cholecystokinin and Pancreatic-Neoplasms

Topics: Animals; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Cholecystokinin; Drug Resistance, Neoplasm; Humans; Immune Checkpoint Inhibitors; Insulin-Secreting Cells; Mice; Mutation; Neoplasm Recurrence, Local; Obesity; Pancreatic Neoplasms; Risk Factors

The gastrointestinal peptide cholecystokinin (CCK) causes the release of pancreatic digestive enzymes and growth of the normal pancreas. Exogenous CCK administration has been used in animal models to study pancreatitis and also as a promoter of carcinogen-induced or Kras-driven pancreatic cancer. Defining CCK receptors in normal human pancreas has been problematic because of its retroperitoneal location, high concentrations of pancreatic proteases, and endogenous RNase. Most studies indicate that the predominant receptor in human pancreas is the CCK-B type, and CCK-A is the predominant form in rodent pancreas. In pancreatic cancer cells and tumors, the role of CCK is better established because receptors are often overexpressed by these cancer cells and stimulation of such receptors promotes growth. Furthermore, in established cancer, endogenous production of CCK and/or gastrin occurs and their actions stimulate the synthesis of more receptors plus growth by an autocrine mechanism. Initially it was thought that the mechanism by which CCK served to potentiate carcinogenesis was by interplay with inflammation in the pancreatic microenvironment. But with the recent findings of CCK receptors on early PanIN (pancreatic intraepithelial neoplasia) lesions and on stellate cells, the question has been raised that perhaps CCK actions are not the result of cancer but an early driving promoter of cancer. This review will summarize what is known regarding CCK, its receptors, and pancreatic cancer, and also what is unknown and requires further investigation to determine which comes first, the chicken or the egg, "CCK or the cancer."

Topics: Animals; Cholecystokinin; Disease Progression; Humans; Mice; Pancreatic Neoplasms; Rats; Receptors, Cholecystokinin; Signal Transduction

The gastrointestinal peptide hormones gastrin and cholecystokinin (CCK) are well known for their ability to stimulate gastric acid secretion and pancreatic enzyme secretion, respectively. The suggestion that gastrin and CCK might also promote the development of cancers of the gastrointestinal tract has been controversial, but an increasing body of evidence now supports the view that the amidated and non-amidated forms of gastrin act as growth factors via different receptors in different regions of the gut. For example, animal experiments indicate that amidated gastrins are involved in cellular differentiation and repair in the gastric mucosa, and synergize with Helicobacter pylori infection in the development of gastric carcinoma. In contrast, non-amidated gastrins stimulate colonic mucosal growth, accelerate the early steps in colorectal carcinoma formation, and are elevated in the tumour and circulation of patients with colorectal cancer. Although human pancreatic carcinomas express CCK-1 and CCK-2 receptors, the role of gastrins and CCK in pancreatic carcinogenesis is yet to be established. Further investigation of the possible role of the CCK-2 receptor in gastric and pancreatic neoplasia, and of the hypothesis that gastrin precursors act as autocrine growth factors in colorectal carcinoma, is warranted. However, therapies aimed at the gastrins must be targeted to the relevant gastrin/gastrin receptor combination.

Topics: Cholecystokinin; Colorectal Neoplasms; Gastrins; Gastrointestinal Neoplasms; Humans; Pancreatic Neoplasms; Receptors, Cholecystokinin; Stomach Neoplasms; Tumor Cells, Cultured

Pancreatic secretion can be influenced by cholecystokinin (CCK) either directly via actions on acinar cells or indirectly via actions on nerves. The presence and functional roles of CCK receptors on human pancreatic acinar cells remains unclear. In the current study human pancreatic acini were isolated and then treated with CCK-8, gastrin and/or carbachol. Functional parameters were measured including intracellular [Ca2+] and amylase secretion. It was observed that human acini did not respond to CCK agonists but did respond to carbachol with robust increases in functional parameters. Adenoviral-mediated gene transfer of CCK1 or CCK2 receptors to the human cells resulted in cell responses to CCK agonists. In order to determine the reason for the lack of responsiveness of the human acini, expression of receptor mRNAs was determined using quantitative RT-PCR and localized by in situ hybridization. mRNA levels for CCK1 receptors were approximately 30 times lower than those of CCK2 receptors, which were approximately 10 times lower than those of m3 Ach receptors as measured by quantitative PCR. Neither CCK1 nor CCK2 receptors were localized in adult human pancreas by in situ hybridization. These results indicate that human pancreatic acinar cells do not respond directly to CCK receptor activation and this is likely due to an insufficient level of receptor expression.

Topics: Amylases; Carcinoma, Acinar Cell; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization; Pancreatic Neoplasms; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction; Sincalide

In this paper the possible roles of cholecystokinin (CCK), gastrin, or gastrin-related peptides and their receptors in human gastrointestinal diseases are reviewed. For CCK/CCK(A) receptors (CCK(A)-R), the evidence for their proposed involvement in diseases caused by impaired CCK release or CCK(A)-R mutations, pancreatic disorders (acute/chronic pancreatitis), gastrointestinal motility disorders (gallbladder disease, irritable bowel syndrome), pancreatic tumor growth and satiety disorders, is briefly reviewed. The evidence that has established the involvement of gastrin/CCK(B)-R in mediating the action of hypergastrinaemic disorders, mediating hypergastrinaemic effects on the gastric mucosa (ECL hyperplasia, carcinoids, parietal cell mass), and acid-peptic diseases, is reviewed. The evidence for their possible involvement in mediating growth of gastric and pancreatic tumours and possible involvement of gastrin-related peptides in colon cancers, is reviewed briefly.

Topics: Animals; Cholecystokinin; Gastrins; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Neoplasms; Humans; Pancreatic Neoplasms; Receptors, Cholecystokinin

Gastrointestinal peptides including mammalian bombesin-like peptides, cholecystokinin (CCK), gastrin, and neurotensin stimulate DNA synthesis and cell proliferation in cultured cells and are implicated as growth factors in a number of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation. These agonists bind to G protein-coupled receptors (GPCRs) that promote Galpha q-mediated activation of beta isoforms of phospholipase C to produce two second messengers: Inositol (1,4,5) trisphosphate {Ins (1, 4, 5) P3} that mobilises Ca2+ from internal stores, and diacylglycerol that activates the classic and new isoforms of the protein kinase C (PKC) family. PKCs play a critical part in transducing bombesin/gastrin releasing peptide (GRP) receptor signals into activation of protein kinase cascades. Protein kinase D (PKD), a serine/threonine protein kinase with distinct structural and enzymological properties, is activated by phosphorylation in living cells through a new PKC-dependent signal transduction pathway. GPCR agonists including bombesin/GRP induce a rapid and striking activation of PKD by PKC. These results indicate that PKD functions downstream from PKCs and identify a new phosphorylation cascade that is activated by gastrointestinal peptide agonists. The bombesin/GRP GPCR also promotes rapid Rho-dependent assembly of focal adhesions, formation of actin stress fibres and tyrosine phosphorylation of multiple cellular proteins. We identified p125 focal adhesion kinase (FAK), p130 Crk-associated substrate (CAS) and paxillin as prominent targets of gastrointestinal peptide-stimulated tyrosine phosphorylation and developed a model that envisages a G12/Rho-dependent pathway connecting GPCR activation to the tyrosine phosphorylation of these focal adhesion proteins. Separate pathways mediate gastrointestinal peptide stimulation of additional tyrosine kinase pathways including transactivation of Src and epidermal growth factor receptor (EGFR). Tyrosine phosphorylation has a critical role in gastrointestinal peptide-induced cellular migration and cooperates with Gq-stimulated events to promote mitogenesis. The growth-promoting effects of neuropeptides and the elucidation of the signalling pathways that mediate their effects assume an added importance because these agonists and their receptors are increasingly implicated in sustaining the proliferation of clinically aggressive solid tumours including those from lu

Topics: Animals; Bombesin; Carcinoma, Small Cell; Cholecystokinin; Colonic Neoplasms; ErbB Receptors; Gastrins; Humans; Lung Neoplasms; Mice; Neuropeptides; Neurotensin; Pancreatic Neoplasms; Phosphorylation; Protein Kinase C; Receptors, Leukotriene B4; Receptors, Purinergic P2; rho GTP-Binding Proteins; Signal Transduction; Swiss 3T3 Cells

Several gastrointestinal (GI) hormones, such as gastrin, cholecystokinin, and bombesin, have been reported to affect the development of pancreatic cancer. The receptors for these hormones are found in normal and neoplastic pancreatic cells. Activation of these receptors enhances pancreatic carcinogenesis and promotes the growth of established pancreatic carcinoma either in vitro or in vivo. On the other hand, some studies have shown that these GI hormones may have no effect or may play an inhibitory role in the development of pancreatic cancer. The reasons for the apparent discrepancies in the published literature are discussed in this review. In recent years, increasing emphasis has been placed on the effects of GI hormones on cancer invasion and metastasis. As the transition from noninvasion to the invasive state is the crucial event in cancer development, further investigation of the way in which GI hormones affect the invasion and metastasis of pancreatic cancer may be important for the development of new therapeutic approaches with eventual clinical utility.

Topics: Animals; Bombesin; Carcinogens; Cholecystokinin; Cricetinae; Gastrins; Gastrointestinal Hormones; Humans; Lymphatic Metastasis; Pancreas; Pancreatic Neoplasms; Rats; Risk Assessment; Sensitivity and Specificity; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Cholecystokinin; Digestive System Diseases; Gastrointestinal Hormones; Glucagon; Glucagonoma; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Somatostatinoma; Vipoma; Zollinger-Ellison Syndrome

Topics: Animals; Cholecystokinin; Female; Humans; In Vitro Techniques; Male; Pancreas; Pancreatic Neoplasms; Receptors, Cholecystokinin; RNA, Messenger; Tumor Cells, Cultured

Topics: Animals; Cholecystokinin; Humans; Pancreatic Neoplasms

Topics: Androgens; Cholecystokinin; Drug Evaluation; Estrogens; Gonadal Steroid Hormones; Humans; Pancreatic Neoplasms; Protein Binding; Receptors, Estrogen; Sex Hormone-Binding Globulin; Tamoxifen

The gut hormone cholecystokinin exerts various actions on the gastrointestinal tract, including the regulation of growth. The hormone has been reported to induce hypertrophy and hyperplasia of the pancreas and to enhance chemically-induced pancreatic carcinogenesis in animals. Stimulation of endogenous cholecystokinin secretion through the induction of deficiency of intraintestinal proteases and bile salts by trypsin-inhibiting nutrients, bile salt-binding drugs or surgical intervention is also capable of stimulating growth and tumour development in the rat. In man, factors suggested to increase the risk of pancreatic cancer, such as a high-fat and high-protein diet or gastrectomy, are known to stimulate plasma cholecystokinin secretion. Receptors for cholecystokinin have been demonstrated on human pancreatic adenocarcinomas, and cholecystokinin has been demonstrated to enhance the growth of xenografted pancreatic cancer and to inhibit growth of gastric and bile duct cancer. The recently developed cholecystokinin-receptor antagonists inhibit not only pancreatic growth but also pancreatic carcinogenesis in animals. These new drugs may be valuable new tools for inhibiting pancreatic cancer growth in humans.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Biliary Tract Neoplasms; Cholecystokinin; Gastrointestinal Neoplasms; Humans; Pancreatic Neoplasms

Topics: APUD Cells; Apudoma; Cholecystokinin; Endocrine Glands; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Humans; Neurotransmitter Agents; Pancreatic Neoplasms; Peptides; Secretin

Gastrointestinal hormones (GI hormones) have received growing interest in endocrinology, gastroenterology and neuroendocrinology. Because of new methodological techniques, they can be measured in plasma and therefore be related to different pathophysiological conditions. In childhood, our present knowledge is as yet limited to the physiological rôle of gastrin at different ages and in some diseases (gastrinoma; Verner-Morrison syndrome) caused by humoral dysfunction. The present review relates the clinical important GI hormones to chemically classified families. The diagnostic value of determining endogenous hormone concentration in plasma and the validity of function tests carried out by administration of exogenous hormones are pointed out. Particular emphasis is given to the trophic action of GI hormones in the development and function of the gastrointestinal tract during childhood. More speculatively, GI hormones are involved in the complex function of the central nervous system, thus making food intake a trophotropic action in a broader sense.

Topics: Adenoma, Islet Cell; Bombesin; Ceruletide; Child; Cholecystokinin; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Motilin; Neurotensin; Pancreatic Neoplasms; Pancreatic Polypeptide; Secretin; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Chenodeoxycholic Acid; Cholecystokinin; Cholelithiasis; Dehydration; Diabetes Mellitus; Duodenal Ulcer; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Humans; Motilin; Pancreatic Neoplasms; Secretin; Syndrome; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

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

Topics: Biopsy; Carcinoembryonic Antigen; Celiac Artery; Cholangiography; Cholecystokinin; Lactoferrin; Laparoscopy; Mesenteric Arteries; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Radionuclide Imaging; Secretin; Tomography, X-Ray Computed; Ultrasonography

Topics: Amylases; Bicarbonates; Biliary Tract Diseases; Carbohydrate Metabolism; Child; Cholecystokinin; Chymotrypsin; Duodenum; Feces; Humans; Lipase; Methods; Pancreas; Pancreatic Diseases; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatitis; Radiography; Secretin; Trypsin

Topics: Abdomen; Biopsy; Carcinoma, Intraductal, Noninfiltrating; Celiac Disease; Cholecystokinin; Diabetes Mellitus; Hepatomegaly; Humans; Jaundice; Laparotomy; Mental Disorders; Pain; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Prednisolone; Prognosis; Radioisotopes; Radionuclide Imaging; Secretin; Selenium

Tumoral secretions and pathophysiology of diarrhea were studied in 1 patient with pancreatic cholera. High concentrations of vasoactive intestinal peptide were found in both systemic blood and tumoral extracts, together with increased plasma levels of calcitonin and protaglandins E and Falpha. Gastric inhibitory peptide and gastrointestinal and pancreatic hormones were absent from the tumor, except for small amounts of glucagon, and their blood levels were normal. Decreased basal but normal pentagastrin-stimulated gastric acid secretion, normal basal and secretin-stimulated pancreatic secretion, increased volume of gallbladder bile with high bicarbonate, and low bile salt concentrations were observed, but the electrolyte content and flow rate of fluid passing the duodenojejunal junction were within normal limits. Small intestine was found to be the origin of the water and electrolyte fasting losses. Jejunum was the site of bicarbonate secretion. Jejunal glucose and leucine-stimulated water and sodium transports were also strikingly decreased, whereas the absorption rates of the sugar and amino acid were normal. Colon reabsorbed high amounts of water and sodium but increased potassium losses. Biological effects of vasoactive intestinal peptide may explain most of the patient's upper digestive secretion abnormalities and small intestinal function impairments, whereas secondary aldosteronism might explain the modified colonic function.

Topics: Adult; Bile; Blood Vessels; Calcitonin; Cholecystokinin; Cholera; Colon; Depression, Chemical; Diarrhea; Duodenum; Feces; Female; Gastric Mucosa; Gastrins; Glucagon; Humans; Ileostomy; Insulin; Insulin Secretion; Intestinal Secretions; Intestine, Small; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Peptides; Prostaglandins E; Prostaglandins F; Secretin; Stomach

Topics: Achlorhydria; Acute Kidney Injury; Adenoma, Islet Cell; Adult; Cholecystokinin; Dehydration; Diarrhea; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Hypercalcemia; Hypokalemia; Kidney Diseases; Male; Pancreatic Neoplasms; Protein Precursors; Secretin; Syndrome; Zollinger-Ellison Syndrome

Topics: Age Factors; Amylases; Angiography; Cholecystokinin; Colic; Diabetes Complications; Diagnosis, Differential; Emaciation; Germany, West; Humans; Jaundice; Pancreatic Cyst; Pancreatic Neoplasms; Pancreatitis; Portography; Secretin

Topics: Animals; Biogenic Amines; Carcinoid Tumor; Cholecystokinin; Chromaffin System; Diabetes Mellitus; Digestive System; Digestive System Physiological Phenomena; Gastric Juice; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon; Humans; Insulin; Insulin Secretion; Intestines; Pancreas; Pancreatic Neoplasms; Peptic Ulcer; Secretin; Syndrome

Topics: Amylases; Celiac Disease; Cholecystokinin; Duodenum; Fasting; Food; Food Analysis; Humans; Intubation, Gastrointestinal; Liver Diseases; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Secretin; Time; Trypsin

Topics: Anticonvulsants; Cholecystokinin; Chronic Disease; Humans; Oxazoles; Pancreas; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin; Trimethadione

Topics: Acute Disease; Adenoma, Islet Cell; Cholecystokinin; Chronic Disease; Gastrins; Humans; Methods; Pancreas; Pancreas Transplantation; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Radiography; Secretin; Transplantation, Homologous; Zollinger-Ellison Syndrome

Apart from smoking, known risk factors for the development of pancreatic carcinoma are few, gastric resection being proposed as one. The trophic effect of cholecystokinin (CCK) on the pancreatic gland is well known from animal experience and increased concentrations of CCK in plasma have been shown to induce pancreatic neoplasia experimentally. In several studies the release of CCK in response to food ingestion has been shown to be increased following gastric surgery. However, in those studies, the time between surgery and investigation of the CCK response was short, and methods of CCK analysis have since improved.. In patients, partially gastrectomized 8 years (median) earlier, we studied the plasma concentrations of CCK, insulin and gastrin, as well as some specific pancreatic enzymes. The findings were compared to an age-matched control group of individuals not subjected to gastric surgery.. Basal CCK concentrations in the operated group were found to be lower, but increased postprandially to the same level as in controls. Serum levels of specific pancreatic enzymes were equal in the 2 groups.. It is possible that a disturbed regulation of pancreatic secretion, or a secretory dysfunction within the gland, following partial gastrectomy, could contribute to the development of pancreatic carcinoma. However, our findings do not favor the idea of plasma CCK as a promotor of pancreatic carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Cholecystokinin; Cohort Studies; Female; Gastrectomy; Gastrins; Humans; Insulin; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Postoperative Period; Radioimmunoassay; Reference Values; Sensitivity and Specificity

The effect of a cyclic versus a continuous enteral feeding protocol on postoperative delayed gastric emptying, start of normal diet, and hospital stay was assessed in patients undergoing pylorus-preserving pancreatoduodenectomy (PPPD).. Delayed gastric emptying occurs in approximately 30% of patients after PPPD and causes prolonged hospital stay. Enteral nutrition through a catheter jejunostomy is used to provide postoperative nutritional support. Enteral infusion of fats and proteins activates neurohumoral feedback mechanisms and therefore can potentially impair gastric emptying and prolong postoperative gastroparesis.. From September 1995 to December 1996, 72 consecutive patients underwent PPPD at the Academic Medical Center, Amsterdam. Fifty-seven patients were included and randomized for either continuous (CON) jejunal nutrition (0-24 hr; 1500 kCal/24 hr) or cyclic (CYC) enteral nutrition (6-24 hr; 1125 kCal/18 hr). Both groups had an equal caloric load of 1 kCal/min. The following parameters were assessed: days of nasogastric intubation, days of enteral nutrition, days until normal diet was tolerated orally, and hospital stay. On postoperative day 10, plasma cholecystokinin (CCK) levels were measured during both feeding protocols.. Nasogastric intubation was 9.1 days in the CON group (n = 30) and 6.7 days in the CYC group (n = 27) (not statistically significant). First day of normal diet was earlier for the CYC group (15.7 vs. 12.2 days, p < 0.05). Hospital stay was shorter in the CYC group (21.4 vs. 17.5 days, p < 0.05). CCK levels were lower in CYC patients, before and after feeding, compared with CON patients (p < 0.05).. Cyclic enteral feeding after PPPD is associated with a shorter period of enteral nutrition, a faster return to a normal diet, and a shorter hospital stay. Continuously high CCK levels could be a cause of prolonged time until normal diet is tolerated in patients on continuous enteral nutrition. Cyclic enteral nutrition is therefore the feeding regimen of choice in patients after PPPD.

Topics: Adult; Aged; Cholecystokinin; Common Bile Duct Neoplasms; Enteral Nutrition; Female; Gastric Emptying; Humans; Intubation, Gastrointestinal; Length of Stay; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Pancreaticoduodenectomy; Postoperative Period; Prospective Studies; Time Factors

MK-329 is a nonpeptidal, highly specific cholecystokinin (CCK) receptor antagonist, with affinity for pancreatic and gallbladder CCK receptors similar to CCK itself. MK-329 and its progenitor, asperlicin, can inhibit the growth of CCK receptor-positive human pancreatic cancer in athymic mice. Based on these activities and the ability of MK-329 to transiently increase food intake and enhance morphine analgesia in murine models, we conducted an open trial of MK-329 in 18 patients with advanced pancreatic cancer in whom the CCK receptor status of the tumors was unknown. Tumor response, pain control, and nutritional parameters (hunger rating, caloric intake, body weight, and anthropometrics) were serially assessed. The results of the study failed to demonstrate any impact of MK-329 on tumor progression, pain, or nutrition. Toxicity was mild and limited to nausea, vomiting, diarrhea, and abdominal cramps, with 17 of 18 patients able to tolerate treatment. While a role for MK-329 in the management of patients with advanced pancreatic cancer cannot be supported by the results of this trial, additional studies of this agent in patients with known CCK receptor-positive tumors, at escalated doses, and possibly in conjunction with other growth antagonists, appear warranted.

Topics: Adenocarcinoma; Adult; Aged; Analgesia; Benzodiazepinones; Cholecystokinin; Devazepide; Female; Humans; Male; Middle Aged; Nutritional Physiological Phenomena; Pancreatic Neoplasms; Receptors, Cholecystokinin

Topics: Androgens; Cholecystokinin; Drug Evaluation; Estrogens; Gonadal Steroid Hormones; Humans; Pancreatic Neoplasms; Protein Binding; Receptors, Estrogen; Sex Hormone-Binding Globulin; Tamoxifen

In a study to determine the effect of saturation of fats on their ability to stimulate cholecystokinin (CCK) release six normal volunteers ate five test meals containing different fats with intervals of 1 week. Plasma CCK levels were measured by a specific radioimmunoassay and the gallbladder volume was calculated from ultrasound measurements. The sodium salt of the monounsaturated fatty acid oleic acid (3.5 g) produced a significantly greater integrated CCK response than that of the saturated fatty acid stearic acid (mean [SEM] 103 [41] vs 8[41] pmol.l-1.min). The gallbladder contracted to 42 (3)% of its initial volume after oleate but remained at 89 (8)% of its initial volume after stearate. Integrated CCK responses to dietary triglycerides (30 g) also differed significantly according to the degree of saturation--277 (58) pmol.l-1.min after corn oil (predominantly diunsaturated), 143 (14) pmol.l-1.min after olive oil (predominantly monounsaturated), and 44 (12) pmol.l-1.min after suet (predominantly saturated). The finding that unsaturated fats are stronger stimulants of CCK release than saturated fats may explain the promotion of pancreatic carcinogenesis in rats by unsaturated but not saturated fats and may support the role of CCK in this effect.

Topics: Adult; Cholecystokinin; Dietary Fats; Dietary Fats, Unsaturated; Female; Gallbladder; Humans; Male; Oleic Acids; Pancreatic Neoplasms; Stearates; Stimulation, Chemical; Triglycerides

Secretin and cholecystokinin (CCK) have trophic effects on the pancreas and may therefore have a place in the treatment of pancreatic cancer. The present study was performed to examine whether these hormones may cause harm in patients with pancreatic cancer receiving cytostatics. The cytostatics were 5-fluorouracil, adriamycin, and mitomycin C(FAM). Secretin plus Thr28Nle31CCK25-33, in doses stimulating pancreatic secretion to about 60% of maximal, were given as a continuous 6-day intravenous infusion just before (four patients) or immediately after (five patients) starting treatment with FAM. Five patients received FAM only. When considering symptoms, laboratory findings, abdominal CT scans, and survival, no evidence was found that secretin and CCK may cause serious or unpleasant side effects in patients with pancreatic cancer receiving cytostatics.

