diseases; Endoderm; Female; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia; Neoplasms; Pancreatic Neoplasms; Parathyroid Diseases; Parathyroid Hormone; Peptides; Stomach Neoplasms; Zollinger-Ellison Syndrome | 1975 |
Proceedings: The distribution of vasoactive intestinal peptide (VIP) in the primate gastrointestinal tract and characterization of VIP from human tumours.
Topics: Animals; Cholecystokinin; Digestive System; Gastrins; Gastrointestinal Hormones; Haplorhini; Humans; Neoplasms; Papio; Peptides; Radioimmunoassay; Secretin | 1973 |
Endocrine and metabolic manifestations of cancer.
Topics: Adrenal Gland Diseases; Endocrine System Diseases; Erythrocytes; Female; Gastrins; Gynecomastia; Hormones, Ectopic; Humans; Hypercalcemia; Hyperplasia; Hyperthyroidism; Hypoglycemia; Male; Malignant Carcinoid Syndrome; Metabolic Diseases; Neoplasms; Neurologic Manifestations; Polycythemia; Prognosis; Puberty, Precocious; Vasopressins | 1972 |
[Gastrin and secretion producing tumors].
Topics: Gastrins; Hormones, Ectopic; Humans; Neoplasms; Secretin; Zollinger-Ellison Syndrome | 1971 |
Zollinger-Ellison syndrome in a patient with multiple carcinoid-islet cell tumors of the duodenum.
Topics: Adenoma, Islet Cell; Adult; Carcinoid Tumor; Diagnosis, Differential; Duodenal Neoplasms; Gastric Mucosa; Gastrins; Histamine; Humans; Male; Neoplasms; Peptic Ulcer; Postoperative Complications; Radiography; Serotonin; Tissue Extracts; Zollinger-Ellison Syndrome | 1968 |
Secretion of various endocrine substances by ACTH-secreting tumors--gastrin, melanotropin, norepinephrine, serotonin, parathormone, vasopressin, glucagon.
Topics: Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Female; Gastrins; Glucagon; Humans; Male; Melanocyte-Stimulating Hormones; Middle Aged; Neoplasms; Norepinephrine; Parathyroid Hormone; Serotonin; Vasopressins | 1968 |
Ectopic production of multiple hormones (ACTH, MSH and gastrin) by a single malignant tumor.
Topics: ACTH Syndrome, Ectopic; Adenoma, Islet Cell; Adrenocorticotropic Hormone; Adult; Fatal Outcome; Female; Gastrins; Humans; Islets of Langerhans; Melanocyte-Stimulating Hormones; Neoplasms; Neuroendocrine Tumors; Pancreatic Neoplasms | 1965 |
ISLET-CELL CARCINOMA (ZOLLINGER-ELLISON SYNDROME) WITH FULMINATING ADRENOCORTICAL HYPERFUNCTION AND HYPOKALEMIA.
The production of ACTH-like material by tumours arising in non-endocrine tissue may initiate severe adrenocortical hyperfunction. The pathogenesis and clinical and laboratory features of Cushing's syndrome associated with such tumours are characteristic. The autonomous production by the tumour of ACTH-like material cannot be suppressed by exogenous corticoids. The onset of clinical symptoms is rapid; muscle wasting, general weakness, thirst and peripheral edema predominate, and the classical signs of Cushing's syndrome may be absent. High levels of plasma 17-hydroxycorticosteroids and urinary 17-hydroxycorticosteroids and 17-ketosteroids, usually with normal levels of urinary aldosterone, commonly occur. Hypokalemic alkalosis unresponsive to replacement therapy may cause death. In the case reported herein, the intriguing possibility exists that two hormone-like substances were produced by the primary growth and its metastases: one, ACTH-like, to account for the adrenal hyperplasia and Cushing's syndrome; and another, gastrin-like, giving rise to the ulcerogenic diathesis. Topics: 17-Hydroxycorticosteroids; 17-Ketosteroids; Adenoma, Islet Cell; Adrenalectomy; Adrenocortical Hyperfunction; Autopsy; Carcinoma, Islet Cell; Chloramphenicol; Cushing Syndrome; Drug Therapy; Gastrins; Humans; Hypokalemia; Neoplasm Metastasis; Neoplasms; Pancreatic Neoplasms; Pathology; Spironolactone; Zollinger-Ellison Syndrome | 1965 |
WATERY DIARRHOEA AND AN ISLET CELL TUMOUR.
It is suggested that there are two hormonal syndromes associated with noninsulin-secreting islet cell tumours and this case is an example of the non-gastrin-secreting type with watery diarrhoea and hypokalaemia. The patient had histamine-fast achlorhydria and a normal gastric biopsy and no gastrin was recovered from the tumour tissue. The watery diarrhoea was isosmotic with plasma and was increased by an intravenous saline load. There was a dramatic response to steroids. Topics: Achlorhydria; Adenoma, Islet Cell; Aldosterone; Cortisone; Dexamethasone; Diarrhea; Feces; Gastrins; Humans; Hypocalcemia; Hypokalemia; Neoplasms; Pancreatic Neoplasms; Potassium; Prednisone; Sodium; Surgical Procedures, Operative; Urine; Water-Electrolyte Balance; Zollinger-Ellison Syndrome | 1964 |
GASTRIN ACTIVITY OF TUMOUR TISSUEIN A CHILD WITH THE ZOLLINGER-ELLISON SYNDROME.
Topics: Child; Gastrins; Humans; Liver Neoplasms; Neoplasms; Pancreatic Neoplasms; Pathology; Zollinger-Ellison Syndrome | 1963 |
Zollinger-Ellison syndrome in a Bantu woman, with isolation of a gastrin-like substance from the primary and secondary tumors. II. Extraction of gastrin-like activity from tumors.
Topics: Adenoma, Islet Cell; Gastric Juice; Gastrins; Gastrointestinal Hormones; Humans; Neoplasms; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome | 1961 |