Topics: Adenocarcinoma; Aged; Alanine Transaminase; Alkaline Phosphatase; Amylases; Antineoplastic Combined Chemotherapy Protocols; Bilirubin; Cholecystokinin; Doxorubicin; Drug Evaluation; Female; Fluorouracil; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Pancreatic Neoplasms; Peptide Fragments; Pilot Projects; Secretin

Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.

Topics: Aged; Blood Glucose; Case-Control Studies; Cholecystokinin; Chromatography, Liquid; Enzyme-Linked Immunosorbent Assay; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Tract; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Glucose Tolerance Test; Humans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pancreatitis; Peptide Fragments; Proteomics; Radioimmunoassay; Tandem Mass Spectrometry

Neuroendocrine tumors in the pancreas and the gastrointestinal tract may secrete hormones which cause specific syndromes. Well-known examples are gastrinomas, glucagonomas, and insulinomas. Cholecystokinin-producing tumors (CCKomas) have been induced experimentally in rats, but a CCKoma syndrome in man has remained unknown until now.. Using a panel of immunoassays for CCK peptides and proCCK as well as for chromogranin A, we have examined plasma samples from 284 fasting patients with gastroenteropancreatic neuroendocrine tumors. In hyperCCKemic samples, plasma CCK was further characterized by chromatography.. One of the patients displayed gross hyperCCKemia. She was a 58-year old woman with a pancreatic endocrine tumor, liver metastases, 500-1000-fold elevated basal CCK concentration in plasma, diarrhea, severe weight loss, recurrent peptic ulcer and bilestone attacks from a contracted gallbladder. The CCK concentrations in plasma were not affected by resection of the pancreatic tumor, but decreased to normal after hemihepatectomy with removal of the metastases.. A CCKoma syndrome with severe hypersecretion of CCK exists in man. The duodenal ulcer disease and diarrhea with permanently low gastrin in plasma suggest that CCKomas may mimic gastrinoma-like symptoms, because CCK peptides are full agonists of the gastrin/CCK-B receptor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Child; Cholecystokinin; Denmark; Female; Gastrinoma; Gastrins; Humans; Intestinal Neoplasms; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Pancreas; Pancreatic Neoplasms; Rats; Stomach Neoplasms; Young Adult

The cholecystokinin (CCK) receptor is known as a receptor that is overexpressed in many human tumors. The present study was designed to investigate the targeting ability of cyclic CCK analogue in AR42J pancreatic cells. The CCK analogues, DOTA-K(glucose)-Gly-Trp-Nle-Asp-Phe (DOTA-glucose-CCK) and DOTA-Nle-cyclo(Glu-Trp-Nle-Asp-Phe-Lys-NH2) (DOTA-[Nle]-cCCK), were synthesized and radiolabeled with (177)Lu, and competitive binding was evaluated. The binding appearance of synthesized peptide with AR42J cells was evaluated by confocal microscopy. And bio-distribution was performed in AR42J xenografted mice. Synthesized peptides were prepared by a solid phase synthesis method, and their purity was over 98%. DOTA is the chelating agent for (177)Lu-labeling, in which the peptides were radiolabeled with (177)Lu by a high radiolabeling yield. A competitive displacement of (125)I-CCK8 on the AR42J cells revealed that the 50% inhibitory concentration value (IC50) was 12.3 nM of DOTA-glucose-CCK and 1.7 nM of DOTA-[Nle]-cCCK. Radio-labeled peptides were accumulated in AR42J tumor in vivo, and %ID/g of the tumor was 0.4 and 0.9 at 2 h p.i. It was concluded that (177)Lu-DOTA-[Nle]-cCCK has higher binding affinity than (177)Lu-DOTA-glucose-CCK and can be a potential candidate as a targeting modality for a CCK receptor over-expressing tumors.

Topics: Animals; Cell Line, Tumor; Cholecystokinin; Heterografts; Humans; Lutetium; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Pancreatic Neoplasms; Peptides, Cyclic; Protein Binding; Radioisotopes; Radioligand Assay; Receptors, Cholecystokinin

Obesity and dietary fat are associated with increased risk of several malignancies including pancreatic cancer. The incidence of pancreatic cancer is increased in countries that consume diets high in fat.. The purpose of this study was to assess the relationship and mechanism of action between dietary fat and endogenous cholecystokinin (CCK) on pancreatic tumor growth and metastasis in an immunocompetent animal model.. C57BL/6 mice were placed on regular, low-fat, or high-fat diets for 8 weeks before establishment of Panc-02 orthotopic pancreatic tumors. Mice were then treated with a CCK-A receptor antagonist, devazepide, or vehicle for an additional 2.5 weeks. Pancreas tumors were weighed and metastases counted. Blood CCK levels were measured by radioimmunoassay (RIA). Tissues were examined histologically and studied for genes associated with metastasis by RT-PCR array. Effects of the CCK antagonist on Panc-02 cells invasiveness was assessed in a Matrigel invasion assay.. Mice that received the high-fat diet had larger tumors and tenfold higher serum CCK levels by RIA compared to normal diet controls (p < 0.01). Pancreatic tumors in high-fat diet mice treated with the antagonist had fewer intravascular tumor emboli and metastases compared to controls. The reduction in tumor emboli correlated with decreased vascular endothelial growth factor-A (VEGF-A) expression in tumors (p < 6 × 10(-9)). In vitro invasiveness of Panc-02 cells also was reduced by CCK-A receptor antagonist treatment (p = 1.33 × 10(-6)).. CCK is a mediator of dietary fat-associated pancreatic cancer. CCK is also involved in the invasiveness of pancreatic tumors through a mechanism involving VEGF-A.

Topics: Animals; Blood Glucose; Cell Line, Tumor; Cholecystokinin; Devazepide; Dietary Fats; Dose-Response Relationship, Drug; Embolism; Hormone Antagonists; Male; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Metastasis; Pancreatic Neoplasms; Radioimmunoassay

Exogenous administration of cholecystokinin (CCK) induces hypertrophy and hyperplasia of the pancreas with an increase in DNA content. We hypothesized that endogenous CCK is involved in the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer.. The presence of CCK receptors in early PanIN lesions was examined by immunohistochemistry in mouse and human pancreas. Pdx1-Cre/LSL-Kras transgenic mice were randomized to receive either untreated drinking water or water supplemented with a CCK receptor antagonist (proglumide, 0.1 mg/mL). Pancreas from the mice were removed and examined histologically for number and grade of PanINs after 1, 2, or 4 months of antagonist therapy.. Both CCK-A and CCK-B receptors were identified in early stage PanINs from mouse and human pancreas. The grade of PanIN lesions was reversed, and progression to advanced lesions arrested in mice treated with proglumide compared with the controls (P = 0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared with vehicle (P < 0.001).. These findings demonstrate that endogenous CCK is in part responsible for the development and progression of pancreatic cancer. The use of CCK receptor antagonists may have a role in cancer prophylaxis in high-risk subjects and may reduce fibrosis in the microenvironment.

Topics: Animals; Carcinoma in Situ; Cholecystokinin; Disease Progression; Drug Screening Assays, Antitumor; Fibrosis; Humans; Mice; Mice, Transgenic; Pancreas; Pancreatic Neoplasms; Pancreatitis; Precancerous Conditions; Proglumide; Random Allocation; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B

In the quest for novel tools for early detection and treatment of cancer, we propose the use of multimers targeting overexpressed receptors at the cancer cell surface. Indeed, multimers are prone to create multivalent interactions, more potent and specific than their corresponding monovalent versions, thus enabling the potential for early detection. There is a lack of tools for early detection of pancreatic cancer, one of the deadliest forms of cancer, but CCK2-R overexpression on pancreatic cancer cells makes CCK based multimers potential markers for these cells. In this Letter, we describe the synthesis and evaluation of CCK trimers targeting overexpressed CCK2-R.

Topics: Biomarkers, Tumor; Cholecystokinin; Humans; Pancreatic Neoplasms; Receptors, Cholecystokinin

Topics: Animals; Cholecystokinin; Chromogranin A; Diagnosis, Differential; Fatal Outcome; Female; Gastrins; Humans; Liver; Liver Neoplasms; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

The cholecystokinin-2 receptor (CCK2R), is expressed in cancers where it contributes to tumor progression. The CCK2R is over-expressed in a sub-set of tumors, allowing its use in tumor targeting with a radiolabel ligand. Since discrepancies between mRNA levels and CCK2R binding sites were noticed, we searched for abnormally spliced variants in tumors from various origins having been previously reported to frequently express cholecystokinin receptors, such as medullary thyroid carcinomas, gastrointestinal stromal tumors, leiomyomas and leiomyosarcomas, and gastroenteropancreatic tumors. A variant of the CCK2R coding for a putative five-transmembrane domains receptor has been cloned. This variant represented as much as 6% of CCK2R levels. Ectopic expression in COS-7 cells revealed that this variant lacks biological activity due to its sequestration in endoplasmic reticulum. When co-expressed with the CCK2R, this variant diminished membrane density of the CCK2R and CCK2R-mediated activity (phospholipase-C and ERK activation). In conclusion, a novel splice variant acting as a dominant negative on membrane density of the CCK2R may be of importance for the pathophysiology of certain tumors and for their in vivo CCK2R-targeting.

Topics: Alternative Splicing; Amino Acid Sequence; Animals; Binding Sites; Carcinoma, Medullary; Chlorocebus aethiops; Cholecystokinin; COS Cells; Extracellular Signal-Regulated MAP Kinases; Gastrins; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Insulinoma; Leiomyoma; Leiomyosarcoma; Molecular Sequence Data; Pancreatic Neoplasms; Protein Structure, Tertiary; Receptor, Cholecystokinin B; RNA, Messenger; Signal Transduction; Thyroid Neoplasms; Type C Phospholipases

Cholecystokinin (CCK) and gastrin stimulate growth of pancreatic cancer. Although down-regulation of gastrin inhibits growth of pancreatic cancer, the contribution of endogenous CCK to tumor growth is unknown. The purpose of this study was to evaluate the role of endogenous CCK on autocrine growth of pancreatic cancer. Pancreatic cancer cell lines were analyzed for CCK mRNA and peptide expression by real-time RT-PCR and radioimmunoassay, respectively. The effect of endogenous CCK on growth was evaluated by treating cancer cells with CCK neutralizing antibodies and by down-regulating CCK mRNA by RNAi. Wild-type pancreatic cancer cells expressed significantly lower CCK mRNA and peptide levels than gastrin. Neither treatment of pancreatic cancer cells with CCK antibodies nor the down-regulation of CCK mRNA and peptide by shRNAs altered growth in vitro or in vivo. Conversely, when gastrin mRNA expression was down-regulated, the same cells failed to produce tumors in spite of having sustained levels of endogenous CCK. Pancreatic cancer cells produce CCK and gastrin; however, the autocrine production of gastrin is more important for stimulating tumor growth.

Topics: Adenocarcinoma; Animals; Antibodies, Neutralizing; Autocrine Communication; Cell Line, Tumor; Cell Proliferation; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; RNA, Messenger; RNA, Small Interfering; Tissue Distribution; Xenograft Model Antitumor Assays

To construct eukaryotic expression plasmid of porcine CCK gene pIRES2-EGFP/CCK and express it in COS-7 cells and hamsters. Methods The aimed segments were obtained from intermediate vector pMD18-T/CCK and were inserted into an eukaryotic expression plasmid pIRES2-EGFP to construct a recombinant expression plasmid pIRES2-EGFP/CCK. The recombinant expression plasmid was transfected into COS-7 cells by liposome-mediated gene transfer method and was observed through fluorescence microscope. The plasmid was injected into the skeletal muscle of hamsters directly to detect the expression of the recombinant plasmid in vivo.. A recombinant eukaryotic expression plasmid pIRES2-EGFP/CCK was successfully constructed. Green fluorescent protein could be detected in the transfected COS-7 cells 24, 48, and 72 hours after the transfection. On the 4th day postinjection into the skeletal muscle of hamsters, the protein could be detected at the injection site and the fluorescence intensity became much stronger on the 14th day than that on the 4th day. On the 42nd day the protein level increased. The green fluorescence protein was never expressed in the untransfected cells.. The porcine CCK gene eukaryotic expression plasmid pIRES2-EGFP/CCK is constructed successfully, and is expressed in mammal COS-7 cells and hamsters in vivo. The research paves the way for the cross immunity therapy of hamster pancreatic carcinoma.

Topics: Animals; Base Sequence; Cancer Vaccines; Chlorocebus aethiops; Cholecystokinin; COS Cells; Cricetinae; Eukaryotic Cells; Green Fluorescent Proteins; Molecular Sequence Data; Muscle, Skeletal; Pancreatic Neoplasms; Plasmids; Recombinant Fusion Proteins; Swine; Transfection

Protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) have been implicated in the effects of regulatory peptides on proliferation. We studied how ERK was activated by PKC following regulatory peptide or phorbol ester stimulation and we also investigated the effect of ERK activation on proliferation in Panc-1 cells. Panc-1 cells transfected with CCK1 receptors were treated with cholecystokinin (CCK), neurotensin (NT), or phorbol 12-myristate 13-acetate (PMA). DNA synthesis was studied by measuring tritiated thymidine incorporation. PKC isoforms were selectively inhibited with Gö6983 and 200 nM Ro-32-0432, their translocation was detected by confocal microscopy and by subcellular fractionation followed by immunoblotting. ERK cascade activation was detected with phosphoERK immunoblotting and inhibited with 20 microM PD98059. PMA and CCK inhibited, NT stimulated DNA synthesis. These effects were inhibited by Ro-32-0432 but not by Gö6983 suggesting the involvement of PKCepsilon in proliferation control. Confocal microscopy and subcellular fractionation demonstrated that PMA, CCK, and NT caused cytosol to membrane translocation of PKCepsilon and ERK activation that was inhibited by Ro-32-0432 but not by Gö6983. ERK activation was prolonged following PMA and CCK, but transient after NT treatment. PMA, CCK, and NT all activated cyclinD1, while p21CIP1 expression was increased by only PMA and CCK, but not by NT; each of these effects is inhibited by PD98059. In conclusion, our results provide evidence for PKCepsilon-mediated differential ERK activation and growth regulation in Panc-1C cells. Identification of the mechanisms by which these key signaling pathways are modulated could provide a basis for the development of novel therapeutic interventions to treat pancreatic cancer.

Topics: Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cholecystokinin; DNA; Extracellular Signal-Regulated MAP Kinases; Humans; Neurotensin; Pancreatic Neoplasms; Phorbol Esters; Protein Kinase C; Protein Kinase C-epsilon; Signal Transduction; Tetradecanoylphorbol Acetate; Transfection

To study the therapeutic effect of recombinant plasmid pcDNA3.1/CCK containing porcine gene of cholecystokinin (CCK).. The confirmed fragments of porcine CCK cDNA were cloned into the pcDNA3.1 vector. Recombinant plasmid pcDNA3.1/CCK was injected into the muscles of Syrian golden hamsters. Before gene transfer, orthotopic tumor model and liver metastasis model of hamster pancreatic cancer have been established by injection of 1 x 10(6) PGHAM-1 cells into the pancreas and spleen of golden hamsters. Then the CCK expression in vivo and the tumor inhibiting effect were analyzed.. Our data revealed that recombinant plasmid pcDNA3.1/CCK had long-term expression in hamsters and induced generation of specific antibody. Antibody level correlated with the number of inoculations. Compared to the control, significant reduction in tumor volume, decrease in number of liver metastasis and a remarkable enhancement of survival rate were detected.. Intramuscular injection of recombinant plasmid pcDNA3.1/CCK has significant antitumor and antimetastatic effect in vivo.

Topics: Animals; Antibodies; Apoptosis; Cell Proliferation; Cholecystokinin; Cricetinae; Female; Gene Expression; Genetic Therapy; Injections; Liver Neoplasms; Muscle, Skeletal; Pancreatic Neoplasms; Plasmids; RNA, Messenger; Swine; Xenograft Model Antitumor Assays

We showed previously that cholecystokinin (CCK)-induced 70-kd S6 kinase activation is partly mediated by protein kinase C (PKC) in pancreatic acinar AR42J cells. Here, we examined which isoform of PKC is involved in this process.. AR42J cells were infected with adenovirus vectors carrying the kinase-deficient alpha, delta, and epsilon isoforms of PKC, the dominant-negative form of the 85-kd regulatory subunit of phosphatidylinositol (PI) 3-kinase, and the dominant-negative form of Sos. CCK-induced p70 S6 kinase activation was determined in AR42J cells infected with these adenovirus vectors.. CCK-induced p70 S6 kinase activity was significantly reduced in cells overexpressing the dominant-negative p85 subunit of PI 3-kinase but not in cells overexpressing dominant-negative Sos or beta-galactosidase. CCK-induced p70 S6 kinase activity was inhibited in parallel with the expression levels of kinase-deficient PKCalpha, whereas it was unaffected by the expression of kinase-deficient PKCdelta or PKCepsilon.. PKCalpha is implicated in CCK-induced activation of p70 S6 kinase in AR42J cells.

Topics: Adenoviridae; Animals; Cholecystokinin; Enzyme Activation; Gene Expression; Mutagenesis; Pancreas, Exocrine; Pancreatic Neoplasms; Protein Kinase C-alpha; Rats; Ribosomal Protein S6 Kinases, 70-kDa; Tumor Cells, Cultured

To investigate the effects of gastrin and cholecystokinin (CCK) and their specific antagonists on the growth of pancreatic and biliary tract cancer cell lines.. Five pancreatic and 6 biliary cancer cell lines with 2 conrtol cells were used in this study. Cell proliferation study was done using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test and direct cell count method. Reverse transcription-polymerase chain reaction (RT-PCR) and slot blot hybridization were performed to examine and quantify the expression of hormonal receptors in these cell lines.. SNU-308 showed a growth stimulating effect by gastrin-17, as did SNU-478 by both gastrin-17 and CCK-8. The trophic effect of these two hormones was completely blocked by specific antagonists (L-365, 260 for gastrin and L-364, 718 for CCK). Other cell lines did not respond to gastrin or CCK. In RT-PCR, the presence of CCK-A receptor and CCK-B/gastrin receptor mRNA was detected in all biliary and pancreatic cancer cell lines. In slot blot hybridization, compared to the cell lines which did not respond to hormones, those that responded to hormones showed high expression of receptor mRNA.. Gastrin and CCK exert a trophic action on some of the biliary tract cancers.

Topics: Biliary Tract Neoplasms; Cell Count; Cell Division; Cell Line, Tumor; Cholecystokinin; Gastrins; Hormone Antagonists; Humans; Pancreatic Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; Tetrazolium Salts; Thiazoles

Gastrin and cholecystokinin (CCK) have trophic action on cells expressing wild type A or B CCK receptors. Potential relevance to pancreatic and colonic cancers was raised by the demonstration of a misspliced type B CCK receptor that, when expressed in Balb3T3 cells, had constitutive activity to stimulate intracellular calcium. We attempted to confirm and extend this observation in CHO cells by establishing lines expressing similar densities of variant or wild type B CCK receptor. While both were capable of normal binding and agonist-induced signaling, neither expressed constitutive signaling and both had similar basal growth. Agonist stimulation of cells expressing misspliced receptor had greater increases in calcium and greater growth rates than control cells despite similar MAP kinase phosphorylation responses. Thus, this variant receptor can potentiate peptide-stimulated signaling and trophic action and may contribute to the proliferation of neoplasms expressing it.

Topics: Alternative Splicing; Animals; Binding, Competitive; Cell Proliferation; CHO Cells; Cholecystokinin; Colonic Neoplasms; Cricetinae; Cricetulus; Gastrins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mutation; Pancreatic Neoplasms; Phosphorylation; Receptor, Cholecystokinin B; RNA, Messenger; Transfection

Organ-preserving surgery, such as pylorus-preserving pancreatoduodenectomy (PPPD), duodenum-preserving pancreatic head resection (DPPHR), or medial pancreatectomy (MP), is one of the recent advances in pancreatic surgery. There was a previous report that preservation of the duodenum maintained pancreatic function. However, concerning the resected pancreas, patients were divided into two groups; one group included pancreatic head resections such as Whipple, PPPD, and complete DPPHR, and the other group included MP that removed only the pancreatic neck and preserved the pancreatic head and distal pancreas. The present study was designed to clarify the significance of duodenum preservation, in comparison with duodenum removal, in patients with pancreatic head resection, in terms of pancreatic function, determined by a pancreatic function diagnostant (PFD) test and cholecystokinin (CCK) secretion.. The subjects were 61 patients (10 with Whipple, 41 with PPPD, and 10 with complete DPPHR). PFD tests and postprandial plasma CCK secretion were used for evaluation.. There was a significant difference between pre- and postoperative PFD values in the patients who received Whipple or PPPD; however, there was no difference in those who had complete DPPHR. Concerning the postoperative PFD value, complete DPPHR was superior to Whipple and PPPD. Regarding postprandial CCK secretion, the pre- and postoperative values were significantly different in the patients with Whipple or PPPD, but there was no difference in those with complete DPPHR. Comparing the three kinds of operations, complete DPPHR was superior to the other two procedures in its maintenance of pancreatic function. There was the significant correlation between CCK and PFD in our patients in the Spearman Rank Correlation (P < 0.0029) and Fisher's r to z (P < 0.0058).. When pre- and postoperative pancreatic exocrine function and postprandial CCK secretion were measured in patients with pancreatic head resection, it was found that preservation of the entire duodenum was an important factor for maintaining pancreatic function.

Topics: Cholecystokinin; Duodenum; Female; Humans; Male; Middle Aged; Pancreas, Exocrine; Pancreatectomy; Pancreatic Function Tests; Pancreatic Neoplasms

To construct eukaryotic expression plasmid of porcine CCK gene pIRES2-EGFP/ CCK and express it in COS-7 cells and hamsters.. The aimed segments were obtained from intermediate vector pMD18-T/CCK by the method of restricted enzymatic resection and were inserted into a eukaryotic expression plasmid pIRES2-EGFP to construct a recombinant expression plasmid pIRES2-EGFP/CCK. The recombinant expression plasmid was transfected into COS-7 cells by liposome-mediated gene transfer method and observed through Fluorescence microscopy. The plasmid was injected into the skeletal muscle of hamsters directly to detect the expression of the recombinant plasmid in vivo.. A recombinant eukaryotic expression plasmid pIRES2-EGFP/CCK was successfully constructed. Green fluorescent protein could be detected in the transfected COS-7 cells 24, 48, and 72 hours post transfection and the expression of green fluorescent protein reached its peak 72 h post transfection. The green fluorescent protein could be detected at the injection site on the 4th day post injection and the fluorescence intensity became stronger on the 14th day. The level of fluorescence became ever stronger on the 42nd day. No expression of green fluorescence was detected in the control group.. Porcine CCK cDNA eukaryotic expression plasmid pIRES2-EGFP/CCK has been successfully constructed and expressed in mammal cells COS-7 and hamster in vivo. The research paved the way for cross immunity therapy of hamster pancreatic carcinoma.

Topics: Animals; Chlorocebus aethiops; Cholecystokinin; COS Cells; Cricetinae; Female; Green Fluorescent Proteins; Humans; Immunotherapy; Mesocricetus; Pancreatic Neoplasms; Plasmids; Recombinant Fusion Proteins; Swine; Transfection

To determine the immunoreactivity of cholecystokinin (CCK) during the development of the human fetal pancreas and pancreatic adenocarcinoma, given that, CCK positive cells were demonstrated either in its embryonic anlage or in pancreatic cancer. In order to obtain possible parallels in the expression pattern of neoplastic cells in adults (well--moderately--poorly differentiated), we investigated the pattern of CCK expression in the pancreatic tissue during the various stages of development and compared these with the proliferation of tissue assessed by proliferating cell nuclear antigen (PCNA) immunohistochemistry.. Tissue sections from 15 pancreatic fetal specimens, and equal number of ductal adenocarcinoma specimens, were assessed using immunohistochemical methods for CCK.. The density of positive cells in the primitive exocrine ductal walls and outgrowing buds was significantly higher than the relevant density in the neoplastic pancreatic tissue of mixed (ductal-endocrine) and pure ductal type (p1=0.004, p2 < 0.0005, p3 < 0.0005 and p4=0.023 respectively). The above values were estimated from 20th to 22nd weeks of gestation. There was no significant difference in the density of positive cells in the islet cell epithelium from 25-30 weeks, and the neoplastic tissue of mixed (p5=0.10) and pure ductal type (p6=0.15).. The immunostaining for CCK identifies a sub-group of pancreatic ductal adenocarcinomas with a neuroendocrine component (initially considered as pure ductal tumors), and mixed ductal-endocrine tumors. This pattern of expression in neoplasms recapitulates the normal pattern during the embryonal development of the organ, and may be important for the development of new therapeutic approaches with eventual clinical utility.

Topics: Adenocarcinoma; Aged; Cholecystokinin; Female; Gestational Age; Humans; Immunohistochemistry; Male; Middle Aged; Pancreas; Pancreatic Neoplasms

The cholecystokinin (CCK)/secretin pancreatic function tests to diagnose pancreatic exocrine insufficiency are time consuming and invasive. Our aim was to develop a rapid pancreatic function test performed during upper endoscopy that could discriminate between patients with normal from impaired exocrine pancreatic secretion.. We prospectively evaluated 412 patients for possible pancreatic diseases. During upper endoscopy, 1 CU/kg of secretin was given intravenously and duodenal juice (collected for 10 min) was assayed for concentrations of bicarbonate and lipolytic and trypsin activity. Final diagnosis was by histology, imaging, and a previously validated scoring system (for chronic pancreatitis). Of 412 patients, 117 patients had normal pancreas, 72 patients had chronic pancreatitis, and 116 patients had pancreatic adenocarcinoma. The remaining 107 patients had miscellaneous disease of the peripancreatic region. In 28 patients we also validated the secretin test with the standard CCK pancreatic function test.. There was no difference between bicarbonate or trypsin concentrations among the groups. Lipolytic concentration was significantly lower in chronic pancreatitis (115 +/- 18) and in pancreatic adenocarcinoma (87 +/- 10) compared with patients with normal pancreas (229 +/- 23; P < 0.03 and P < 0.0001, respectively). The overall accuracy of the endoscopic secretin test was 79%, with positive and negative predictive values of 73% and 85%, respectively. The concentration of lipolytic activity obtained by the endoscopic secretin test in 28 patients correlated moderately well (r = 0.41, P < 0.03) with lipolytic output obtained by the CCK pancreatic function test.. Lipolytic concentration in duodenal juice after intravenous secretin collected for 10 minutes during upper endoscopy was significantly lower in chronic pancreatitis and pancreatic adenocarcinoma compared with patients with normal pancreas, but was not accurate enough for routine clinical use.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Bicarbonates; Cholecystokinin; Chronic Disease; Diagnosis, Differential; Endoscopy, Gastrointestinal; Female; Humans; Lipase; Male; Middle Aged; Pancreatic Function Tests; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin; Sensitivity and Specificity; Trypsin

AR42J rat pancreatic acinar carcinoma cells have retained the potential to secrete digestive enzymes in addition to their ability to proliferate upon stimulation with regulatory peptides. We investigated the involvement of p42ERK2 and p125FAK (extracellular signal-regulated protein kinase and focal adhesion protein kinase, respectively) by cholecystokinin and bombesin stimulation with regard to secretion and mitogenesis.. The p42ERK2 activity was measured by kinase assay and the activation of p125FAK by antiphosphotyrosine Western blot analysis of p125FAK immunoprecipitates. The expression of both kinases was determined by Western blot analysis, the amylase secretion by colorimetry, and the DNA synthesis by [3H]thymidine incorporation.. p42ERK2 and p125FAK were activated by cholecystokinin and bombesin with maximum stimulation at concentrations above 10 nM. Bombesin was a weaker activator of p42ERK2 and p125FAK, causing only half of the kinase activity induced by stimulation with cholecystokinin. PD98059 was shown to inhibit p42ERK2, while tyrphostin 25 blocked p125FAK tyrosine phosphorylation. Preincubation of AR42J cells with PD98059 or tyrphostin 25 was without influence on cholecystokinin- or bombesin-stimulated secretion in normal or 72-hour dexamethasone-pretreated cells. In contrast, inhibition of both protein kinases leads to reduced cholecystokinin-stimulated [3H]thymidine incorporation rates.. Cholecystokinin induced proliferation of AR42J cells by strong activation of p42ERK2 and p125FAK. Bombesin failed to stimulate DNA synthesis, probably due to its reduced potency to stimulate these kinases. Both protein kinases are not implicated in the process of enzyme secretion.

Topics: Animals; Bombesin; Cell Division; Cholecystokinin; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Flavonoids; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Mitogen-Activated Protein Kinase 1; Pancreatic Neoplasms; Protein-Tyrosine Kinases; Rats; Tumor Cells, Cultured

Topics: Cholecystokinin; Gastrins; Humans; Pancreatic Neoplasms

Topics: Adenocarcinoma; Aged; Case-Control Studies; Cholecystokinin; Female; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms

It has been assumed that gastrin stimulates the growth of pancreatic cancer in an autocrine way through co-expression of gastrin and the cholecystokinin-B receptor (CCK-BR). However, pancreatic cancer cell lines established directly from patients have revealed a great heterogeneity in cell proliferation when exposed to CCK, gastrin and their receptor antagonists. The aim of this study was therefore to examine co-expression of CCK-A and CCK-B receptor (CCK-AR and CCK-BR), and gastrin mRNA as well as the secretion of CCK and gastrin peptides in these cell lines.. Fourteen cell lines were established from primary pancreatic cancers or their metastases. Total RNA was isolated from the cell lines and reverse-transcribed into single-stranded cDNA. A PCR technique based on Taq polymerase-antibody interaction and CCK-AR, CCK-BR and gastrin-specific primers, followed by Southern blot analysis, were the methods used. The incubation mediums were analysed for the presence of secreted CCK/proCCK and gastrin/progastrin peptides by specific radioimmunoassays (RIA).. By means of nested Reverse-Transcribed Polymerase Chain Reaction (nested RT-PCR), combined with Southem blot analysis of the PCR amplified products, CCK-AR and gastrin mRNA co-expression was detected in cell lines LPC-6p and LPC-10m, whereas CCK-BR and gastrin mRNA could be detected in cell lines LPC-8p and LPC-12m. A low level of secreted CCK peptides was detected in cell line LPC-6p, which also expressed CCK-AR mRNA. In no other cases were CCK or gastrin peptides detected in the cell culture mediums.. The lack of CCK-BR and gastrin mRNA co-expression, and not detectable levels of secreted CCK and gastrin in culture media, does not lend support to the hypothesis that concomitant gene-expression of CCK receptors and gastrin or CCK are essential to maintaining pancreatic cancer cell proliferation.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Aged; Biopsy; Blotting, Southern; Carcinoma, Ductal, Breast; Carcinoma, Papillary; Cell Division; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Radioimmunoassay; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Alpha-amidated gastrin promotes the growth of nontransfected pancreatic cell lines expressing the gastrin/cholecystokinin (CCK)-B receptor. Gastrin/CCK-B and CCK-A receptors recently were demonstrated in human pancreatic adenocarcinomas, but to the authors' knowledge expression of their ligands to date have not been adequately investigated. As a prerequisite for making suggestions regarding local growth stimulation, the authors examined whether gastrin and the homologous CCK peptides as well as their specific receptors were expressed in consecutively collected solid human pancreatic adenocarcinomas.. Using a library of radioimmunoassays specific for different epitopes on proCCK, progastrin, their processing intermediates, and bioactive end products, CCK and gastrin gene expression was measured in extracts of solid human pancreatic adenocarcinomas (n = 19), resection margins (n = 15), and normal pancreatic tissue (n = 8). Moreover, CCK, CCK-A receptor, and gastrin/CCK-B receptor mRNA were measured by reverse transcriptase-polymerase chain reaction.. Amidated gastrins were synthetized in 14 of 19 carcinomas (median, 0.4 pmol/g; range, < 0.1-84.0 pmol/g) and in 12 of 15 resection margin samples (median, 0.3 pmol/g; range, < 0.1-6.1 pmol/g). In contrast, normal human pancreatic tissue expressed only traces of poorly processed progastrin. Gastrin/CCK-B receptor mRNA was present in all carcinomas, resection margins, and normal pancreatic tissue. CCK-A receptor mRNA was detected in most tumors, but neither the mature ligands (alpha-amidated and O-sulfated CCK peptides) nor their precursors were expressed in carcinoma and normal pancreatic tissue.. The results of the current study demonstrate that alpha-amidated gastrin peptides and their receptor invariably are coexpressed in pancreatic adenocarcinoma. Therefore these findings support the contention of a role for local gastrin regulatory mechanisms, but no CCK mechanisms, in pancreatic carcinoma.

Topics: Adenocarcinoma; Cholecystokinin; Humans; Neoplasm Proteins; Pancreas; Pancreatic Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; RNA, Messenger

We have previously reported that cholecystokinin (CCK) plays an important role in the invasiveness and the production of matrix metalloproteinase-9 (MMP-9) in two human pancreatic cancer cell lines. In this study we investigated the pathway of the invasiveness associated with MMP-9 of those lines regulated by CCK. Two human pancreatic cancer cell lines were treated with CCK-8 alone, CCK-8 and staurosporine, or CCK-8 and indomethacine. The invasiveness and the production of MMP-9 were decreased with staurosporine but not indomethacine. These results suggest that CCK may regulate the invasiveness and the production of MMP-9 via protein kinase C in human pancreatic cancer cell lines.

Topics: Blotting, Western; Cholecystokinin; Collagenases; Cyclooxygenase Inhibitors; Dinoprostone; Dopamine Agents; Enzyme Induction; Enzyme Inhibitors; Humans; Immunoenzyme Techniques; Indomethacin; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Pancreatic Neoplasms; Protein Kinase C; Signal Transduction; Sincalide; Staurosporine; Tumor Cells, Cultured

Cholecystokinin (CCK) secretion may be affected in patients with chronic pancreatitis (CP), but little is known on the effect of pancreatic surgery on CCK secretion. We measured CCK secretion (radioimmunoassay, RIA) in response to bombesin infusion (100 ng/kg/20 min) for 120 min to test CCK secretory capacity, to ingestion of a liquid diet (400 kcal) for 120 min, and in response to a solid fat-rich meal (500 kcal) for 120 min. These studies were performed in 45 patients with CP (25 with exocrine insufficiency), 15 patients after duodenum-preserving pancreatic head resection (DPRHP), 18 patients after the Whipple operation, 12 patients after distal pancreatectomy (DP), and 35 control subjects. In CP patients, the CCK secretory capacity was preserved, but the postprandial CCK response was reduced, depending on meal composition and the presence of exocrine insufficiency. In patients after Whipple's operation, CCK secretory capacity and postprandial CCK secretion were significantly (p < 0.05) reduced. In patients after DPRHP, CCK secretory capacity was not affected, but the postprandial CCK response was significantly (p < 0.05) reduced, depending on meal composition and the presence of exocrine insufficiency. In patients after DPRHP, fasting plasma CCK levels were significantly (p < 0.01) increased, pointing to the absence of feedback inhibition on CCK secretion by intraluminal enzymes. After DP, the CCK secretory capacity was not affected.. alterations in CCK secretion are observed in patients with chronic pancreatitis and after pancreatic surgery. These alterations are related not only to the disease process (exocrine insufficiency) but also to the type of surgery and type of stimulus.

Topics: Adult; Bombesin; Cholangiopancreatography, Endoscopic Retrograde; Cholecystectomy; Cholecystokinin; Chronic Disease; Digestive System Surgical Procedures; Duodenum; Eating; Female; Gastrectomy; Humans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pancreatitis; Postprandial Period; Reference Values

In this article, we show that glucagon-like peptide 1 (GLP-1) can induce AR42J cells to differentiate into insulin, pancreatic polypeptide, and glucagon-positive cells. In their natural state, these cells, which are derived from a chemically induced pancreatic tumor, possess exocrine and neuroendocrine properties but are negative for islet hormones and their mRNAs. We found that when these cells were exposed to GLP-1 (1 or 10 nmol), a peptide normally released from the gut in response to food and a modulator of insulin release, intracellular cAMP levels were increased, and proliferation of cells was increased for the first 24 h, followed by inhibition. Up to 50% of the cells became positive for islet hormones. The mRNAs for glucose transporter 2 and glucokinase were detected in the GLP-1-treated cells. Insulin was detected by radioimmunoassay (RIA) in the medium of GLP-1-treated cells, and the cells were capable of releasing insulin in a glucose-mediated fashion. Exendin-4, an analog of GLP-1, in some critical experiments performed in a similar manner to GLP-1, with the exception of it being 10-fold more potent. We therefore propose that GLP-1 and exendin-4 are capable of causing pancreatic precursor cells to differentiate into islet cells.

Topics: Adenylyl Cyclases; Amylases; Animals; Cell Cycle; Cell Differentiation; Cholecystokinin; Dexamethasone; Exenatide; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Insulin; Kinetics; Pancreatic Neoplasms; Peptide Fragments; Peptides; Protein Precursors; Rats; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured; Venoms

The presence of cholecystokinin (CCK)-B (gastrin) receptors has been shown in more than 90% of medullary thyroid cancers (MTCs) and in a high percentage of small cell lung cancers, stromal ovarium cancers and several other tumor types.. The aim of this study was to evaluate in vitro and in vivo whether 111In-labeled CCK-B receptor-specific CCK8 analog [D-Asp26,Nle28,31]CCK26-33 (D-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2) is suitable for CCK-B receptor scintigraphy based on the finding that unlabeled nonsulfated diethylenetriamine pentaacidic acid [DTPA0]CCK8 and tetraazacyclododecanetetraacetic acid [DOTA0]CCK8 analogs show high and specific binding for CCK-B receptors in human tumors. Fifty percent inhibitory concentrations were in the low nanomolar range.. In vitro, [111In-DOTA0]CCK8 showed specific internalization in CCK-B receptor-positive rat pancreatic tumor cells AR42J. Internalization of the analog appeared to be time and temperature dependent and receptor specific. From the data obtained with [111In-DOTA0]CCK8 and (125I)I-gastrin, the latter being a specific ligand for the CCK-B receptor, the rat pancreatic cell line CA20948 also appeared to be CCK-B receptor positive. This provides an in vitro and in vivo rat tumor model because this cell line can be grown to solid tumors in Lewis rats. In vivo biodistribution experiments in CA20948 tumor-bearing Lewis rats showed rapid clearance of [111In-DOTA0]CCK8, and specific uptake was found in the CCK-B receptor-expressing stomach and tumor. Furthermore, comparing [111In-DOTA0]CCK8 with the radioiodinated nonsulfated CCK10 analog (D-Tyr-Gly-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2), both ligands having high affinity for the CCK-B receptor, tumor-to-blood ratios were significantly higher for [111In-DOTA0]CCK8 than for 125I-CCK10, analogous to the findings with radioiodinated and 111In-labeled octreotide. The study in humans with [111In-DTPA0]CCK8 showed receptor-specific uptake in the CCK-B receptor-positive stomach and in metastases in the neck region up to 48 h after injection.. [111In-DOTA0]CCK8 is most promising for scintigraphy and, after coupling to therapeutic radionuclides, for radionuclide therapy of human CCK-B receptor-positive tumors such as MTC and small cell lung cancer.

Topics: Animals; Cholecystokinin; Drug Evaluation; Female; Humans; Indium Radioisotopes; Male; Mice; Mice, Inbred BALB C; Middle Aged; Pancreatic Neoplasms; Peptide Fragments; Radionuclide Imaging; Rats; Rats, Inbred Lew; Rats, Wistar; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Thyroid Neoplasms; Tissue Distribution; Tumor Cells, Cultured

The role of cholecystokinin (CCK) and gastrin in the development and growth of pancreatic cancer cells is controversial. The aim of this study was to evaluate the role of CCK-8S, gastrin-17, bombesin, and their antagonists on cell lines from patients with pancreatic cancer.. Cell lines were established from pancreatic cancers operated on at our department. The cells were grown in 10% fetal calf serum (FCS). The effects of CCK-8S, gastrin-17, bombesin, and their antagonists in different concentrations and for different time intervals were studied. The cell number was evaluated with the XTT method.. The cell line LN 36 responded with increased cell number to stimulation by gastrin-17 and decreased cell number to inhibition by the CCK-B receptor antagonist L-365,260. In contrast, LPC 1 responded with increased cell number to CCK-8S and decreased cell number to the CCK-A receptor antagonist devazepide. LPC 2, 6, and 7 were stimulated by CCK-8S, gastrin-17, and their antagonists. LPC 3 showed decreased cell number after inhibition by the antagonists, and LPC 5 and 10 showed increased cell number after stimulation by CCK-8S and gastrin-17. LPC 4 was stimulated by CCK-8S, and LPC 8 was stimulated by all substances except gastrin-17. Intermittent administration of the substances to LN 36 led to a greater effect on the cell number than administration every day, which was not the case with LPC 1 and LPC 3. Bombesin led to an increased growth in LPC 5 but not in LPC 3.. CCK-8S and gastrin-17 led to an increased cell number in some cell lines. A blockade of the CCK-A and CCK-B receptors by their antagonists led to an increased, an unaffected, or a decreased cell number of the cell lines. The effect of bombesin on different cell lines also varied. This shows a great heterogenicity among pancreatic cancer cells from different patients.

Topics: Benzodiazepinones; Bombesin; Cell Division; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Gastrins; In Vitro Techniques; Pancreatic Neoplasms; Phenylurea Compounds; Receptors, Cholecystokinin; Tumor Cells, Cultured

For more than two decades, our research group has been studying the pancreatic actions of three groups of regulatory peptides: members of the cholecystokinin/gastrin family, bombesin-like peptides and somatostatin. Investigating these peptides, our work has focused on three particularly interesting aspects: peptidergic regulation of pancreatic enzyme secretion and growth in adult rats, peptidergic control of pancreatic enzyme secretion and growth during postnatal development in rats, and peptidergic regulation of proliferation and differential gene expression in pancreatic adenocarcinoma cells. Our data confirmed that the control of the exocrine function of the pancreas is complex, and that it involves peptides such as the cholecystokinin/gastrin-like peptides, bombesin-like peptides and somatostatin. In these investigations, it became evident that selective peptide receptor agonists, antagonists and monoclonal antibodies raised against peptides are useful tools to identify the role of these bioactive peptides in pancreatic exocrine secretion and cell proliferation.

Topics: Adenocarcinoma; Animals; Bombesin; Cell Division; Cholecystokinin; Gastrins; Gene Expression; Pancreas; Pancreatic Neoplasms; Rats; Somatostatin

In order to examine the effect of cholecystokinin on spontaneous and induced pancreatic carcinogenesis in the hamster, two sets of experiments were carried out, one involving long-term hypercholecystokininemia and one involving cancer induction during hypercholecystokininemia. The effect of hypercholecystokininemia, induced by pancreaticobiliary diversion (PBD), was studied for 8 months. Neither PBD animals nor sham-operated controls developed premalignant or malignant pancreatic lesions. However, in the PBD group the mean pancreatic weight, total protein content and DNA content were increased by 30, 29 and 27% respectively. No such increases were found in PBD animals receiving a cholecystokinin-A receptor antagonist during the last 24 days of the experiment. In the cancer induction study, the effect of PBD on N-nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis was studied for 3 months. Putative premalignant pancreatic lesions were diagnosed in all PBD hamsters and in four of 15 sham-operated controls. Pancreatic ductular carcinoma in situ was only found in PBD animals. The [3H]thymidine labeling index of the pancreatic lesions was significantly higher in the PBD group than in the controls. No such increase was observed in PBD animals receiving a cholecystokinin-A receptor antagonist during the last 5 days of the experiment. It is concluded that chronic endogenous hypercholecystokininemia promotes early phase pancreatic carcinogenesis, but does not per se cause development of premalignant or malignant pancreatic lesions in the hamster.

Topics: Animals; Carcinogens; Cholecystokinin; Cricetinae; Duodenum; Gastrins; Male; Mesocricetus; Nitrosamines; Organ Size; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms

Several immortalized cell lines serve as models for procholecystokinin (pro-CCK) processing. Rin5F cells, derived from a rat insulinoma, and STC-1 cells, derived from a murine intestinal tumor, process pro-CCK mainly to amidated CCK 8. Both also make significant quantities of amidated CCK 22, a slightly larger form found in the gut. Many modifications are necessary during pro-CCK processing including cleavages performed by endoproteases, the identities of which are unknown. A candidate endoprotease is prohormone convertase 1 (PC1) also known as PC3, a Ca2+-dependent serine endoprotease of the subtilisin family. Constitutive expression of antisense PC1 message in stably transfected Rin5F cells resulted in a significant reduction of the cellular content of CCK 8 as measured by radioimmunoassay. Several affected cell lines displayed about 80% reduction in CCK content in early passages after transfection. Expression of antisense PC1 message in these cell lines resulted in a selective depletion of CCK 8 and a comparative sparing of CCK 22. The induction of antisense PC1 message within a single subclone of Rin5F cells using the Lac Switch system also resulted in a significant inhibition of CCK content. Expression of antisense PC1 message in a stably transfected STC-1 cell line also resulted in a decrease in CCK content and in PC1 protein expression, and the specific depletion of CCK 8 with comparative sparing of CCK 22. These observations support the hypothesis that PC1 is necessary for pro-CCK processing in Rin5F and STC-1 cells and suggests a role for PC1 endoprotease in the biosynthesis of CCK 8 in vivo.

Topics: Animals; Aspartic Acid Endopeptidases; Cholecystokinin; Chromatography, Gel; Insulinoma; Intestinal Neoplasms; Models, Chemical; Oligonucleotides, Antisense; Pancreatic Neoplasms; Peptide Fragments; Proprotein Convertases; Rats; Sincalide; Tumor Cells, Cultured

To examine the effect of gastrin on spontaneous and induced pancreatic carcinogenesis in the hamster.. Two sets of experiments were carried out, one involving long term hypergastrinaemia and one involving cancer induction during hypergastrinaemia. The effect of hypergastrinaemia accomplished by gastric fundectomy was studied for eight months. Neither fundectomised hamsters nor sham operated controls developed premalignant or malignant pancreatic lesions. In the fundectomy group, the mean pancreatic weight, total protein content, and DNA content was increased by 28%, 25%, and 25% respectively. No such increases were found in fundectomised animals receiving a cholecystokinin-B receptor antagonist during the last 24 days of the experiment. In the cancer induction study, the effect of fundectomy on N-nitrosobis(2-oxopropyl) amine induced pancreatic carcinogenesis was studied for three months. There were no significant differences in the incidence or [3H]-thymidine labelling index of focal pancreatic lesions between fundectomised and sham operated control animals.. Fundectomy with chronic hypergastrinaemia induces pancreatic hypertrophy, but does not enhance N-nitrosobis (2-oxopropyl)amine induced pancreatic carcinogenesis in the hamster. The increases in growth were inhibited by a cholecystokinin-B receptor antagonist, indicating that the trophic effect of fundectomy is mediated by gastrin.

Topics: Animals; Benzodiazepinones; Carcinogens; Cholecystokinin; Cricetinae; Disease Models, Animal; Gastric Fundus; Gastrins; Hypertrophy; Male; Mesocricetus; Neoplasms, Experimental; Nitrosamines; Pancreas; Pancreatic Neoplasms; Phenylurea Compounds; Receptors, Cholecystokinin

Cholecystokinin (CCK) plays an important role in pancreatic carcinogenesis. While human CCK-A and -B receptors have been fully characterized, their relative roles in human pancreatic adenocarcinoma remain unclear. Thus, expression of CCK-A and -B receptors in normal human pancreas, pancreatic adenocarcinomas, and other human extrapancreatic tissues and malignancies was examined, using reverse transcription followed by the polymerase chain reaction (RT-PCR). mRNA isolated from 15 normal pancreas specimens, 22 pancreatic adenocarcinomas, and 58 extrapancreatic tissues and tumors was subjected to RT-PCR using primers specific for human CCK-A and -B receptors. Expression of CCK-B receptors was detected in all tissues arising from pancreas and in most extrapancreatic tissues and tumors. In contrast, CCK-A receptors exhibited a more selective pattern of expression in gall bladder, intestine, brain, ovary, spleen, and thymus. Of significance, CCK-A receptors were expressed selectively in all pancreatic adenocarcinomas, but not in any normal pancreas specimens. In situ hybridization, using receptor-specific riboprobes, localized CCK-A receptor expression to ductal cells, the presumed origin of most human pancreatic adenocarcinomas. Southern blot analysis revealed no evidence of CCK-A receptor gene amplification or rearrangement in pancreatic adenocarcinomas. Because of its selective expression, the CCK-A receptor may serve as selective biomarker for pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Biomarkers, Tumor; Cholecystokinin; Humans; Pancreas; Pancreatic Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin

Several peroxisome proliferators have been shown to produce pancreatic acinar cell hyperplasia/adenocarcinomas in 2-year bioassays with rats: ammonium perfluorooctanoate (C8), clofibrate, methylclofenapate, HCFC-123, and Wyeth-14,643 (WY). We have used in vitro (C8, WY) and in vivo (WY) approaches to examine several possible mechanisms of pancreatic tumorigenesis by peroxisome proliferating compounds. These mechanisms include cholecystokinin receptor agonism (CCK(A)), trypsin inhibition, alterations in gut fat content, cholestasis, and altered bile flow/composition. All of these mechanisms enhance pancreatic growth either by binding to the CCK(A) receptor or by increasing plasma CCK levels. In vitro experiments using a receptor competition binding assay demonstrated that WY and C8 do not bind directly to the CCK(A) receptor. In a continuous spectrophotometric assay, WY and C8 also failed to inhibit trypsin, a common mechanism for increasing plasma CCK levels. These in vitro results suggested that WY was not acting via the two most common mechanisms for modulation of pancreas growth. Two types of in vivo experiments were conducted. The subchronic study (2-month duration) was designed primarily to detect early changes in pancreatic growth such as those mediated by compounds that inhibit trypsin or act as CCK(A) receptor agonists. The chronic study (6 months) was designed primarily to evaluate whether the pancreatic lesions were secondary to hepatic changes such as cholestasis and/or altered bile flow/composition. In the in vivo experiments, male Crl:CDBR rats were fed diets containing 0 or 100 ppm WY. In the subchronic study WY-treated rats had a twofold increase in mean relative liver weights, an eightfold increase in hepatic peroxisomal proliferation, and a fourfold increase in hepatocyte cell proliferation after 1 week which remained elevated throughout the 2 months of treatment. In contrast, no pancreatic weight effects, increases in plasma CCK, or acinar cell proliferation was seen through 2 months in the WY group when compared to the control group. Fecal fat concentrations were also measured at 2 months and demonstrated no difference between control and WY-treated animals. The absence of any early pancreas changes in the subchronic study is consistent with the in vitro data which demonstrated that WY is not a CCK(A) agonist or a trypsin inhibitor. The chronic study demonstrated increases in pancreatic weights at 3 months (6% above control) and 6 month

Topics: Adenoma; Animals; Binding, Competitive; Carcinogens; Carcinoma, Acinar Cell; Cholecystokinin; Liver; Male; Microbodies; Mutagens; Pancreas; Pancreatic Neoplasms; Pyrimidines; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Trypsin Inhibitors

Two endocrine tumor cell lines from pancreas (RIN5F) and intestine (STC-1) express cholecystokinin (CCK) messenger RNA and are able to posttranslationally process pro-CCK to CCK-22 and CCK-8 amide. Both of these forms are also secreted by these cells. Because they make and secrete forms of amidated CCK larger than CCK-8, they represent a model of pro-CCK processing in the gut and allow investigation of possible mechanisms for tissue differences in prohormone processing. Both of these cells express two endoproteases convertase-1 (PC1) also known as PC3 and prohormone convertase-2 (PC2), which may be involved in pro-CCK processing. We have previously shown than inhibition of PC1 expression in these cells using stable expression of antisense messenger RNA caused a significant reduction in cellular content of amidated CCK and caused a selective depletion of CCK-8 with a comparative sparing of CCK-22. We demonstrate here that inhibition of PC2 expression in these cells also caused a large initial decrease in CCK content and produced a selective depletion of CCK-22 and a comparative sparing of CCK-8. These results support both a role for both PC1 and PC2 in pro-CCK processing in these cells and the hypothesis that tissue-specific processing of pro-CCK may be explained by differences in expression or activity of PC1 and PC2.

Topics: Cholecystokinin; Gene Expression; Intestinal Neoplasms; Pancreatic Neoplasms; Peptide Fragments; Proprotein Convertase 2; RNA, Antisense; RNA, Messenger; Sincalide; Subtilisins; Transfection; Tumor Cells, Cultured

The mechanism by which high-fat diets potentiate pancreatic cancer is not known, but pancreaticotrophic hormones such as cholecystokinin (CCK) may be involved. The effect of CCK receptor blockade on carcinogenesis during the entire promotion period was investigated in Syrian Golden hamsters fed a high- or low-fat diet and treated with N-nitrosobis(2-oxopropyl)amine (3 x 10 mg/kg at weekly intervals). One-half of the hamsters fed a high-fat diet received the CCK-A receptor antagonist devazepide (25 nmol/kg/hr) for the duration of the experiment. At 39 weeks the incidence of pancreatic malignancies was significantly higher in hamsters fed the high-fat diet than in those fed the low-fat diet (p < 0.05). Tumor incidence was not changed by CCK receptor blockade. Potentiation of pancreatic cancer by a high-fat diet in hamsters does not appear to be influenced by endogenous CCK during the tumor promotion period.

Topics: Animals; Benzodiazepinones; Carcinogens; Cholecystokinin; Cricetinae; Devazepide; Dietary Fats; Male; Mesocricetus; Nitrosamines; Organ Size; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms; Receptors, Cholecystokinin

The effect of a calcium channel blocker, verapamil, on cholecystokinin (CCK)-enhancement of pancreatic carcinogenesis induced by azaserine was investigated in Wistar rats. During and after 25 weekly injections of azaserine, each rat received alternate-day injections of CCK-octapeptide (CCK-8) and/or verapamil. Carcinogen-induced pancreatic lesions staining for mu class glutathione S-transferase (GST-mu) were examined histochemically at week 62. Prolonged administration of CCK-8 significantly increased the number and area as a percentage of parenchyma of GST-mu-positive lesions. Concomitant administration of verapamil significantly attenuated the enhancing effect of CCK-8. These findings indicate that calcium may play an important role in CCK-enhancement of pancreatic carcinogenesis.

Topics: Animals; Azaserine; Calcium Channel Blockers; Cholecystokinin; Drug Synergism; Glutathione Transferase; Male; Pancreatic Neoplasms; Rats; Rats, Wistar; Verapamil

Somatostatin inhibits proliferation of many solid tumors. The current study examines whether inhibition of the growth of pancreatic cancer by the somatostatin analog, octreotide, requires tumor expression of somatostatin receptors.. We studied five human pancreatic cancer cell lines, Capan-1, Capan-2, CAV, MIA PaCa-2, and Panc-1. Solid tumors were established in nude mice (n = 20/cell line) by flank injection of tumor cells. Subcutaneous octreotide (500 micrograms/kg/day) was administered by osmotic pumps to 10 of the animals in each group, and the other 10 received control infusions of saline solution. On day 36, the tumors were excised and weighed. Plasma levels of the putative trophic peptides cholecystokinin, epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and insulin were assessed by radioimmunoassay. Each of the five cell lines was assayed for the presence of cell surface somatostatin receptors by using whole cell competitive binding assays with 125I-somatostatin. Expression of the somatostatin receptor subtype-2 (SSR2) gene was determined with reverse transcriptase-polymerase chain reactions. Southern blot hybridization was used to assess the presence of the SSR2 gene.. Octreotide inhibited tumor growth in the MIA PaCa-2 group (512 +/- 75 mg control versus 285 +/- 71 mg treated; p < 0.05) but had no significant effect on tumor weight in the other four cell lines. Plasma levels of cholecystokinin, epidermal growth factor, insulin-like growth factor-1, and insulin were not altered by chronic octreotide infusion. Cell surface somatostatin receptors and SSR2 gene expression were detected only in the MIA PaCa-2 tumors. The gene for the SSR2 receptor was found in all five tumor lines.. Octreotide-mediated inhibition of pancreatic cancer growth is dependent on expression of somatostatin receptors. The expression of somatostatin receptors should be considered in the design and interpretation of clinical trials with somatostatin analogs for treatment of pancreatic cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Hormonal; Base Sequence; Binding, Competitive; Blotting, Southern; Cell Division; Cholecystokinin; DNA, Neoplasm; Epidermal Growth Factor; Gene Expression Regulation, Neoplastic; Humans; Insulin; Insulin-Like Growth Factor I; Mice; Mice, Nude; Molecular Sequence Data; Octreotide; Pancreatic Neoplasms; Peptides; Polymerase Chain Reaction; Receptors, Somatostatin; Tumor Cells, Cultured

The growth of pancreatic cancers may be influenced by certain gut peptides. However, the alteration of gut peptide receptors in the progress of pancreatic carcinogenesis is largely unknown. With storage phosphor autoradiography, this study visualized and characterized receptors for cholecystokinin (CCK), somatostatin (SST), bombesin (BBS), secretin and vasoactive intestinal peptide (VIP) in pancreata of control hamsters (n = 7) and pancreatic preneoplastic lesions (n = 10) or adenocarcinomas (n = 10) of N-nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters. The specific CCK-A and secretin receptors expressed in normal pancreata were markedly reduced in pancreatic preneoplastic lesions and absent in adenocarcinomas. In the development of pancreatic tumours, the subgroup of SST receptors did not change, but both the affinity and binding capacity declined. In comparison with the binding of VIP to normal pancreata, specific VIP binding was significantly lower in preneoplastic lesions and almost absent in pancreatic adenocarcinomas. No specific binding for BBS was detected in normal pancreas or (pre)neoplastic lesions of hamster pancreas. The reduction or absence of receptors for CCK, secretin, SST and VIP in hamster pancreas with the progress of carcinogenesis suggests that in BOP-treated hamsters, pancreatic adenocarcinomas have, to a large extent, lost the hormone-dependent characteristics of the original tissue.

Topics: Adenocarcinoma; Animals; Carcinogens; Cholecystokinin; Cricetinae; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Receptors, Cholecystokinin; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Receptors, Somatostatin; Receptors, Vasoactive Intestinal Peptide; Secretin; Somatostatin; Vasoactive Intestinal Peptide

Intracellular signaling by an increase in [Ca2+]i was observed in pancreatic AR42J cells in response to agonists whose receptors are G-protein coupled including cholecystokinin (CCK), bombesin, carbachol, substance P, pituitary adenylate cyclase activating peptide (PACAP), bradykinin, ATP, calcitonin gene related peptide (CGRP), and in response to growth factors EGF and FGF whose receptors are tyrosine kinases. The response to growth factors was smaller both in magnitude and in the percentage of cells responding but was independent of extracellular Ca2+. CCK and carbachol induced sizeable increases in inositol phosphates while growth factors did not. The responses to both carbachol and EGF, however, were blocked by the phospholipase C inhibitor U73122. The tyrosine kinase inhibitor, genestein, blocked the response to EGF but not that to CCK. These data are consistent with two types of signaling mechanisms in AR42J cells. Secretagogues act on receptors which couple through G proteins to induce a large amount of inositol phosphate production and subsequent intracellular Ca2+ mobilization. Growth factors act on receptors which signal through tyrosine kinase activity and in this cell type produced limited amounts of inositol phosphate and a smaller increase in intracellular Ca2+.

Topics: Adenosine Triphosphate; Animals; Binding Sites; Bombesin; Bradykinin; Calcitonin Gene-Related Peptide; Calcium; Carbachol; Cholecystokinin; Epidermal Growth Factor; Estrenes; Fibroblast Growth Factors; GTP-Binding Proteins; Hydrolysis; Inositol Phosphates; Neuropeptides; Neurotransmitter Agents; Pancreas; Pancreatic Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein-Tyrosine Kinases; Pyrrolidinones; Rats; Receptors, Neuropeptide; Substance P; Tumor Cells, Cultured; Type C Phospholipases

The influences of (a) intraluminal bile deficiency due to common bile duct obstruction and (b) intraduodenal administration of pooled own bile and bovine trypsin on the plasma cholecystokinin (CCK) response to oral fat (Lipomul) ingestion were investigated in seven patients with periampullary tumors and 10 healthy volunteers. Basal and fat-stimulated plasma CCK levels in the patients were significantly higher than in the normal controls. Intraduodenal administration of pooled own bile at a rate of 100 ml/h significantly suppressed both basal and fat-stimulated CCK secretion. Simultaneous administration of pooled own bile (100 ml/hr) and bovine trypsin (600 mg/hr) caused further significant suppression of fat-stimulated CCK secretion compared with that under bile infusion alone. These results indicate that both intraluminal bile and trypsin exert a negative feedback effect on the release of CCK in humans.

Topics: Aged; Bile; Bile Duct Neoplasms; Carcinoma; Cholecystokinin; Cholestasis; Dietary Fats; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Trypsin

We compared morphological, biological and molecular biological patterns of a newly established, spontaneously immortalized pancreatic ductal cell line, TAKA-1, with a hamster pancreatic ductal adenocarcinoma cell line, PC-1. PC-1 cells grew in a monolayer on plastic tissue culture flasks, whereas TAKA-1 cells required type I collagen gel matrix to propagate. The growth rate and argyrophilic nuclear organizer region (Ag-NOR) counts were greater in PC-1 cells than in TAKA-1 cells. More TAKA-1 cells were in G0/G1 and less were in the S cell cycle phase than PC-1 cells. Karyotypically, the consistent change in TAKA-1 cells was an abnormal no. 3 chromosome, whereas additional chromosomal abnormalities were found in PC-1 cells. Ultrastructurally, TAKA-1 cells formed ductal structures and were composed of two types of cells, as in the normal hamster pancreatic ducts, whereas PC-1 cells were pleomorphic, showed evidence for loss of differentiation and contained intracytoplasmic lumens. Unlike the PC-1, TAKA-1 cells did not show a point mutation at codon 12 in the c-Ki-ras oncogene and did not grow in soft agar. Receptor binding assay showed specific epidermal growth factor binding to both cell lines, but secretin binding only to TAKA-1 cells. Both cells produced and released transforming growth factor-alpha in serum-free medium. Both cell lines expressed blood group A antigen, carbonic anhydrase, coexpressed cytokeratin and vimentin, and reacted with tomato and Phaseolus vulgaris leucoagglutinin (L-PHA) lectins. The results demonstrate that chromosomal abnormalities, cell cycle patterns, expression of cytokeratin 18, lectin bindings and the c-Ki-ras mutation are the features that distinguish the benign from the malignant pancreatic ductal cells in Syrian hamster.

Topics: Adenocarcinoma; Animals; Base Sequence; Cell Adhesion; Cell Cycle; Cell Division; Cell Line; Cholecystokinin; Cricetinae; Epidermal Growth Factor; Flow Cytometry; Gastrin-Releasing Peptide; Genes, ras; Immunohistochemistry; Karyotyping; Kinetics; Light; Mesocricetus; Microscopy; Microscopy, Electron; Molecular Sequence Data; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms; Peptides; Point Mutation; Secretin; Tumor Cells, Cultured

Administration of raw soya containing a trypsin inhibitor stimulated excessive release of cholecystokinin (CCK) which led to pancreatic hypertrophy, hyperplasia and cancer in the rats (Booth et al. (1964) Proc. Soc. Exp. Biol. Med., 116, 1067). More postprandial CCK release in healthy humans was observed after ingestion of a single dose of raw soya than heat-treated soya (Calam et al. (1989) Br. J. Nutr., 58, 175). The effect of chronic ingestion of a heat-treated soya product on postprandial CCK release was investigated in six healthy adult males after ingestion of a 36-oz. portion of soymilk daily for 1 month and at 2-3 months after termination of soymilk ingestion. Subjects fasted for 15 h, ingested Lipomul (1.5 g/kg) and provided blood at timed intervals for CCK analysis. The results show that 1-month ingestion of soymilk decreased the magnitude of Lipomul-induced postprandial CCK release in plasma of all six subjects by 5-60% (P < 0.05) compared to those obtained at 2-3 months after the withdrawal from soymilk ingestion. Plasma pancreatic polypeptide (PP) levels were similarly decreased in five of the six subjects by 19-67% (P = 0.03) in line with the regulation of PP by CCK. Thus, prolonged exposure of humans to a heat-treated soya inhibited slightly meal-induced CCK release in contrast to that found in rats after raw soya diets.

Topics: Adult; Animals; Anticarcinogenic Agents; Cholecystokinin; Corn Oil; Gastrins; Glycine max; Hot Temperature; Humans; Male; Pancreatic Neoplasms; Pancreatic Polypeptide; Rats; Trypsin Inhibitors

The present study reports the first evidence that the gastrointestinal peptide gastrin stimulates the growth of several human pancreatic cancer cells in culture and in tumors transplanted to nude mice. Gastrin promoted growth of all cell lines tested at a dose comparable to the binding affinity, providing evidence for a physiologically relevant receptor. The stimulatory effects of gastrin were blocked by the CCK-B/gastrin receptor antagonist L-365,260 and not by the CCK-A receptor antagonist L-364,718. Growth of PANC-1 cells in culture were inhibited by L-365,260, suggesting that gastrin is tonically produced by PANC-1 cells for regulation of growth. Athymic nude mice bearing PANC-1 xenografts were treated for 24 days subcutaneously with either 1% bovine serum albumin (diluent), pentagastrin (1 mg/kg), or L-365,260 (1 mg/kg) twice daily. Tumors from the pentagastrin-treated mice were found to weigh more and have greater protein and DNA content than controls, whereas these values were all decreased in tumors of L-365,260-treated mice. Receptor binding capacity changed in tumors of animals treated with the peptide or antagonist, suggesting a regulatory process. Gastrin immunoreactivity was detected in a transplanted PANC-1 human tumor. These results identify gastrin as a potent trophic peptide that actively stimulates growth of human pancreatic cancer and does so through a CCK-B/gastrin-like receptor.

Topics: Animals; Benzodiazepinones; Cell Division; Cell Line; Cholecystokinin; Devazepide; Gastrins; Growth Substances; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Pentagastrin; Phenylurea Compounds; Receptors, Cholecystokinin; Transplantation, Heterologous; Tumor Cells, Cultured

The bile salt-stimulated cholesterol esterase is a digestive enzyme synthesized by the acinar cells of the pancreas. Previous results have shown that cholesterol esterase biosynthesis and secretion in the AR42J pancreatoma cells could be increased 3-5-fold by intestinal hormones such as cholecystokinin (CCK). The purpose of the current study is to explore the signalling mechanism by which CCK stimulation of AR42J cells results in increased biosynthesis and secretion of the cholesterol esterase. The results showed that the CCK-induced cholesterol esterase secretion could be mimicked by addition of the Ca2+ ionophore A23187 or by transient incubation of AR42J cells with the protein kinase C activator phorbol 12-myristate 13-acetate (PMA). Cholesterol esterase stimulation by CCK, A23187 and PMA could be abolished by the calcium chelator BAPTA or by specific protein kinase C inhibitors such as chelerythrine. Additionally, prolonged incubation of AR42J cells with PMA to reduce the protein kinase C level, also reduced CCK-stimulated cholesterol esterase secretion to a level similar to that observed in control cells. Taken together, these data suggested that CCK activation of cholesterol esterase secretion may be mediated by a Ca(2+)-dependent protein kinase C pathway, requiring increases in calcium mobilization and activation of protein kinase C.

Topics: Animals; Calcimycin; Calcium; Cholecystokinin; Egtazic Acid; Enzyme Activation; Pancreas; Pancreatic Neoplasms; Protein Kinase C; Rats; Sterol Esterase; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

The importance of Ca2+ in the regulation of secretion is well-known. However, recent experiments suggest that a rise in intracellular Ca2+ (Ca2+i) does not necessarily trigger secretion in pancreatic acinar cells. In AR4-2J cells the role of the Ca2+ mobilization induced by cholecystokinin/gastrin (CCK/G), which is dependent of the intracellular calcium store and the calcium influx operating through voltage-dependent calcium channels, has never been directly demonstrated. Therefore, we attempted to determine whether Ca2+i and/or extracellular Ca2+ (Ca2+e) mobilized by CCK/G plays a role in the amylase secretion of these cells. We measured the [Ca2+]i by spectrofluorometry and amylase release in different experimental procedures modulating the two pools of calcium. Ionomycin increased both [Ca2+]i and amylase related. In Ca(2+)-depleted cells or in the presence of thapsigargin the transient rise in Ca2+i and the amylase secretion induced by CCK/G were suppressed. A 50 mM K+ solution or Bay K 8644, which activated the Ca2+ influx, did not induce any variation of the basal amylase secretion. Moreover, amylase secretion induced by CCK/G did not change significantly in Ca(2+)-free medium or in the presence of nifedipine. These results indicate that in AR4-2J cells, amylase secretion is dependent of the large increase in Ca2+i induced by CCK/G and independent of the Ca2+ influx through voltage-dependent calcium channels dihydropyridine sensitive.

Topics: Amylases; Animals; Calcium; Calcium Channel Blockers; Calcium Channels; Cholecystokinin; Enzyme Inhibitors; Gastrins; Intracellular Fluid; Ion Channel Gating; Ionomycin; Ionophores; Nifedipine; Pancreatic Neoplasms; Rats; Spectrometry, Fluorescence; Terpenes; Thapsigargin; Tumor Cells, Cultured

We have studied the effects of acetylcholine (ACh), and other agents that modulate pancreatic bicarbonate secretion, on the anion permeability of a human ductal adenocarcinoma cell line (BxPC-3). Anion permeability was monitored using an 125I efflux assay. ACh (10 microM) markedly stimulated 125I efflux from BxPC-3 cells and this response was abolished by atropine (10 microM), indicating that it is mediated by muscarinic receptors. Using transport inhibitors and ionophores, we obtained data indicating that some of the ACh-induced 125I efflux results from the opening of K+ channels, which would hyperpolarise the cell and increase the electrical driving force for 125I exit. The remaining ACh-induced 125I efflux is not mediated by anion exchangers or by Na+/K+/2Cl- cotransporters, and is probably explained by activation of an anion channel in the BxPC-3 cell membrane. Ionomycin (0.5 microM) caused a small rise in 125I efflux, indicating that this process can be triggered by an increase in intracellular calcium concentration. ATP (100 microM), ADP (100 microM), bombesin (10 nM), and cholecystokinin (CCK) (10 nM) also stimulated 125I efflux, indicating that receptors for these agents are expressed on BxPC-3 cells. We speculate that bicarbonate secretion from the human pancreas could be modulated by ACh, ATP, bombesin, and CCK via a direct effect on the duct cell.

Topics: Acetylcholine; Adenine Nucleotides; Adenocarcinoma; Adenosine Triphosphate; Bombesin; Cholecystokinin; Humans; Iodine Radioisotopes; Ion Channels; Ionomycin; Pancreatic Neoplasms; Potassium Channels; Tumor Cells, Cultured

Cholecystokinin (CCK) is an important trophic hormone for the pancreas, and CCK receptors are present on pancreatic carcinoma cells. We sought to determine whether either CCK itself or an antagonist of CCK could modulate the sensitivity of the human pancreatic cell line MIA-PaCa2 to cisplatin (DDP). The IC50 for a 1-h exposure to DDP was 35.3 +/- 3.2(SD) microM. Exposure to CCK8 octapeptide at physiologic and supra-physiologic concentrations did not alter the sensitivity of MIA-PaCa2 cells to DDP. The CCK receptor antagonist MK-329 was directly cytotoxic to the MIA-PaCa2 cells on a constant exposure schedule with an IC50 of 9.5 +/- 1.4 (SD) microM. MK-329 enhanced the sensitivity of MIA-PaCa2 cells to DDP by a factor of 3.5, and the interaction between DDP and MK-329 was shown to be synergistic by median-effect analysis. At a level of 50% cell kill, the combination index was 0.58 +/- 0.10. The ability of MK-329 to sensitize cells to DDP was schedule-dependent and required prolonged exposure to the antagonist following a 1-h exposure to DDP. MK-329 had no effect on the uptake of a radiolabeled analog of cisplatin ([3H]-dichloro(ethylenediamine)platinum) and did not affect intracellular glutathione content. MK-329 had no effect on the cell-cycle-phase distribution of MIA-PaCa2 cells and did not alter the DDP-induced cell-cycle perturbations. The cytotoxic effect of MK-329 and its ability to interact synergistically with DDP could not be reversed by CCK. We conclude that MK-329 is directly cytotoxic to pancreatic carcinoma cells and can enhance their sensitivity to DDP by a mechanism not related to its ability to antagonize the CCK receptor.

Topics: Antineoplastic Agents; Benzodiazepinones; Cell Cycle; Cholecystokinin; Cisplatin; Devazepide; Dose-Response Relationship, Drug; Drug Synergism; Humans; Organoplatinum Compounds; Pancreatic Neoplasms; Time Factors; Tumor Cells, Cultured

Gastrin and cholecystokinin (CCK) have proven trophic effects on the gut. We have previously demonstrated that these peptides stimulate an early event in cellular proliferation, namely ornithine decarboxylase activity (ODC), in a rat exocrine pancreatic cell line AR4-2J. Furthermore, this effect is mediated through a G/CCKB receptor. Thus, in the present study we sought to examine the signal transduction mechanisms linked to the G/CCKB receptor occupancy. Both gastrin and CCK induced a rapid (maximum at 40 s) increase in inositol triphosphates (InsP3) and diacylglycerol (DAG) formation in a dose-dependent manner (EC50 = 5.6 nM) that quickly returned to baseline. Although InsP3 levels remained at baseline, DAG levels demonstrated a second gradual increase that was maximal at 15 min. CCK/gastrin efficiency to stimulate DAG and InsP3 formation (EC50 = 5.6 nM) could be correlated to the G/CCKB receptor occupancy, suggesting a coupling of this receptor to phospholipase C. To examine the involvement of protein kinase C (PKC) activation in the increase in ODC activity, we stimulated the AR4-2J cells with the phorbol ester TPA and observed an increase in ODC activity with a maximal effect at 100 nM. TPA stimulation of ODC activity was completely abolished by the PKC inhibitor staurosporine (50 nM). However, 50 nM staurosporine inhibited only 65% of the gastrin and CCK induced increase in ODC activity suggesting that a portion of the G/CCKB receptor-mediated increase in ODC activity is PKC independent.

Topics: Alkaloids; Animals; Binding Sites; Cholecystokinin; Diglycerides; Dose-Response Relationship, Drug; Enzyme Activation; Gastrins; Inositol 1,4,5-Trisphosphate; Inositol Phosphates; Ornithine Decarboxylase; Pancreas; Pancreatic Neoplasms; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Protein Kinase C; Rats; Receptors, Cholecystokinin; Signal Transduction; Staurosporine; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured; Type C Phospholipases

Topics: Animals; Azaserine; Carcinogens; Cell Division; Cholecystokinin; Male; Pancreas; Pancreatic Neoplasms; Peptide Fragments; Precancerous Conditions; Rats; Rats, Inbred Lew; Receptors, Cholecystokinin; Sincalide; Tetragastrin

Raw soya diet in the hamster had short-term trophic effects on the pancreas, causing significant increases in pancreatic weight, DNA, RNA, and protein. These changes appear to be mediated by cholecystokinin (CCK) because the increases were blocked by infusion of the CCKA receptor antagonist, MK329. Raw soya diet significantly increased plasma levels of CCK in both the short-term and long-term studies. However, raw soya did not potentiate pancreatic cancer in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Infusion of MK329 during the initiation period of carcinogenesis did not change tumor incidence or yield, suggesting that endogenous CCK does not influence tumor induction during the initiation period in the hamster.

Topics: Animals; Carcinogens; Cholecystokinin; Cocarcinogenesis; Cricetinae; Diet; Glycine max; Male; Mesocricetus; Nitrosamines; Organ Size; Pancreas; Pancreatic Neoplasms; Receptors, Cholecystokinin

The mechanism by which high-fat diet potentiates pancreatic cancer is not known, but trophic hormones may be involved. In preliminary growth studies, hamsters fed a high fat diet (17.5% lard, 17.5% corn oil) for 14 days showed a 16.3% increase (P < 0.01) in pancreatic weight compared to controls on low fat diet (2.5% lard, 2.5% corn oil). A significant increase was also seen at 28 days. Similar increases were seen in pancreatic DNA (29%, P < 0.01) and pancreatic RNA (22%, P < 0.05) at 14 days. Plasma cholecystokinin (CCK) levels at 14 days were 2.5 fold higher in the animals fed high fat (P < 0.01). Infusion of the CCK antagonist MK329 (25 nmol/kg/h) completely abolished the increase in pancreatic weight, pancreatic DNA and pancreatic RNA. The effect of CCK receptor blockade during the initiation period of carcinogenesis was investigated in hamsters fed the same diets used in the growth studies. One hundred animals received a single injection of N-nitrosobis(2-oxopropyl)amine, (BOP, 20 mg/kg). Half of the hamsters in each diet group received a 2 week infusion of MK329 (25 nmol/kg/h), beginning 8 days before carcinogen administration. At the time of death, 55 weeks after carcinogen administration, non-fasting plasma CCK levels were 31% higher in the high fat fed hamsters than in the low fat fed animals (P < 0.01). The high-fat diet group had a 3-fold increase in total cancer incidence and a 5-fold increase in advanced lesions (adenocarcinomas). Tumor incidence and yield were not changed in either diet group by CCK-receptor blockade during the initiation period. Cholecystokinin appears to mediate the short-term trophic effect that high-fat feeding has on the pancreas. However, potentiation of pancreatic cancer by high-fat diet in the hamster cancer model does not appear to be influenced by endogenous cholecystokinin at the time of tumor induction.

Topics: Animals; Benzodiazepinones; Carcinogens; Cholecystokinin; Cricetinae; Devazepide; Diet; Dietary Fats; DNA; Male; Mesocricetus; Nitrosamines; Organ Size; Pancreas; Pancreatic Neoplasms; Proteins; Receptors, Cholecystokinin; RNA

The binding and biological effect of pituitary adenylate cyclase activating polypeptide (PACAP), a novel hypothalamic peptide with high sequence homology to vasoactive intestinal polypeptide (VIP), were studied in rat AR 4-2 J pancreatic carcinoma cells and isolated rat pancreatic acini. PACAP(1-27) and analogue PACAP(1-23, VIP-24-28), but not VIP, displaced potently and reversibly 125I-PACAP(1-27) from binding to an abundantly expressed high affinity PACAP-preferring receptor on AR 4-2 J cells, referred to as "PACAP-1 receptor." High affinity binding was dependent on N-terminal and C-terminal residues of PACAP(1-27): PACAP(1-24,Cys-25) (7.3 +/- 1.6 microM), PACAP(1-23) (8.2 +/- 1.5 microM), VIP (> 30 microM), PACAP(3-27), PACAP(1-19), PACAP(3-19), PACAP(1-12), and PACAP(18-38) (all > 50 microM) showed low or no binding potency. In contrast, high and low affinity binding of 125I-VIP to AR 4-2 J cells was displaced equipotently by PACAP(1-27) and VIP, thus defining on these cells, in addition, two scarcely expressed binding sites, designated "VIP/PACAP-2 receptor," similar or identical to the previously described high and low affinity acinar VIP receptor. Binding of 125I-PACAP(1-27) to a high and low affinity binding site on rat pancreatic acini was inhibited equipotently by PACAP(1-27) and VIP, identifying these sites as VIP/PACAP-2 receptors. PACAP(1-23) recognized both type 2 binding sites with only slightly lower affinity. PACAP(1-27), PACAP(1-38), PACAP(1-23, VIP-24-28), and PACAP(1-23) equipotently stimulated acinar lipase release and cyclic AMP production in pancreatic acini. Co-incubation of PACAP(1-27) or VIP with cholecystokinin-8 or carbachol revealed additive effects on enzyme secretion. Our results suggest the predominant expression of VIP/PACAP-2 receptors on rat pancreatic acini, whereas AR 4-2 J cells express mainly PACAP-1 receptors. PACAP is a potent ligand for both receptor types and has to be regarded as a novel VIP-like pancreatic secretagogue.

Topics: Amino Acid Sequence; Animals; Carbachol; Cholecystokinin; In Vitro Techniques; Iodine Radioisotopes; Lipase; Molecular Sequence Data; Neuropeptides; Neurotransmitter Agents; Pancreas; Pancreatic Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Second Messenger Systems; Sequence Homology, Amino Acid; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Cholecystokinin is thought to be an important factor regulating the growth of human pancreatic cancers. The study was designed to evaluate the effects of the cholecystokinin antagonist loxiglumide (CR1505) on the growth of human pancreatic cancer.. Human gastrointestinal cancer xenografted tumors (one esophageal, one gastric, two colorectal, two biliary tract, and two pancreatic cancers) were transplanted into nude mice. The mice were given CR1505 at 250 mg/kg daily for 14 days, either subcutaneously or intragastrically, and the tumor volumes before and after treatment were compared. In vitro effects of CR1505 were assessed by measuring the DNA synthesis (3H-thymidine incorporation).. CR1505 inhibited the growth of the two pancreatic cancer lines but did not inhibit the growth of the other lines. CR1505 also inhibited in vitro DNA synthesis in the two pancreatic cancer lines at lower concentrations than in the other lines. This pancreatic cancer-specific inhibitory effect of CR1505 was retarded by exogenously administered cholecystokinin in one pancreatic cancer line but was augmented in the other line. The effect of CR1505 was inhibited by oral administration of the trypsin-inhibitor camostate (FOY-305) in both pancreatic cancer lines.. These results suggest that CR1505 may specifically inhibit the growth of human pancreatic cancers and may be suitable for clinical study. However, its antiproliferative effect may not necessarily be dependent on its cholecystokinin-antagonism but may be mediated through the proteolytic enzymes found in the lysosomes of the pancreatic cancer cells.

Topics: Animals; Cell Division; Chloroquine; Cholecystokinin; DNA; Esters; Gabexate; Guanidines; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Organ Culture Techniques; Pancreatic Neoplasms; Proglumide; Sincalide; Transplantation, Heterologous

In the radioimmunoassay of human plasma cholecystokinin (CCK) using an antiserum OAL-656, it has been difficult to get stable fasting values as well as prominent postprandial increase. Therefore, we tried to extract human plasma with ethanol before the radioimmunoassay, and could solve these problems, that is fasting concentrations became stable (16.7 +/- 2.5 pg/ml) (mean +/- S.D., n = 9), and CCK concentrations were augmented promptly after feeding and were kept at higher levels for a certain period.

Topics: Adult; Aged; Cholecystokinin; Crohn Disease; Ethanol; Food; Humans; Immune Sera; Male; Pancreatic Neoplasms; Radioimmunoassay

The gastrointestinal peptide cholecystokinin (CCK) has been shown to stimulate growth of human pancreatic adenocarcinoma in vitro and in vivo, although CCK receptors have not been identified in pancreatic cancer cells. The purpose of this study was to characterize the CCK receptors in pancreatic cancer cells and to correlate the receptor binding studies with the trophic action of CCK agonists and antagonists. With the use of homogenates of PANC-1 human pancreatic cancer cell line grown in culture, the binding of 125I-labeled CCK octapeptide (125I-CCK-8) was examined under various conditions to characterize the CCK receptor. Specific and saturable binding of 125I-CCK-8 was detected in PANC-1 cells; data were consistent with a single binding site. Scatchard analysis yielded a binding affinity [dissociation constant (Kd)] of 2.8 nM and a binding capacity of 26 fmol/mg protein. Binding was dependent on protein concentration, time, temperature, the presence of protease inhibitors, and pH and was sensitive to Na+, K+, Mg2+, and ethylene glycolbis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. Competition experiments indicated that L-365,260, a selective CCK-B (gastrin) receptor antagonist, was the most potent displacer of 125I-CCK-8, and no significant displacement of binding was found with the selective CCK-A receptor antagonist. Growth of PANC-1 cells in culture was stimulated by CCK at a concentration consistent with the Kd, and CCK-stimulated growth was inhibited by the CCK-B receptor antagonist (L-365,260) not the CCK-A receptor antagonist (L-364,718).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Binding, Competitive; Cations; Cholecystokinin; Humans; Hydrogen-Ion Concentration; Osmolar Concentration; Pancreatic Neoplasms; Receptors, Cholecystokinin; Sincalide; Temperature; Time Factors; Tumor Cells, Cultured

Cholecystokinin (CCK) has been shown to stimulate the growth of both normal pancreas and azaserine-induced putative preneoplastic pancreatic lesions in the rat. The present study was performed to determine whether these effects are mediated by way of CCK-A receptors, CCK-B receptors, or both. Sixteen-day-old male Lewis rats were given i.p. injections of azaserine at 30 mg/kg body weight. Starting on day 21, rats were given s.c. injections, 5 days/week for 16 consecutive weeks, of either (a) CCK octapeptide (nonselective CCK agonist) (2.50 micrograms/kg body weight, n = 17), (b) tert-butyloxycarbonyl-Trp-Lys(epsilon-N-2-methylphenylaminocarbonyl++ +)-Asp- (N-methyl)-Phe-NH2 (highly selective CCK-A agonist) (1.84 micrograms/kg body weight, n = 18), (c) [(2R,3S)-beta-MePhe28,N-MeNle31]CCK26-33 (highly selective CCK-B agonist) (2.40 micrograms/kg body weight, n = 18), or (d) normal saline solution (control, n = 17). Rats were subsequently sacrificed, pancreatic weights were determined, and quantitative morphometric analysis of atypical acinar cell foci and nodules was performed. Both CCK octapeptide and the selective CCK-A agonist tert-butyloxycarbonyl-Trp-Lys(epsilon-N-2- methylphenylaminocarbonyl)-Asp-(N-methyl)-Phe-NH2 stimulated pancreatic growth and the development of acidophilic atypical acinar cell foci and nodules. Furthermore, the effect produced by the selective CCK-A agonist tert-butyloxycarbonyl-Trp-Lys(epsilon-N-2- methylphenylaminocarbonyl)-Asp-(N-methyl)-Phe-NH2 was greater than that produced by CCK octapeptide. In contrast, the selective CCK-B agonist [(2R,3S)-beta-MePhe28,N-MeNle31]CCK26-33 had no effect. These findings suggest that the growth of putative preneoplastic lesions (acidophilic atypical acinar cell foci and nodules) in the rat pancreas during the early stages of azaserine-induced pancreatic carcinogenesis is mediated specifically by way of CCK-A receptors.

Topics: Animals; Azaserine; Cholecystokinin; Chronic Disease; Male; Organ Size; Pancreas; Pancreatic Neoplasms; Pancreatitis; Peptide Fragments; Precancerous Conditions; Rats; Rats, Inbred Lew; Receptors, Cholecystokinin; Sincalide; Tetragastrin

The effects of cholecystokinin (CCK) and a CCK antagonist, loxiglumide (CR-1505), on four freshly separated and six xenografted human pancreatic cancers, were investigated. The level of DNA synthesis in only one of five tested pancreatic cancers was enhanced by CCK at concentrations of 0.01-10 nM, while in the other four cancers DNA synthesis was not affected. The levels of DNA, RNA, and protein synthesis (by 3H-thymidine, 3H-uridine, and 3H-leucine incorporation tests, respectively) in all the tested cancers were dose-dependently inhibited by loxiglumide at concentrations of 20-2000 microM, and the IC50 of loxiglumide for DNA synthesis in pancreatic cancers was 156 +/- 80 microM (means +/- SD). The in vivo effect of loxiglumide was assessed using a xenografted line (PC-HN) transplanted in nude mice. The in vivo 50% lethal dose of loxiglumide for nude mice was about 500 mg/kg. Death was caused by respiratory failure due to severe congestion of the lung after the administration of a large dose of loxiglumide. The growth of a PC-HN transplanted in the nude mice was significantly inhibited by subcutaneous loxiglumide at 250 mg/kg, twice a day for 28 days, which did not cause death. It is suggested that loxiglumide inhibits the in vivo and in vitro growth of human pancreatic cancer, perhaps independently of its action as a CCK antagonist, and this study also suggests that loxiglumide may be a new type of therapeutic agent to be used for the treatment of human pancreatic cancer.

Topics: Animals; Carcinoma, Intraductal, Noninfiltrating; Cholecystokinin; DNA, Neoplasm; Dose-Response Relationship, Drug; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Proglumide; RNA, Neoplasm; Transplantation, Heterologous; Tumor Cells, Cultured

The role of intraduodenal bile in regulation of plasma cholecystokinin (CCK) levels were investigated in patients with obstructive jaundice under external bile diversion and under physiological bile flow into the duodenum by internal bile drainage. Basal plasma CCK levels determined by a specific and sensitive bioassay in patients under external bile drainage (2.2 +/- 0.2 pmol/liter; mean +/- SE) were significantly higher than those in control subjects (1.0 +/- 0.3 pmol/liter). In control subjects, the peak CCK response (6.2 +/- 0.7 pmol/liter) to a test meal was seen at 45 min, whereas that in patients under external bile drainage, it was seen at 20 min after a test meal (17.6 +/- 3.2 pmol/liter; P < 0.01 vs controls). After peak response, plasma CCK levels in controls gradually decreased, but remained significantly elevated during a 3-hr observation period. In patients under bile diversion, the test meal caused a prompt plasma CCK peak, with a transient fall followed by a continuous rise until 180 min postprandially. In six patients, external bile diversion was changed to internal biliary drainage with a stent tube within two weeks to maintain physiological bile flow into the duodenum. Internal bile drainage normalized basal (0.9 +/- 0.2 pmol/liter) as well as meal-stimulated CCK release (peak value: 5.0 +/- 0.8 pmol/liter). These results demonstrate that endogenous bile exerts tonic inhibition on basal and postprandial plasma CCK levels in humans.

Topics: Adenoma, Bile Duct; Adult; Aged; Ampulla of Vater; Bile; Bile Duct Neoplasms; Cholecystokinin; Cholestasis; Common Bile Duct Neoplasms; Drainage; Eating; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Time Factors

We previously established pluripotent transformed rat islet cell lines, MSL-cells, of which certain clones have been used to study processes of islet beta-cell maturation, including the transcriptional activation of the insulin gene induced by in vivo passage. Thus, successive sc transplantation in NEDH rats resulted in stable hypoglycemic insulinoma tumor lines, such as MSL-G2-IN. Occasionally, hypoglycemia as well as severe weight loss were observed in the early tumor passages of MSL-G and the subclone, NHI-5B, which carry the transfected neomycin and human insulin genes as unique clonal markers. By selective transplantation, it was possible to segregate stable anorectic normoglycemic tumor lines, MSL-G-AN and NHI-5B-AN, from both clones. These tumors cause an abrupt onset of anorexia when they reach a size of 400-500 mg (< 0.3% of total body weight), and the observed weight loss parallels that of starved rats until death results from cachexia. After tumor resection, animals immediately resume normal feeding behavior. Comparative studies of hormone release and mRNA content in anorectic lines, MSL-G-AN and NHI-5B-AN, vs. those in the insulinoma line, MSL-G2-IN, revealed selective glucagon gene expression in both of the anorectic tumors, whereas insulin and islet amyloid polypeptide gene expression were confined to the insulinoma. Both tumor phenotypes produced cholecystokinin and gastrin in variable small amounts, making it unlikely that these hormones contribute to the anorectic phenotype. Tumor necrosis factor (cachectin) was not produced by any of the tumors. Proglucagon was processed as in the fetal islet to products representative of both pancreatic alpha-cell and intestinal L-cell phenotypes, with glucagon and Glp-1 (7-36)amide as the major extractable products. In contrast to the administration of cholecystokinin, neither glucagon, Glp-1 (7-36)amide, nor their combination, affected feeding behavior in fasted mice, suggesting the presence of a hitherto unidentified anorectic substance released from the glucagonoma. We conclude 1) that glucagonomas and insulinomas can be derived from a common clonal origin of pluripotent MSL cells, thus supporting the existence of a cell lineage relationship between islet alpha- and beta-cell during ontogeny; and 2) that our glucagonomas release an anorexigenic substance(s) of unknown nature that causes a severe weight loss comparable to that reported in animals carrying tumor necrosis factor-producing experimental

Topics: Adenoma, Islet Cell; Animals; Anorexia; Base Sequence; Blotting, Northern; Cholecystokinin; Eating; Gastrins; Gene Expression; Glucagon; Hormones; Hypoglycemia; Molecular Sequence Data; Neoplasm Transplantation; Pancreatic Neoplasms; Protein Precursors; Rats; Tumor Cells, Cultured; Weight Loss

The role of cholecystokinin (CCK) has been explored in pancreatic carcinogenesis following pancreatobiliary diversion (PBD), using the specific CCK receptor antagonist CR-1409. Male Wistar rats (n = 80) weighing 70-100 g were given weekly i.p. injections of azaserine (30 mg kg-1 week-1) for 3 consecutive weeks. One week later animals were randomised to receive either PBD or sham PBD and thereafter to receive s.c. injections of either saline or CR-1409 (10 mg kg-1 day-1, 5 days a week). Six months after operation surviving rats were killed as follows: sham + saline 20, PBD + saline 19, sham + CR-1409 14, PBD + CR-1409 11. Cardiac blood was taken for CCK assay and the pancreas was excised for wet weight measurement and quantitative estimation of atypical acinar cell foci (AACF), the precursor of carcinoma. PBD reduced median body weight (3-20% less than shams) but trebled the absolute and relative pancreatic weights (P < 0.001). CR-1409 blunted this adaptive response to PBD, reducing absolute pancreatic weight by 35% (P < 0.005). PBD quadrupled circulating CCK concentrations, regardless of the antagonist treatment. Acidophilic AACF occurred only in rats with PBD. CR-1409 markedly reduced the number of observed acidophilic AACF by 90% (P < 0.001) and the number of foci per pancreas by 93% (P < 0.001). Moreover, CR-1409 reduced the mean focal diameter of each lesion by 18% (P < 0.005), the mean focal volume by 58% (P < 0.05) and the percentage of pancreas occupied by acidophilic foci by 95% (P < 0.001). PBD enhances pancreatic carcinogenesis by causing hypercholecystokininaemia, and CR-1409 largely inhibits this enhancement.

Topics: Animals; Azaserine; Biliopancreatic Diversion; Body Weight; Cholecystokinin; Cocarcinogenesis; Male; Organ Size; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Proglumide; Rats; Rats, Wistar

The effects of pancreaticobiliary diversion (PBD) and gastric fundectomy on the pancreas in azaserine-treated rats were studied over 14 months. Sham-operated azaserine-treated animals served as controls. A significant increase in pancreatic weight and total DNA and protein content was found in PBD-operated and fundectomized animals. DNA flow cytometry showed a significantly increased ratio of tetraploid to diploid cells in pancreatic tissue in both experimental groups. Mean values of all these variables were significantly higher after PBD than after fundectomy. Acidophilic atypical acinar cell foci of the pancreas were observed in all of the experimental and 75% of the control animals. The volume density of these foci was significantly higher in each experimental group than in the controls. The volume density, radioactive thymidine labeling index, and mitotic index of the foci were significantly higher after PBD than after fundectomy. Changes consistent with pancreatic adenoma were diagnosed in the PBD group only. It is concluded that not only PBD with endogenous hypercholecystokininemia, but also fundectomy with endogenous hypergastrinemia lasting about half of the life span in rats, induces pancreatic hypertrophy and enhances the development of precancerous pancreatic changes after azaserine treatment. In comparison with PBD, fundectomy caused less pronounced changes and no observable neoplasia.

Topics: Animals; Azaserine; Bile Ducts; Cholecystokinin; DNA; Gastric Fundus; Male; Pancreatic Ducts; Pancreatic Neoplasms; Rats; Rats, Wistar

In order to clarify the interaction of hormones which exert various effects on the exocrine pancreas, we investigated the effect of cholecystokinin (CCK) and secretin on subsequent insulin binding to pancreatic acini and cultured AR42J cells derived from azaserine-induced acinar cell carcinoma of the pancreas. CCK at concentrations of 100pM-10nM inhibited subsequent 125I-insulin binding to pancreatic acini. 12-O-tetradecanoylphorbol 13-acetate (TPA) inhibited 125I-insulin binding whereas A23187 had little effect, suggesting that the inhibitory effect of CCK is mediated by protein kinase C. On the other hand, 100pM-10nM secretin had no effect on subsequent 125I-insulin binding to pancreatic acini, although higher concentrations of forskolin and 8 bromoadenosine 3', 5'-cyclic monophosphate inhibited 125I-insulin binding. In addition, secretin exerted no potentiating effect on the inhibitory effect of CCK on 125I-insulin binding to pancreatic acini. Based on these results, we further investigated the effect of CCK and TPA on subsequent 125I-insulin binding to AR42J cells. In this carcinoma cell line, inhibitory effect of CCK and TPA on insulin binding was completely abolished. The present results suggest, therefore, that hormonal interaction may play an important role in the regulation of exocrine pancreatic function including acinar cell growth.

Topics: Animals; Cholecystokinin; Dose-Response Relationship, Drug; Insulin; Male; Pancreas; Pancreatic Neoplasms; Rats; Rats, Wistar; Secretin; Tumor Cells, Cultured

We studied on the effect of combined use of CR1505 with UFT for the subcutaneously transplanted pancreatic cancer induced by BOP (N-nitrosobis (2-oxopropyl) amine) in the Syrian golden hamsters. The tumor growth in the group treated with both CR1505 and UFT was significantly inhibited compared with that in the group treated with only CR1505 or UFT. Labelling index judged by BrdU immunohistochemistry in the group with the combined use was significantly lower than that in the group with the single use. The differences of the body weights and blood analysis were not obscured in the both groups. Moreover, the concentrations of 5-FU and FT207 in tumors were not different between them. These results suggest that a new therapy of the combined use with CR1505 and UFT for the pancreatic cancer should be effective.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cholecystokinin; Cricetinae; Mesocricetus; Neoplasm Transplantation; Nitrosamines; Pancreatic Neoplasms; Proglumide; Tegafur; Uracil

Pancreatic nodules were produced in rats by either feeding raw soya flour alone or by injection of azaserine plus raw soya flour feeding. The resulting nodules were studied to determine whether there was any functional difference between this tissue and the relatively normal internodular pancreas. Tissue DNA and trypsin content were significantly elevated in nodules compared to the adjacent tissue. With fasting, protein and enzyme content increased significantly and equally in both nodular and internodular tissues. RNA levels fell significantly and the decrease was more pronounced in nodular tissue. The responsiveness of the multinodular pancreas to cholecystokinin was examined by measuring pancreatic secretion basally and in response to cholecystokinin. Both the volume and protein content secreted by the multinodular pancreas were greatly elevated above control levels. When corrected for pancreatic weight, the difference remained significant and appeared to be due to increased basal secretion by the nodular pancreas. These studies demonstrate that azaserine-raw soya flour induced nodules are functionally efficient. Furthermore, the secretory response to cholecystokinin of these nodules is equal to or higher than that of normal tissue.

Topics: Amylases; Animals; Azaserine; Cholecystokinin; Fasting; Male; Pancreas; Pancreatic Neoplasms; Rats; Rats, Wistar; Trypsin

The rat insulinoma RIN 5F and the mouse pituitary AtT-20 cell line, which are known to express several biologically active peptides, were found to express CCK mRNA, to correctly process, and to release immunoreactive cholecystokinin (CCK) peptides. They expressed low levels of these peptides (about 0.4 and 0.2 ng/mg protein, respectively) and both cell lines processed pro-CCK to a form which co-eluted with CCK 8 sulfate on Sephadex gel filtration chromatography and HPLC. The major CCK 8 immunoreactive peptide which they secreted co-eluted with CCK 8 on Sephadex G-50 chromatography. The secretion of CCK from both cell lines was significantly enhanced by treatment for 24 h with forskolin + IBMX (3-isobutyl-1-methyl-xanthine, a phosphodiesterase inhibitor). This treatment also doubled the CCK content of the AtT-20 cells. It appears that the ability of different endocrine tumor cells to express and process CCK is not as uncommon as previously thought. These cells should be useful for future studies of CCK expression, processing, and regulation of secretion.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Blotting, Northern; Cholecystokinin; Chromatography, High Pressure Liquid; Colforsin; Cyclic AMP; Gene Expression; Insulinoma; Mice; Pancreatic Neoplasms; Pituitary Neoplasms; Protein Precursors; Rats; RNA, Messenger; Sincalide; Tumor Cells, Cultured

The effect of unsulfated cholecystokinin on pancreatic growth was evaluated in two experimental models in vivo and in vitro. Mice were injected with sulfated cholecystokinin (CCKs) or unsulfated cholecystokinin (CCKu) (10 or 20 micrograms/kg) or vehicle twice daily for 15 days. Animals were then killed and pancreatic weights, protein, amylase, and DNA content were evaluated. In vitro, growth was evaluated by DNA synthesis and viable cell counts. MIA PaCa-2 and BxPC-3 human pancreatic cancer cells were treated with CCKs or CCKu (10(-12) to 10(-9) M) for 48 or 72 h in the presence of [3H]thymidine to evaluate DNA synthesis. Viable cell counts were performed on both cell lines grown in the presence or absence of unsulfated CCK (10(-12) to 10(-9) M) for 96 h. Pancreatic weight, protein, amylase, and DNA were significantly increased in animals treated with either CCKs or CCKu. However, pancreatic weight, protein, and amylase were significantly higher in mice treated with CCKs compared to CCKu (p less than 0.005). DNA content and index of hyperplasia were the same whether mice were treated with CCKs or CCKu. CCKu was as potent a stimulus for DNA synthesis as CCKs in MIA PaCa-2 and BxPC-3 cells. Finally, CCKu increased cell counts in both pancreatic cancer cell lines. These data suggest that the mechanisms responsible for CCK-induced growth of normal pancreas and pancreatic cancer may differ from those that regulate secretion.

Topics: Amylases; Animals; Cholecystokinin; DNA; Female; Humans; Hyperplasia; Mice; Mice, Inbred BALB C; Organ Size; Pancreas; Pancreatic Neoplasms; Proteins; Sulfates; Tumor Cells, Cultured

Surgery for peptic ulcer disease may increase the risk of pancreatic cancer. The effect of duodenogastric reflux on pancreatic carcinogenesis was tested, and changes in the circulating levels of cholecystokinin (CCK) and gastrin were measured. Male Wistar rats (n = 40) weighing 250-300 g were randomized to undergo gastrotomy (control) or split gastrojejunostomy (to produce complete duodenogastric reflux) and then to receive azaserine (30 mg/kg/week intraperitoneally) or saline injections for 3 weeks. At 6 months, blood CCK was assayed and the pancreas was excised for quantitative estimation of atypical acinar cell foci (AACF), the precursor lesions of carcinoma. Rats that had undergone split gastrojejunostomy weighed 15-19 per cent less than controls (P < 0.05), but their relative pancreatic weight (mg pancreas per 100 g body-weight) was 52-60 per cent greater (P < 0.001). Acidophilic AACF occurred only in azaserine-treated rats with duodenogastric reflux. Although plasma CCK concentrations were unchanged, split gastrojejunostomy increased basal and postprandial gastrin levels by 98-175 per cent (P < 0.05). Duodenogastric reflux produces sustained hypergastrinaemia and promotes experimental pancreatic carcinogenesis.

Topics: Anastomosis, Surgical; Animals; Cholecystokinin; Duodenogastric Reflux; Gastrins; Jejunum; Male; Pancreatic Neoplasms; Postoperative Complications; Rats; Rats, Inbred Strains; Stomach

Cholecystokinin and bombesin have been shown to promote pancreatic growth and development of azaserine-induced acidophilic atypical acinar cell nodules in rat pancreas after treatment for 16 weeks. Lorglumide, a specific cholecystokinin receptor antagonist, inhibited the stimulating effect of cholecystokinin, but not of bombesin. The present study was carried out to determine effects of cholecystokinin and bombesin, alone and in combination with lorglumide, on pancreatic growth and carcinogenesis after chronic treatment. The animals were killed 8 months after the start of treatment. Growth of the pancreas and the development of acidophilic atypical acinar cell nodules in exocrine pancreas was enhanced significantly by both cholecystokinin and bombesin, but the number of carcinomas was increased only by bombesin. Lorglumide inhibited the effects of cholecystokinin on both pancreatic growth and on the development of acidophilic nodules. The effects of bombesin on pancreatic growth and development of pancreatic lesions, except for adenomas, were not inhibited by lorglumide.

Topics: Animals; Azaserine; Bombesin; Carcinogens; Cholecystokinin; Drug Synergism; Male; Pancreatic Neoplasms; Proglumide; Rats; Rats, Wistar; Receptors, Cholecystokinin

Effects of caerulein (CCK), 5-FU and CCK antagonist, loxiglumide (CR1505), were studied on the growth of human pancreatic cancer cell line, KP-1 N, in vitro. And effects of UFT and CR 1505 were also studied on liver metastasis in nude mice. The growth of KP-1 N was stimulated approximately 40% by addition of 10(-10) M of CCK in vitro. CR1505 antagonized the action of CCK, that is, the 40% growth rate increase was suppressed by addition of 25 microM of CR1505. Moreover, the growth rate of the cells dose-dependently decreased by the addition of CR1505. 5-FU also dose-dependently inhibited the growth of KP-1 N in culture. 5-FU additionally decreased the growth rate of KP-1 N in combination with CR1505. A number of metastatic nodules were found in the liver of nude mice a month after injections of KP-1 N cells into the spleen CR1505 suppressed the liver metastasis in nude mice which were administered with UFT. These results suggest that CR1505 would be useful for the treatment of human pancreatic cancer in combination with UFT.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cholecystokinin; Humans; Liver Neoplasms; Mice; Mice, Nude; Pancreatic Neoplasms; Proglumide; Tegafur; Tumor Cells, Cultured; Uracil

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cholecystokinin; Cricetinae; Drug Synergism; Mesocricetus; Neoplasm Transplantation; Pancreatic Neoplasms; Proglumide; Tegafur; Uracil

The Human pancreatic carcinoma cell line KP-1N and its clone KP-1NL which has a high rate of liver metastasis were established. Ki-ras DNA point mutation on the codon 12 was found. The growth of KP-1N was stimulated by a physiological range of concentration (10(-11)-10(-10) M) of cholecystokinin and the increase was inhibited by the addition of a cholecystokinin receptor antagonist (CR 1505). Daily injections of CR 1505 (35 mg/kg) diminished the number of tumor colonies in the liver that were formed after an intrasplenic injection of the highly liver metastatic KP-1NL cells. These results suggest that cholecystokinin antagonists may be useful as growth inhibitors for some pancreatic cancer.

Topics: Adenocarcinoma; Animals; Ceruletide; Cholecystokinin; Humans; In Vitro Techniques; Liver Neoplasms; Mice; Mice, Nude; Pancreatic Neoplasms; Proglumide; Tumor Cells, Cultured

The controversial issue of enhanced pancreatic carcinogenesis following partial gastrectomy has been explored in male Wistar rats (n = 40) weighing 250-300 g. Animals were randomised to receive either 60% distal gastrectomy with Roux-en-Y reconstruction or gastrotomy and resuture (control). Immediately after operation each group was further divided into two subgroups, receiving i.p. injections of either saline or azaserine (30 mg kg-1 wk-1 for 3 weeks). At 15 months blood was obtained at 0, 5, 15 and 30 min after a fatty meal for cholecystokinin (CCK) assay; rats were then killed. Pancreatic wet weight was measured, and histological sections were examined for atypical acinar cell foci (AACF), the putative precursor lesion of carcinoma. There were no significant differences in body weight or pancreatic weight between controls and rats with gastrectomy. Only azaserine-treated rats had acidophilic AACF. Partial gastrectomy substantially increased the number of acidophilic AACF per pancreas (median 26.05 vs 2.09; P less than 0.005), with a 9-fold increase in their volume (P less than 0.005). Basal and postprandial plasma CCK concentrations were higher after gastrectomy than in controls (P less than 0.05). Partial gastrectomy has an enhancing effect on azaserine-induced pancreatic carcinogenesis, probably by means of increased CCK release.

Topics: Anastomosis, Roux-en-Y; Animals; Azaserine; Cholecystokinin; Dietary Fats; Follow-Up Studies; Gastrectomy; Male; Neoplasms, Experimental; Organ Size; Pancreas; Pancreatic Neoplasms; Postoperative Complications; Precancerous Conditions; Rats; Rats, Inbred Strains; Stomach

The role of cholecystokinin in dietary fat-promoted pancreatic carcinogenesis was investigated in azaserine-treated rats, using lorglumide, a highly specific cholecystokinin-receptor antagonist. The animals were killed 8 months after the start of treatment. Cholecystokinin, but not dietary unsaturated fat, increased pancreatic weight. Rats treated with cholecystokinin developed more acidophilic atypical acinar cell nodules, adenomas and adenocarcinomas than control animals. Rats maintained on the high-fat diet developed significantly more adenomas and adenocarcinomas than controls given a diet low in unsaturated fat. Lorglumide largely inhibited the enhancing effect of cholecystokinin, but not of dietary fat, on pancreatic carcinogenesis indicating that it is unlikely that the promoting effect of dietary unsaturated fat on pancreatic carcinogenesis is mediated via cholecystokinin.

Topics: Animals; Azaserine; Body Weight; Cholecystokinin; Dietary Fats; Liver; Male; Organ Size; Pancreas; Pancreatic Neoplasms; Proglumide; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin

This study investigates digestive and lysosomal enzyme secretion of azaserine-induced pancreatic acinar carcinomas in response to cholecystokinin in rats. After 15-20 months of treatment, 95% of the animals developed pancreatic acinar carcinomas encompassing more than 90% of the tissue. In anesthetized rats basal trypsin output was significantly elevated in the tumor group despite diminished fluid secretion. There was a linear correlation between tumor size and basal amylase and trypsin secretion. Intravenous infusion of cholecystokinin (25 IDU.kg-1.h-1) induced a significantly lower secretion of fluid per gram pancreas, as well as decreased amylase and trypsin output, in the tumor group compared with the control group. Plasma amylase and lipase levels were significantly elevated in the tumor group under both basal and stimulated conditions. The output of the lysosomal enzymes beta-D-glucuronidase and alpha-D-glucosidase was significantly increased in the tumor group under background secretin infusion. Additional cholecystokinin infusion caused a sharp increase in glucuronidase output in this group with only minimal increase in controls. Glucosidase output increased similarly in both groups. Amylase, lipase, and trypsin tumor tissue concentrations were markedly reduced by 85%, 90%, and 87%, respectively. It was concluded that the decreased secretory response of digestive enzymes may result from decreased synthesis, lowered storage capabilities, and/or a decreased/increased responsiveness to cholecystokinin. Increased glucuronidase secretion may reflect an augmented cell turnover of malignant tissue.

Topics: Adenoma; alpha-Glucosidases; Amylases; Animals; Azaserine; Carcinoma; Cholecystokinin; Food, Formulated; Glucuronidase; Lipase; Lysosomes; Male; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Secretin; Trypsin

Trypsin inhibitors have been shown to promote pancreatic growth as well as the development of pancreatic tumours in rats. The present study was carried out to examine the effects of the synthetic trypsin inhibitor camostate on the growth of the pancreas and on the development of pancreatic preneoplastic and neoplastic lesions in hamsters treated with N-nitrosobis(2-oxopropyl)amine. A specific cholecystokinin-receptor antagonist was administered to determine the role of cholecystokinin in camostate action. The animals were killed 19 weeks after the first injection with N-nitrosobis(2-oxopropyl)amine. Camostate caused an increase in growth of the pancreas and a decrease in the number of (pre)neoplastic ductular pancreatic lesions. Lorglumide (CR-1409) did not influence these effects of camostate. It was concluded that rats and hamsters behave differently with regard to the effect of camostate on pancreatic growth and carcinogenesis.

Topics: Animals; Carcinogens; Carcinoma; Carcinoma in Situ; Cholecystokinin; Cricetinae; Esters; Gabexate; Guanidines; Male; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms; Proglumide; Reference Values; Trypsin Inhibitors

Cholecystokinin (CCK) has been shown to increase cytosolic calcium and stimulate enzyme release from pancreatic acinar cells and a rat acinar cell line, AR42J. CCK is also trophic to normal pancreas and pancreatic cancer; however, the cellular mechanisms which regulate CCK-stimulated growth are unknown. The effect of CCK on intracellular calcium was evaluated in four human pancreatic cancer cell lines known to grow in response to CCK but not secrete enzymes (SW-1990, MIA PaCa-2, BXPC-3 and PANC-1) and a rat acinar cell line (AR42J) shown to secrete enzymes but not grow with CCK. By using single cell fluorescence microscopy in fura-2 loaded cells, intracellular calcium [Ca2+]i was measured. After obtaining baseline fluorescent cell images, synthetic CCK-octapeptide (CCK8) was added to the cells and images of cell fluorescence captured. [Ca2+]i of the rat acinar cells increased (603%) over the baseline within the first minute after the addition of CCK (4.10(-13) M to 4.10(-10) M) in 77% of cells tested. In contrast [Ca2+]i failed to significantly change in the human cancer cells treated with CCK. To further localize the defect in hormone signal transduction in cancer cells, cells were suspended in low calcium media and the plasma membranes were selectively permeabilized with digitonin. Media free calcium concentration was continuously monitored by fura-2 fluorescence. Addition of inositol 1,4,5-trisphosphate (IP3) resulted in a marked increase in medium calcium concentration indicating IP3 was capable of releasing calcium from intracellular stores in both the AR42J rat acinar cell line and in the human pancreas cancer cell lines. In conclusion, CCK does not increase cytosolic calcium in human pancreatic cancer cells in contrast to rat acinar cells although all contain IP3-sensitive intracellular Ca2+ pools. Our results suggest that growth promoting and secretory effects of CCK on pancreatic cells may occur via two independent signalling pathways.

Topics: Adenocarcinoma; Calcium; Cholecystokinin; Cytosol; Fura-2; Humans; Image Processing, Computer-Assisted; Inositol 1,4,5-Trisphosphate; Pancreas; Pancreatic Neoplasms; Signal Transduction; Tumor Cells, Cultured

Receptor currents generated in response to the application of sulfated octa-cholecystokinin (CCK) and various pancreatic secretagogues were studied in AR42J cells, a rat pancreatic acinar cell line. A whole cell configuration of the patch electrode voltage-clamp technique was utilized in these studies. Over 60% of the cells examined responded to 10(-6) M CCK by generating inward current at a membrane holding potential of -70 mV, accompanied by an increased membrane conductance. The CCK-induced receptor current (ICCK) was typically inactivated within 30 s in the presence of the ligand. The reversal potential (Erev) of the ICCK was approximately 0 mV when recorded in control bathing solution with a pipette containing 154 mM Cl-. When Cl- concentration in the bathing solution or in the recording pipette was modified, the Erev of the ICCK shifted toward the predicted Cl- potential. Na+ and K+ did not show significant contributions to the Erev of ICCK. Hence, the ICCK involves an increased Cl- conductance. This increased Cl- conductance appears to be due to an increase in intracellular Ca2+, since the ICCK could not be recorded from cells using pipettes containing 5 mM EGTA. Application of a Ca2+ ionophore A23187 (5 microM) to cells in control saline induced a similar inward current flow. The source of the Ca2+ involved in the ICCK appears to be mainly intracellular, since the ICCK could be recorded under conditions designed to completely block the voltage-dependent Ca2+ entry. These included exposure of the cells to a Ca2(+)-free saline for a brief period or the presence of 500 microM Cd2+ in the control bathing solution.

Topics: Animals; Calcimycin; Calcium Channels; Cell Line; Chlorides; Cholecystokinin; Egtazic Acid; Kinetics; Membrane Potentials; Mice; Pancreas; Pancreatic Neoplasms; Rats; Receptors, Cholecystokinin; Sodium

The growth responses of six human pancreatic cancer cell lines (SW-1990, PANC-1, MIA PaCa-2, BxPC-3, RWP-2 and CAPAN-2) to cholecystokinin (CCK) were evaluated in serum-free medium (SFM). In each experiment cells were initially plated in media containing fetal calf serum (FCS) grown for 48-72 h, and then washed with saline. Cells were incubated for an additional 72 to 96 h in medium devoid of FCS in the absence (control) or presence of synthetic CCK analogue (Thr4,Nle7)CCK9 (10(-13) to 10(-9) M), or CCK8 (10(-12) to 10(-9) M), or CCK39 (10(-12) to 10(-9) M). Viable cell counts were performed with a hemocytometer. Growth of each cell line was stimulated in the presence of CCK in serum-free medium, although the magnitude of responses differed. The concentrations of (Thr4,Nle7)CCK9 which stimulated the greatest increase in cell counts as compared to controls for each cell line were: SW-1990, 39% (10(-12) M, P less than 0.05); PANC-1, 45% (10(-9) M, P less than 0.005); MIA PaCa-2, 42% (10(-12) M, P less than 0.005); BxPC-3, 32% (10(-13) M, P less than 0.05); RWP-2, 37% (10(-11) M, P less than 0.005). Maximal response to CCK8 occurred at the 10(-9) M dose for each cell line: MIA PaCa-2, 40% (P less than 0.025); PANC-1, 85% (P less than 0.001); RWP-2, 68% (P less than 0.001) and CAPAN-2, 52% (P less than 0.001). The maximal increase in cell count with CCK39 ranged from 44-74% and occurred with either 10(-11) or 10(-10) M. CCK8 in SFM also stimulated cell growth as well as or better than FCS alone in three out of four pancreatic cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Animals; Cell Count; Cell Transformation, Neoplastic; Cholecystokinin; Mice; Mice, Nude; Pancreatic Neoplasms; Tumor Cells, Cultured

Bombesin (BBS) has been shown to promote pancreatic growth as well as the development of pancreatic (pre)neoplasia in rats. The present study was carried out to determine the effects of bombesin on pancreatic growth and on the development of pancreatic (pre)neoplastic lesions in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Bombesin caused an increase in growth of the pancreas accompanied by a decrease in the number of (pre)neoplastic ductular pancreatic lesions. Lorglumide (CR-1409) did not influence these effects of bombesin. It is concluded that in BOP-treated hamsters the effect of bombesin on the pancreas is not mediated by cholecystokinin (CCK). These data support the existence of species difference between rats and hamsters with regard to the effect of bombesin on pancreatic carcinogenesis.

Topics: Animals; Body Weight; Bombesin; Cholecystokinin; Cricetinae; Liver; Male; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms; Proglumide

In the present study, the effects of pancreastatin on growth are evaluated in two human pancreatic cancer cell lines, in vivo and in vitro, and on athymic nude mouse pancreas. SW-1990 and MIA PaCa-2 pancreatic cancer cell lines were grown in serum-supplemented and serum-free medium in the presence of pancreastatin (10(-11)-10(-6) M), or cholecystokinin (CCK) (10(-11)-10(-8) M) or combinations thereof. Growth was evaluated by [3H]thymidine incorporation and cell counts. Pancreastatin significantly inhibited DNA synthesis in both cell lines, and cell counts in SW-1990 on days 3 and 5 but not 7. CCK-stimulated cell growth was inhibited in both cell lines and mouse pancreas by pancreastatin. Pancreastatin had no effect in the presence of fetal bovine serum. In the in vivo experiments, pancreastatin (15 micrograms/kg) did not affect growth of SW-1990 xenografts to nude mice, but inhibited CCK-stimulated growth transiently. Pancreastatin (100 micrograms/kg) transiently decreased volumes of MIA PaCa-2 xenografts to nude mice and significantly decreased weight, protein, and DNA of mouse pancreas. Fasting glucose levels of mice treated with pancreastatin 100 micrograms/kg for 35 days were significantly lower than controls. Our results demonstrate that pancreastatin not only inhibits CCK-stimulated pancreatic growth but also has inhibitory effects by itself.

Topics: Animals; Cell Division; Cells, Cultured; Cholecystokinin; Chromogranin A; DNA; Dose-Response Relationship, Drug; Humans; Mice; Mice, Nude; Pancreas; Pancreatic Hormones; Pancreatic Neoplasms; Thymidine; Transplantation, Heterologous; Tritium; Tumor Cells, Cultured

This study used the rat pancreatoma AR42J as a model system to investigate the possible regulation of cholesterol esterase biosynthesis in pancreas. Initial experiments were performed to verify the synthesis of pancreatic cholesterol esterase by the AR42J cells. Results indicated that this pancreatoma cell line synthesized two forms of cholesterol esterase (Mr = 71,000 and 74,000). The 74-kDa protein is most likely the precursor protein, and the 71-kDa protein is the matured enzyme secreted by the AR42J cells. The synthesis and secretion of cholesterol esterase were stimulated 2-5-fold by incubating the cells with 0.5-4 nM of cholecystokinin or 0.5-2 nM of secretin. Analysis of the RNA isolated from the hormone-stimulated cells revealed that stimulation of cholesterol esterase biosynthesis was not due to an increase in cholesterol esterase mRNA. Furthermore, inhibition of transcription with actinomycin D has no effect on the hormone-induced cholesterol esterase biosynthesis. Therefore, the mechanism of hormone stimulation was not dependent on de novo RNA synthesis. In vitro translation studies showed that the cholesterol esterase mRNA isolated from stimulated AR42J cells were translated more efficiently than those from control cells. Thus, the increased cholesterol esterase biosynthesis induced by gastric hormones was most likely mediated by posttranscriptional modification of the cholesterol esterase mRNA.

Topics: Animals; Cell Line; Cholecystokinin; Dactinomycin; Enzyme Activation; Enzyme Induction; Kinetics; Molecular Weight; Pancreatic Neoplasms; Protein Biosynthesis; Rats; RNA, Neoplasm; Secretin; Sterol Esterase

The effect of truncal vagotomy (TV) on pancreatic carcinogenesis initiated with N-nitrosobis(2-oxopropyl)amine (BOP) was investigated in 81 female Syrian golden hamsters. The animals were divided into four groups according to the treatment, groups 1 and 2 serving as non-initiated controls receiving a single s.c. injection of 0.9% NaCl followed by either a sham operation or TV respectively, at week 2. Groups 3 and 4 were given a single s.c. injection of 70 mg/kg body wt of BOP before the sham operation or TV. All hamsters were killed at week 24, and the pancreas, liver and gall bladder tissues were examined histologically. While TV itself caused no significant change in pancreatic weight, the incidence of pancreatic carcinomas in hamsters from group 4 was 48.4%, significantly higher than the 16.7% evident in hamsters from group 3 (P less than 0.05). GLC analysis of the bile acid composition of gall bladder bile from hamsters not receiving carcinogen 1 and 4 months after TV revealed significantly decreased secondary bile acids. The results thus indicated that changes in bile acid composition may be involved in enhancement of BOP-initiated pancreatic carcinogenesis in hamsters by TV.

Topics: Animals; Bile Acids and Salts; Body Weight; Carcinogens; Cholecystokinin; Cricetinae; Female; Gallbladder; Liver; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms; Vagotomy, Truncal

Several studies have reported effects of gastrointestinal regulatory peptides on growth of experimentally induced pancreatic neoplasms and human cancer cell lines. The growth of human pancreatic cancer lines PANC-1 and MIA PaCa-2 was characterized in vitro, and the effects of cholecystokinin, bombesin, insulin, epidermal growth factor, secretin, vasoactive intestinal peptide, and somatostatin were determined. Fetal bovine serum was required for initiation of growth in both cell lines. Growth effects of peptides were determined by incubating cells with peptides in serum-free medium after a 72-h preincubation in 10% serum-supplemented medium alone. Epidermal growth factor (3.4 x 10(-9) M) and insulin (10(-6) M) significantly (p less than 0.001) increased growth of both cell lines as determined by increases in deoxyribonucleic acid and protein. Bombesin, secretin, vasoactive intestinal peptide, and somatostatin (all 10(-8) M) did not affect growth of either cell line. Neither cholecystokinin-8 nor [Thr4, Nle7] cholecystokinin-9 altered growth in concentrations from 10(-12)-10(-6) M. Anchorage-dependent clonogenic growth of both cell lines was also not altered by cholecystokinin-8. Cholecystokinin added to cultures was degraded by separate effects of serum and cells. Addition of cholecystokinin-8 to cultures every 8 h maintained cholecystokinin levels but did not alter cell growth. These data support roles for epidermal growth factor and insulin as growth factors for human pancreatic cancer cell lines.

Topics: Blood; Carcinoma; Cell Division; Cholecystokinin; Clone Cells; Culture Media; DNA, Neoplasm; Epidermal Growth Factor; Gastrointestinal Hormones; Humans; Insulin; Neoplasm Proteins; Pancreatic Neoplasms; Tumor Cells, Cultured

The effect of a synthetic analogue of CCK (Thr4,Nle7CCK-9) on growth of SW-1990 human pancreatic cancer was examined in two experimental models. Nude mice bearing SW-1990 pancreatic cancer xenografts were injected with CCK (5, 15, or 25 micrograms/kg) or vehicle twice daily for 20 days. Animals were then sacrificed and tumor volume, weight, protein, and deoxyribonucleic acid (DNA) content were evaluated. SW-1990 cells were grown in vitro and the effects of CCK, secretin, vasoactive intestinal peptide (VIP), and proglumide (a CCK-receptor antagonist) on cell number and DNA synthesis were determined. The highest dose of CCK, 25 micrograms/kg, significantly increased tumor weight, protein content, and DNA content (P less than 0.005). In vitro, CCK caused significant increases in cell counts of up to 47% at six days and 66% at 12 days compared to control. Graded concentrations of CCK had a biphasic effect on DNA synthesis with significant increases of up to 65% (P less than 0.005). CCK-induced cell proliferation was inhibited by proglumide. Secretin slightly increased cancer cell growth, although not as potently as CCK, VIP or secretin in combination with CCK did not show potentiation. These results indicate that growth of some human pancreatic cancers may be influenced by gastrointestinal peptides, of which CCK is the most potent.

Topics: Adenocarcinoma; Animals; Cholecystokinin; DNA, Neoplasm; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Nude; Organ Size; Pancreas; Pancreatic Neoplasms; Proglumide; Secretin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The fasting carcinoembryonal antigen (CEA) concentrations in the serum and duodenal juice and after venous stimulation of the exocrine pancreas with the hormones CCK and secretin (Boots) were studied. Radioimmunologic test with a kit of the firm "Labimex"--PPR was used. 28 patients with clinically proved chronic pancreatitis and a control group of 27 healthy persons were examined. The fasting CEA serum concentrations in the patients with chronic pancreatitis were statistically significantly higher than those of the healthy persons--mean--16.5 ng/ml vs mean--8.2 ng/ml (p less than 0.001). In 14% of the healthy persons and 57% of of the patients with chronic pancreatitis the basic CEA concentrations were significantly increased. After stimulation with CCK and secretin the serum CEA concentration did not change substantially. The duodenal juice CEA concentrations after CCK and secretin stimulation were about 11 times higher than those in the serum--mean--113 ng/ml and mean--104 ng/ml for the control group vs mean--118 ng/ml and mean--110 ng/ml for the patients with chronic pancreatitis. No statistically significant difference between the patients with chronic pancreatitis and the control group of healthy persons was established. The results reveal the low specificity of the CEA as a "tumor marker".

Topics: Adult; Carcinoembryonic Antigen; Cholecystokinin; Chronic Disease; Diagnosis, Differential; Duodenum; Evaluation Studies as Topic; Female; Humans; Intestinal Secretions; Male; Middle Aged; Pancreatic Neoplasms; Pancreatitis; Secretin

Cholecystokinin (CCK) receptors were investigated in the tumoral acinar cell line AR 4-2 J derived from rat pancreas, after preincubation with 20 nM dexamethasone. At steady state binding at 37 degrees C (i.e., after a 5 min incubation), less than 10% of the radioactivity of [125I]BH-CCK-9 (3-(4-hydroxy-[125I]iodophenyl)propionyl (Thr34, Nle37) CCK(31-39)) could be washed away from intact cells with an ice-cold acidic medium, suggesting high and rapid internalization-sequestration of tracer. By contrast, more than 85% of the tracer dissociated rapidly after a similar acid wash from cell membranes prelabelled at steady state. In intact AR 4-2 J cells, internalization required neither energy nor the cytoskeleton framework. Tracer internalization was reversed partly but rapidly at 37 degrees C but slowly at 4 degrees C. In addition, two degradation pathways of the tracer were demonstrated, one intracellular and one extracellular. Intracellular degradation occurred at 37 degrees C but not at 20 degrees C and resulted in progressive intracellular accumulation of [125I]BH-Arg that corresponded, after 1 h at 37 degrees C, to 35% of the radioactivity specifically bound. This phenomenon was not inhibited by serine proteinase inhibitors and modestly only by monensin and chloroquine. Besides, tracer degradation at the external cell surface was still observable at 20 degrees C and yielded a peptide (probably [125I]BH-Arg-Asp-Tyr(SO3H)-Thr-Gly). This degradation pathway was partly inhibited by bacitracin and phosphoramidon while thiorphan, an inhibitor of endopeptidase EC 3.4.24.11, was without effect.

Topics: Animals; Arsenicals; Binding, Competitive; Cell Membrane; Chloroquine; Cholecystokinin; Cytochalasin D; Dinitrophenols; Endocytosis; Gastrins; Hydrogen-Ion Concentration; Iodine Radioisotopes; Kinetics; Pancreas; Pancreatic Neoplasms; Rats; Sincalide; Succinimides; Temperature; Tumor Cells, Cultured

Cholecystokinin (CCK) has been shown to promote pancreatic growth and azaserine-induced pancreatic carcinogenesis in rats. The present study was carried out to determine effects of CCK on pancreatic growth and carcinogenesis in the N-nitrosobis(2-oxopropyl)amine (BOP) hamster model. One hundred male Syrian golden hamsters were injected s.c. once weekly with 20 mg BOP/kg body wt at 6, 7 and 8 weeks of age, and divided into four groups of 25 animals each, which received one of the following treatments (once daily, 3 days/week for 16 weeks): gelatin; CR-1409, a potent CCK-receptor antagonist; CCK-8, 2.5 micrograms/kg body wt; or CCK-8 in combination with CR-1409 (30 min before CCK treatment). The animals were killed after 19 weeks. The growth of the pancreas but not the incidence of pancreatic (pre)neoplastic lesions was enhanced by CCK-8. CR-1409 did not influence the effect of CCK on pancreatic growth.

Topics: Animals; Body Weight; Carcinogens; Cholecystokinin; Cocarcinogenesis; Cricetinae; Male; Nitrosamines; Organ Size; Pancreas; Pancreatic Neoplasms; Proglumide

Gastrointestinal hormones regulate growth of cancers as well as normal tissues. We investigated whether long-term cholecystokinin (CCK) administration might affect growth or metabolism of human tumors xenografted in nude mice. In each experiment, approximately 20 nude mice bearing subcutaneous xenografts of the particular cancer line being studied were used. Half received CCK and half received saline solution intraperitoneally twice daily for 14 days. Tumor volume and body weight were measured every 3 days. If the tumors produced marker substances, these were measured in nude mouse serum and also in the xenografts. Tumor growth was significantly retarded by CCK in two of the six cancers studied. In each case, DNA, RNA, and protein reflected tumor volumes. In one of these tumors (SLU 077), serum carcinoembryonic antigen (CEA) levels paralleled the tumor volumes. In another tumor (SLU 132), serum CEA levels and tumor immunolabeling for CEA and pancreatic oncofetal antigen increased in response to CCK administration, whereas tumor volumes did not. These findings suggest that exogenous highdose CCK altered the growth and metabolism in two of six human cancers studied.

Topics: alpha-Fetoproteins; Animals; Antigens, Neoplasm; Biliary Tract Neoplasms; Biomarkers, Tumor; Carcinoembryonic Antigen; Cell Line; Cholecystokinin; Gastrointestinal Neoplasms; Humans; Liver Neoplasms; Male; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Stomach Neoplasms

The effects on the pancreas of chronic (95 wk) dietary exposure to protease inhibitors from soy and potato were compared in rats and mice. Soy and potato trypsin inhibitor (TI) concentrates were prepared from defatted raw soy flour and potato juice, respectively, by selective precipitation and ultrafiltration. Animals were fed a diet in which casein supplied approximately 20% protein. Each concentrate (less than 1% of the diet) was added to provide 100 and 200 mg of trypsin inhibitor activity per 100 g of diet. In short-term (28 d) experiments in rats, both sources of TI decreased the apparent nutritional quality of casein and produced pancreatic hypertrophy consistent with a hormonally mediated feedback mechanism for pancreatic adaptation to diet that is interactive with the nutritional status of the animal. After long-term feeding (95 wk), soy and potato TI produced dose-related pancreatic pathology in rats consisting of nodular hyperplasia and acinar adenoma, which was typical of that associated with raw soy flour. Although mice responded similarly to rats to soy TI in short-term (28-d) feeding experiments, they were resistant to the formation of these lesions following long-term feeding. This considerable species variation in propensity to develop preneoplastic and neoplastic lesions of the pancreas is not predicted by the short-term hypertrophic and hyperplastic response of the pancreas to TI.

Topics: Adenoma; Animals; Body Weight; Carcinogens; Caseins; Cholecystokinin; Data Interpretation, Statistical; Glycine max; Longitudinal Studies; Male; Mice; Mice, Inbred Strains; Nutritive Value; Organ Size; Pancreas; Pancreatic Neoplasms; Rats; Rats, Inbred Strains; Solanum tuberosum; Trypsin Inhibitors

Feeding of raw soya flour or other trypsin inhibitors such as camostate is a well-established method for promoting growth of (pre)neoplastic foci induced in the exocrine pancreas of rats by azaserine. The effect of trypsin inhibitors is thought to be mediated through an increased release of cholecystokinin. Using the specific cholecystokinin receptor antagonist lorglumide (CR-1409), we performed a 16-wk study to investigate the potential of this drug in inhibiting growth of putative preneoplastic foci and to determine whether and to what extent cholecystokinin is responsible for the effect of trypsin inhibitors on pancreatic growth. After initiation with 30 mg/kg of azaserine at 19 days of age, six groups of 15 rats each received one of the following treatments: camostate, cholecystokinin-8, or gelatin control, either or not in combination with CR-1409, once daily, 3 days wk for 16 wk. Plasma cholecystokinin levels, measured 30 min after the stimulus, were similar after camostate and cholecystokinin octapeptide administration. After 16 wk the pancreata were removed, weighted, and quantitatively analyzed for the number and size of putative preneoplastic foci by light microscopy. Both camostate and cholecystokinin octapeptide stimulated pancreatic growth and development of acidophilic putative preneoplastic foci, whereas growth of basophilic putative preneoplastic foci was inhibited by camostate but stimulated by cholecystokinin. CR-1409 almost completely abolished the effect of cholecystokinin and was found to cause a significant decrease in the effects of camostate. It is concluded that (a) cholecystokinin plays a significant role in camostate-stimulated growth of acidophilic putative preneoplastic foci in rat pancreas and (b) CR-1409 inhibits growth of putative preneoplastic foci induced in rat pancreas by azaserine and hence may be of potential value for the treatment of pancreatic cancer in humans.

Topics: Animals; Azaserine; Cholecystokinin; Esters; Gabexate; Glutamine; Guanidines; Male; Pancreatic Neoplasms; Precancerous Conditions; Proglumide; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Sincalide; Trypsin Inhibitors

The influence of intraduodenal bile deficiency due to chronic bile duct obstruction and acute exogenous administration of bile acids on plasma cholecystokinin (CCK) and pancreatic polypeptide (PP) was investigated. Fourteen patients with tumor-induced bile duct stenosis and five healthy volunteers were given a liquid test meal. Four of the patients had a simultaneous pancreatic duct stenosis. On another day 4 g chenodeoxycholic acid were administered concomitantly with the liquid test meal in six of the patients and all controls. Basal and meal-stimulated plasma CCK did not differ between patients and controls. A pancreatic duct stenosis, which was associated with diminished plasma PP concentrations, had no influence on plasma CCK release. Exogenous bile acids significantly reduced the postprandial CCK response in both groups. Bile-induced inhibition was significantly greater in patients than in controls (75 +/- 7% and 44 +/- 11%, respectively; p less than 0.05). It is concluded that intraduodenal bile is an important modulator of the postprandial secretory activity of the CCK cell. Although chronic intraduodenal bile acid reduction in tumor-induced biliary duct stenosis did not influence plasma CCK levels, a negative feedback control of plasma CCK by acute bile acid administration could be demonstrated.

Topics: Adult; Aged; Bile Acids and Salts; Biliary Tract Neoplasms; Cholecystokinin; Cholestasis; Feedback; Gallbladder Neoplasms; Humans; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide

Topics: Adenoma, Islet Cell; Cholecystokinin; Glucagonoma; Humans; Insulinoma; Pancreatic Neoplasms; RNA, Messenger

To examine the effect of cholecystokinin (CCK) on pancreatic carcinogenicity in the hamster model, two sets of experiments were carried out. In one study, CCK (20 IDU/kg body wt) was given 3 h before, simultaneously with or 3 h after a single dose (20 mg/kg body wt) of N-nitrosobis(2-oxopropyl)amine (BOP). In another experiment, hamsters were treated similarly except that both CCK (20 IDU/kg body wt) and BOP (2.5 mg/kg body wt) were given weekly for 20 weeks. The results showed that CCK in the first experiment (single BOP dose) inhibited pancreatic cancer induction in a statistically significant fashion when given either 3 h prior to (P less than 0.05) or simultaneously with BOP (P less than 0.0005); however, CCK, when administered after BOP did not alter the cancer incidence as compared with hamsters treated with BOP alone. In the second experiment (chronic BOP treatment) the pattern and the incidence of pancreatic tumors were not affected by CCK.

Topics: Adenoma; Animals; Carcinogens; Carcinoma, Intraductal, Noninfiltrating; Cholecystokinin; Cricetinae; Female; Male; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms

(Thr28,Nle31)CCK(23-33) (CCK-9) and gastrin(1-17)I (gastrin) inhibited adenylate cyclase activity in membranes from the tumoral rat pancreatic acinar cell line AR 4-2J through a Bordetella pertussis toxin-sensitive mechanism. This contrasted with the stimulatory effect exerted by CCK-9 on adenylate cyclase activity in membranes from normal rat pancreas. The relative potency of CCK-9, gastrin, and related peptides in inhibiting adenylate cyclase, when confronted with previous evidence, suggests that 'non-selective CCK-gastrin CCK-B receptors' predominating over 'selective CCK-A receptors' in the AR 4-2J cell line, favored the coupling of the first receptors to adenylate cyclase through Gi, while CCK-A receptors capable of stimulating the enzyme through Gs were detected only after Bordetella pertussis toxin pretreatment.

Topics: Adenylate Cyclase Toxin; Adenylyl Cyclase Inhibitors; Animals; Cell Membrane; Cholecystokinin; Gastrins; Guanosine Triphosphate; Pancreas; Pancreatic Neoplasms; Pentagastrin; Peptide Fragments; Pertussis Toxin; Rats; Secretin; Tetragastrin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide; Virulence Factors, Bordetella

Specific labeling of a major Mr 85-95 K protein was obtained using the SH, NH2 heterobifunctional cross-linker m-maleimidobenzoyl N-hydroxysuccinimide ester (MBS) to affinity label cholecystokinin (CCK) receptors on rat pancreatic plasma membranes, pancreatic acinar cells and acinar cell tumor membranes with 125I-CCK-33. Endoglycosidase F (endo F) digestion of this species in gel slices indicated that at least two components were present which contain N-linked glycans. The smaller protein of Mr approximately 85 K was digested by endo F to a final product of approximately Mr 62 K while the larger Mr approximately 95 K protein generated two endo F products of Mr 55 K and Mr 43 K. These findings suggest that the receptor for CCK on pancreatic acinar cells exhibits an oligomeric structure, possessing two distinct CCK-binding proteins.

Topics: Animals; Cholecystokinin; Cross-Linking Reagents; Glycoside Hydrolases; Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; Membranes; Molecular Weight; Pancreas; Pancreatic Neoplasms; Rats; Receptors, Cholecystokinin; Succinimides

We examined diurnal changes of pancreatic exocrine secretion and plasma levels of cholecystokinin (CCK) and human pancreatic polypeptide (hPP) in men with postoperative transient external pancreatic drainage (3 with pancreatico-jejunostomy: PJ, and 5 with pancreato-duodenectomy:PD). Plasma CCK levels increased and the pancreatic exocrine secretion showed a corresponding increase after meals in both groups. In the PJ group hPP levels increased after meals and there was a significant correlation between the plasma levels of CCK and hPP. In the PD group the plasma hPP levels were not detectable throughout the study and there was a better correlation between the exocrine secretion and the plasma CCK levels than in the PJ group. Plasma CCK levels showed rhythmic changes associated with pancreatic exocrine secretion, with no significant changes in plasma glucose and insulin in the night (24:00-07:00). These results suggested that (1) the resection of the pancreatic head which is rich in hPP contents led to a complete loss of anti-CCK effects on CCK, and that (2) fluctuation in plasma CCK levels, in the fasting state, might initiate pancreatic exocrine secretion.

Topics: Aged; Cholecystokinin; Chronic Disease; Circadian Rhythm; Humans; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Pancreatic Polypeptide; Pancreatitis; Postoperative Care

Surgical diversion of bile and pancreatic secretions to the mid small bowel has been shown to provoke increased CCK plasma concentration and growth of the pancreas in rats. This study was undertaken to investigate the effects of chronic pancreaticobiliary diversion on pancreatic morphology as well as the circulating concentrations of pancreatic polypeptide, secretin, gastrin, and CCK. Fifteen month diversion provoked 73 and 86% increases in pancreatic weight and volume (p less than 0.001). Cholecystokinin blood concentration increased by 98%, from 20.9 +/- 5.7 pg/ml in controls to 41.3 +/- 5.4 after diversion (p less than 0.05), but pancreatic polypeptide, secretin, and gastrin levels were not affected. The volume of the exocrine pancreas doubled from 1104.6 +/- 78.2 mm3 in controls to 2201.2 +/- 229.2 (p less than 0.001), with a matching increase in interstitial tissue. On the contrary, the volume of the endocrine pancreas remained unchanged. Hyperplastic nodules developed in the exocrine pancreas, in 71% of diverted rats, but not in transected controls. We conclude from these observations that chronic diversion of bile and pancreatic juice stimulated pancreatic growth, most likely through a persistent rise of CCK plasma concentrations. Furthermore, this long lasting stimulation induced the development of exocrine pancreatic nodules.

Topics: Animals; Bile; Cholecystokinin; Hyperplasia; Male; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Rats; Rats, Inbred Strains; Time Factors

Both dietary unsaturated fat and raw soybean products are known to enhance pancreatic carcinogenesis when fed during the postinitiation phase. A comparison of these two dietary components was made to evaluate the relative potency of each ingredient for enhancing pancreatic carcinogenesis and to determine if this enhancement was correlated with an increase in plasma cholecystokinin (CCK) levels. Male Wistar rats were initiated with a single dose of azaserine (30 mg/kg body weight) at 14 days of age. The rats were weaned to test diets formulated from purified ingredients. Dietary protein at 20% by weight was either casein or soy protein isolate (heat treated or raw). Corn oil was the unsaturated fat of major interest and it was fed at either 5 or 20% by weight. Pancreases were quantitatively evaluated for carcinogen-induced lesions at 2- and 4-month postinitiation. In a second experiment designed to closely mimic the above experiment, rats were implanted with cannulae which allowed plasma to be repetitively sampled over a 2.5-week period during which the test diets were fed. Plasma was collected both prior to introduction of the test diets and afterwards. Plasma CCK was measured by a specific radioimmunoassay. Both the 20% corn oil diet and the raw soy protein isolate diet enhanced pancreatic carcinogenesis. The effects of the raw soy protein isolate on the growth of the carcinogen-induced lesions were significantly greater than the effects of the 20% corn oil diet. Plasma CCK values were not elevated in the rats fed the 20% corn oil diet, but they were significantly elevated in the rats fed the raw soy protein isolate. Heat-treated soy protein isolate neither enhanced carcinogenesis nor elevated the plasma CCK level. This study demonstrates that certain plant proteins enhance the growth of carcinogen-induced pancreatic foci and that this effect is considerably greater than the enhancement by high levels of dietary unsaturated fat. Furthermore, the enhancement by the raw soy protein isolate may be mediated by CCK; but this does not appear to be the mechanism by which the unsaturated fat, corn oil, enhances pancreatic carcinogenesis.

Topics: Animals; Azaserine; Cholecystokinin; Dietary Fats; Fatty Acids, Unsaturated; Male; Organ Size; Pancreas; Pancreatic Neoplasms; Plant Proteins, Dietary; Rats; Rats, Inbred Strains; Soybean Proteins

A liver metastasis (MSL) with a remarkable in vitro proliferation potential has been identified in an NEDH rat carrying a transplantable x-ray-induced islet cell tumor. Two insulin-secreting cell lines, MSL-G and MSL-H, with doubling times of 3-5 d were established by repeated limiting dilution cloning. In vivo inoculation of MSL-G cells induced severe hypoglycemia caused by a small but highly heterogeneous tumor as revealed by immunocytochemistry. Whereas most cells stained for the islet hormones, insulin, glucagon, and somatostatin, clustered cells were discovered to contain cholecystokinin (CCK). Additional in vitro-limiting dilution cloning, followed by immunocytochemical characterization, clearly demonstrated the capacity of single cell clones to simultaneously express the same four hormones. Radioimmunoassays with a panel of site-specific antisera of culture supernatants and purified cell extracts showed the MSL-G2 cells to produce, store, and secrete readily detectable amounts of processed and unprocessed CCK. Gastrin was not detected while coexpression of glucagon and CCK were demonstrated. Mutant clones selected for resistance to 6-thioguanine (frequency, 2 X 10(-7] and checked for HAT (hypoxanthine, aminopterin, thymidine) sensitivity retained the capacity for multi-hormone expression. We propose that the MSL tumor contains pluripotent endocrine stem cells. The MSL tumor and the MSL-G2 cells in particular will allow studies of not only CCK biosynthesis and processing but also of mechanisms involved in tumor and islet cell differentiation.

Topics: Adenoma, Islet Cell; Animals; Cholecystokinin; Glucagon; Insulin; Liver Neoplasms; Pancreatic Neoplasms; Rats; Somatostatin

Topics: Adenoma, Islet Cell; Cholecystokinin; Female; Humans; Pancreatic Neoplasms; Secretin; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenocarcinoma; Animals; Carcinogens; Cholecystokinin; Cricetinae; Disease Models, Animal; Neoplasm Metastasis; Nitrosamines; Pancreas; Pancreatic Juice; Pancreatic Neoplasms

Topics: Animals; Cholecystokinin; Gastric Mucosa; Gastrin-Releasing Peptide; Gastrins; Gastrointestinal Neoplasms; Humans; Neurotransmitter Agents; Pancreas; Pancreatic Neoplasms; Peptides; Protein Conformation; Pyloric Antrum; Somatostatin; Vasoactive Intestinal Peptide

Plasma concentrations of human pancreatic polypeptide (HPP) parallel exocrine pancreatic secretion in response to stimulation with cholecystokinin. We determined prospectively the relationships among fasting HPP level, integrated HPP response to infusion of cholecystokinin, and output of trypsin and also the sensitivity, specificity, and predictive values of the fasting HPP level in the diagnosis of exocrine pancreatic disease. Our study group consisted of 19 patients with acute pancreatitis, 17 with chronic pancreatitis, and 25 with ductal adenocarcinoma of the pancreas and 27 control subjects. In the control patients and those with chronic pancreatitis, significant correlations were detected between HPP level and output of trypsin (P less than 0.001) in response to infusion of cholecystokinin and between fasting HPP and integrated HPP levels (P less than 0.004); no correlation was detected between HPP level and steatorrhea. The sensitivity, specificity, and negative and positive predictive values of the fasting HPP level for detection of either chronic pancreatitis or pancreatic cancer were similar and approximated 0.88, 0.67, 0.88, and 0.66, respectively. The HPP concentration had no value in detecting acute pancreatitis. Because the fasting HPP level has a high degree of negative predictability and is simpler to measure than the integrated HPP level or the output of trypsin, it may be a useful test in patients suspected of having either chronic pancreatitis or pancreatic cancer. A fasting HPP level of 125 pg/ml or greater could be used to exclude chronic pancreatitis or pancreatic cancer, but the finding of a value of less than 125 pg/ml necessitates use of other diagnostic tests for reliable determination of the presence of these diseases.

Topics: Acute Disease; Adult; Aged; Carcinoma, Intraductal, Noninfiltrating; Celiac Disease; Cholecystokinin; Chronic Disease; Fasting; Humans; Middle Aged; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatic Polypeptide; Pancreatitis; Prospective Studies; Trypsin

The role of the pancreaticotrophic hormone cholecystokinin (CCK) in modifying the pancreatic response to carcinogen has been examined in the hamster-nitrosamine pancreatic cancer model. Exogenous CCK, 30 IDU kg-1, stimulated a maximal pancreatic secretory response when given intravenously and caused hypertrophy and hyperplasia of the pancreas when given subcutaneously over a period of 6 weeks (pancreatic wet weight, mg per 100 g body weight, controls 295.6 +/- 61; CCK treated 466.4 +/- 77, P less than 0.001). When the same dose of CCK was given to animals receiving N-nitrosobis (2-oxopropyl)amine (BOP; 5 mg kg-1 weekly) there was a reduction in latency period and increase in induction rate of tumour development (CCK + BOP vs. BOP alone, 12 animals with tumours vs. 2 at 15 weeks; P less than 0.02). These effects are consistent with CCK acting as a co-carcinogen or promoter of pancreatic carcinogenesis in this model.

Topics: Adenocarcinoma; Animals; Cholecystokinin; Cocarcinogenesis; Cricetinae; Male; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Precancerous Conditions

Hexose and hexosamine contents were measured in 117 samples of either duodenal or pancreatic juice from 49 subjects. The specimens were obtained by three methods: firstly, through a Dreiling's double lumen tube and with a pancreozymin secretin test performed simultaneously; secondly, by fiber duodenoscopy after an intravenous injection of secretin; thirdly, through a postoperative cannula without stimulation. The hexose content measured by phenol-sulfuric acid reaction correlated well with the hexosamine content measured by the Elson-Morgan method (r = 0.63, p less than 0.005). Since determination of hexose is not as complicated as that of hexosamine, the measurement of hexose content in the pancreatic juice seems to be more useful than measuring hexosamine for obtaining valuable information on pancreatic abnormalities.

Topics: Cholecystokinin; Chronic Disease; Duodenum; Hexosamines; Hexoses; Humans; Intestinal Secretions; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin; Stomach Neoplasms

Topics: Acute Disease; Animals; Cholecystokinin; Diet; Dietary Fats; Glycine max; Humans; Occupational Diseases; Pancreatectomy; Pancreatic Neoplasms; Pancreatitis

The short- and long-term effects of the administration of the pancreas carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) on pancreatic exocrine secretion were examined in Syrian hamsters with and without stimulation by secretin and pancreozymin. Protein concentration, flow rate, pH and ion content, (Na+, K+, Ca2+, Mg2+, HCO3-, Cl-, HPO4(2-) and SO4(2-)) were measured. An immediate effect of BOP is the stimulation of flow rate in females and of protein secretion in both sexes. Multiple doses of BOP significantly altered the parameters mentioned in Section 2 only in the later stages of tumorigenesis. When these animals were stimulated with secretin or pancreozymin large decreases in flow rate and protein content of secretions were observed as early as 8 weeks after BOP treatment. Insulin-like immunoreactivity and growth hormone-like immunoreactivity were detected in collected pancreatic secretions.

Topics: Animals; Carcinogens; Cholecystokinin; Cricetinae; Female; Male; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms; Secretin; Sex Factors

Topics: Animals; Cell Differentiation; Ceruletide; Cholecystokinin; Humans; Ornithine Decarboxylase; Pancreas; Pancreatic Neoplasms; Rats

Topics: Adult; Aged; Animals; Carcinogens; Cholecystokinin; Female; Food; Humans; Male; Middle Aged; Netherlands; Occupational Diseases; Pancreas; Pancreatic Neoplasms; Rats; United States

In cases of surgically proved pancreatic carcinoma, preoperative values of serum CEA, serum amylase and pancreozymin-secretin test (PST) were seen if they related to the macroscopic stages of the tumor determined by "General Rules for Surgical and Pathological Studies on Cancer of Pancreas" offered by Japanese Pancreatic Society in April 1982. Serum CEA was determined in 43 cases, serum amylase in 34 cases and PST was done in 28 cases. All of CEA, amylase and PST showed no statistically significant relationship to the stages of the carcinoma. This may suggest that these tests may not be a useful indicator of the stage of tumor.

Topics: Amylases; Carcinoembryonic Antigen; Cholecystokinin; Humans; Neoplasm Staging; Pancreatic Neoplasms; Secretin

Cholecystokinin (CCK) has trophic actions on abdominal viscera. To determine whether CCK enhances malignant growth in a similar fashion, we gave hamsters CCK together with di-isopropanol nitrosamine (DIPN), a known pancreatic and hepatic carcinogen. After 40 weeks of injections, those animals receiving both DIPN and CCK developed no cancers, while the control animals receiving DIPN alone developed pancreatic and hepatic carcinomas. This suggests that CCK inhibits carcinogenesis in this model. Although the mechanism of this effect is unknown, some implications for human carcinogenesis are testable by currently available methods.

Topics: Animals; Cholecystokinin; Cricetinae; Liver Neoplasms; Male; Mesocricetus; Neoplasms, Experimental; Nitrosamines; Pancreatic Neoplasms

The results of the secretin-pancreozymin test, duodenal aspirate cytology and hypotonic duodenography (the Triple Test), performed during a single duodenal intubation in patients with pancreatic or ampullary carcinoma, chronic pancreatitis and non-pancreatic disease were analysed retrospectively. Thirty-five of 36 carcinoma patients and all 11 chronic pancreatitis patients had an abnormal result. One hundred and sixteen of 170 non-pancreatic disease patients had a normal result. It would appear that the Triple Test (TT) may be a useful screening test for pancreatic disease.

Topics: Cholecystokinin; Chronic Disease; Duodenum; Humans; Intestinal Secretions; Intubation, Gastrointestinal; Pancreatic Diseases; Pancreatic Function Tests; Pancreatic Neoplasms; Pancreatitis; Radiography; Retrospective Studies; Secretin

Topics: Acute Disease; Adenocarcinoma; Carcinoma; Cholangiopancreatography, Endoscopic Retrograde; Cholecystokinin; Chronic Disease; Humans; Insulinoma; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin; Time Factors; Zollinger-Ellison Syndrome

The secretion of protein, like cell proliferation, is an integrated response that reflects structural organization of the cell periphery. Stimulation of protein secretion was thus utilized for comparison of integrated responses of the cell periphery in pancreatic acinar carcinoma of the rat and integrated responses in normal rat pancreas. Results of this comparison include: a) The stimulation of protein secretion in acinar carcinoma fragments by carbamylcholine chloride and cholecystokinin octapeptide, pancreatic secretagogues that interact with specific plasma membrane receptors, was only a fraction (one-fifth to one-half) of that observed in normal pancreatic minilobules. b) The Ca2+ ionophore A23187 and the cyclic nucleotide N6,O2'-dibutyryl cyclic AMP, secretagogues that act independently of specific membrane receptors, did not stimulate secretion in the acinar carcinoma. The observed quantitative and qualitative differences in protein secretion indicate fundamental differences in cell periphery organization between the normal and transformed acinar cells of pancreas.

Topics: Animals; Bucladesine; Calcimycin; Carbachol; Carcinoma; Cell Membrane; Cholecystokinin; Dose-Response Relationship, Drug; In Vitro Techniques; Pancreas; Pancreatic Neoplasms; Peptide Fragments; Proteins; Rats; Secretory Rate; Sincalide; Temperature

Pancreatic secretions from the hamster model for pancreatic ductal adenocarcinoma were analyzed to determine whether alterations had occurred in the protein composition. CCK-and secretin-stimulated secretions were collected from 13 animals with cancer and 16 normal controls. Subsequent separation of the proteins by isoelectric focusing showed the following: (1) Significant changes occurred in the protein composition from animals with carcinoma. An unusually dark band was present at pH 7.5 just below amylase (pH 7.65); two unidentified bands, present in the normals at pH 6.9 and 7.0, were missing; and marked decreases occurred in the cathodic proteins with isoelectric points above pH 9, (2) CCK provided the optimal stimulus for differentiating specimens from animals with carcinoma from the normal controls. (3) The protein concentrations of CCK-stimulated secretions of animals with carcinoma were significantly lower than the controls. We have concluded that the protein alterations which have occurred in the hamster model for pancreatic ductal adenocarcinoma warrant further investigation.

Topics: Animals; Cholecystokinin; Cricetinae; Isoelectric Focusing; Male; Mesocricetus; Neoplasm Proteins; Neoplasms, Experimental; Pancreatic Juice; Pancreatic Neoplasms; Secretin

The intraductal secretin test is an important diagnostic study. It enables the physician to determine the pancreatic secretory function in patients with known pancreatitis and to confirm the diagnosis of pancreatitis in many patients with indeterminate upper abdominal pain in whom ERCP and other diagnostic studies are normal. The IDST also provides the endoscopist and biochemist a new means to establish discriminating tests in differential diagnosis of pancreatic cancer and pancreatitis and to study the physiology of pancreatic secretion.

Topics: Bicarbonates; Cholangiopancreatography, Endoscopic Retrograde; Cholecystokinin; Diagnosis, Differential; Humans; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Proteins; Secretin; Secretory Rate

Topics: Aged; Angiography; Cholecystokinin; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Secretin; Tolazoline; Vasodilator Agents

Sixty-five patients with possible pancreatic disease or long-lasting upper abdominal symptoms were examined by means of the secretin-CCK test and hypotonic duodenography. Both examinations were performed after one duodenal intubation. In patients with pancreatitis functional abnormalities were revealed in 85 per cent while the duodenography was abnormal in 43 per cent. In patients with carcinoma, 77 per cent had abnormal exocrine pancreas function and 70 per cent had abnormalities demonstrated at duodenography. The value of the two examinations for assessment of patients with upper abdominal symptoms and pancreatic disease is discussed.

Topics: Adult; Aged; Bicarbonates; Cholecystokinin; Duodenum; Female; Humans; Male; Middle Aged; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Radiography; Secretin

Pancreatic secretory function is abnormal in at least 90% of patients with pancreatic cancer. These abnormalities may be due to direct involvement of the secretory cells by the malignant process and/or the effects of pancreatic duct obstruction. There is no specific stimulus (secretin and/or cholecystokinin, CCK, or CCK-like hormones) of pancreatic secretion that is clearly superior to any other as a test of pancreatic function. Pancreatic secretion is abnormal in animal models of pancreatic cancer and secretory abnormalities antedate the histologic appearance of the cancer. A decrease in protein secretion after CCK stimulation is the most significant finding in experimental partial pancreatic duct obstruction (the condition most commonly seen in pancreatic cancer). In the absence of any identifiable high-risk group within the population, it is unlikely that the testing of pancreatic function provides a means for the earlier diagnosis of pancreatic cancer.

Topics: Animals; Cats; Cholecystokinin; Cricetinae; Humans; Pancreatic Function Tests; Pancreatic Juice; Pancreatic Neoplasms; Risk; Secretin

Saliva secretion was studied via pilocarpine test in 40 patients with pancreas exocrine insufficiency: 32 patients with chronic pancreatitis and 8 patients with pancreas carcinoma. After pilocarpine stimulation, the volume of saliva secretion was determined in ml., as well the concentration and quantity of the secreted bicarbonates, amylase and protein. The results were compared with a control group of 17 healthy subjects. Statistically significant diminution of all indices of saliva secretion was found in the patients with pancreas exocrine insufficiency (p less than 0.001). The correlation relationship between the changes of pancreas and saliva secretion was studied. Saliva secretion could be used as orientating test for the presence of pancreas exocrine insufficiency.

Topics: Cholecystokinin; Chronic Disease; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Pilocarpine; Saliva; Salivary Glands; Secretin

The classification of accumulative patterns with the pancreatic scintigram findings of chronic pancreatitis and carcinoma of the pancreas were compared with endoscopic retrograde pancreatography (ERP) findings and Pancreozymin-Secretin test (P-S test). I) The frequency of pancreatic cancer was 93%, whilst, the chronic pancreatitis was 88% in the abnormal pancreatic scintigram. II) In the scintigram the type II (localized defect shadows) of pancreatic cancer was comparatively high and it is proportional to evidence derived from ERP. Localized diagnostic certainty is helpful, although the two tests are related. The P-S test is only restricted to the carcinoma of head, whilst, scintigram is more useful to detect the carcinoma of the body and tail of the pancreas. II) As for the chronic pancreatitis, there are various accumulative patterns. This is resemblance to that of ERP findings, but in the P-S normal test, it showed discrepancy in part of the result. Particularly, in the type I (slightly generalized low uptake with density silhouette) and type II. Therefore in order to obtain an accurate diagnosis, it is essential to have both the P-S test and scintigram.

Topics: Cholangiopancreatography, Endoscopic Retrograde; Cholecystokinin; Chronic Disease; Evaluation Studies as Topic; Humans; Pancreas; Pancreatic Neoplasms; Pancreatitis; Radionuclide Imaging; Secretin

Cyclic AMP (cAMP) output in the duodenal contents of 11 normal subjects, 18 patients with chronic pancreatitis, six convalescing from acute pancreatitis and five with pancreatic carcinoma was measured after a single dose of pancreozymin and secretin. The technic was indirect, utilizing recovery of duodenal contents by the Dreiling tube rather than direct measurements of fluid that was not contaminated by bile. In all patients groups, cAMP output reached a peak after this stimulation with a concomitant increase of bicarbonate and amylase outputs. A significantly decreased cAMP output was observed in all pancreatic disease groups compared to the normal group. Patients with chronic pancreatitis showed a slightly decreased cAMP output, considerably decreased bicarbonate output and normal amylase output. In acute pancreatitis cAMP output was reduced with normal bicarbonate and amylase outputs. In pancreatic carcinoma cAMP decreased significantly, bicarbonate output was moderately reduced and amylase output was normal. cAMP output in all groups studied did not correlate with either bicarbonate output or amylase output.

Topics: Acute Disease; Adult; Aged; Cholecystokinin; Chronic Disease; Cyclic AMP; Duodenum; Hormones; Humans; Intestinal Secretions; Middle Aged; Pancreatic Function Tests; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Adult; Aged; Bicarbonates; Carcinoembryonic Antigen; Cholangiography; Cholecystokinin; Duodenum; Female; Glucose Tolerance Test; Humans; Intestinal Secretions; Male; Methods; Middle Aged; Pancreas; Pancreatic Neoplasms; Pancreatitis; Secretin; Trypsin

The pancreas can be studied for obstructive disease by measuring serum lipase levels in the two stage provocative test. The test is nonspecific but noninvasive and applicable to all stages of pancreatic diseases. In this test, the pancreas is stimulated twice in two hour intervals before measuring the serum enzyme levels: first, with pancreozyin and secretin--the stage 1 test and, second, with pancreozymin, secretin, betazole hydrochloride and morphine sulfate--the stage 2 test. Among the pancreatic enzymes measured, lipase was most reliable. Serum lipase level elevation in the stage 1 test indicates a pancreatic abnormality and it completes the test. Patients who fail to respond to the stage 1 test have either a normal pancreas or pancreatic insufficiency and need the stage 2 test for differential diagnosis. In the stage 2 test, the serum lipase level is elevated in patients with a normal pancreas but not in those with pancreatic insufficiency. As a preliminary study, ten patients with carcinoma of the pancreas, two with pancreatitis and ten in the control group were studied. All patients with a known pancreatic disease demonstrated an abnormality in the test. Two of ten in the control group also had abnormal results. The two stage provocative test may be used prior to undertaking more invasive examinations, such as an arteriogram, in patients who are suspected of having pancreatic disease, yet other tests have failed to indicate it.

Topics: Amylases; Betazole; Cholecystokinin; Chymotrypsin; Clinical Enzyme Tests; Female; Humans; Lipase; Male; Morphine; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin; Trypsin

The coexistence of nontropical sprue and advanced pancreatic insufficiency is uncommon. The purposes of this report are to: (a) describe 3 patients with non-tropical spruc and severe pancreatic insufficiency, (b) determine the frequency, magnitude, and clinical importance of diminished pancreatic secretion in nontropical sprue, and (c) assess whether patients with pancreatic insufficency secondary to chronic pancreatitis or pancreatic cancer have jejunal mucosal histologic abnormalities. In each of 3 patients with nontropical sprue and associated severe exocrine pancreatic insufficiency, an optimal clinical response required the appropriate treatment of both causes of malabsorption. Of 31 subjects with proved nontropical sprue, cholecystokinin-stimulated duodenal tryptic activity or lipolytic activity (or both) was reduced in 13 (42%) but severely reduced in only the three case reports (10%). The morphologic structure of the small bowel was normal in 21 patients with primary pancreatic insufficiency secondary to chronic pancreatitis or pancreatic cancer. Mild-to-moderate exocrine pancreatic insufficiency is a frequent finding in untreated nontropical sprue, is presumably reversible, and rarely contributes to the development of steatorrhea. However, if patients with nontropical sprue fail to respond to a gluten-free diet, coexistent severe pancreatic insufficiency is a possible cause for treatment failure.

Topics: Aged; Celiac Disease; Cholecystokinin; Chronic Disease; Female; Humans; Jejunum; Lipase; Middle Aged; Pancreas; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Trypsin

Topics: Amino Acid Sequence; Animals; Cholecystokinin; Gastrins; Humans; Immune Sera; Intestinal Mucosa; Jejunum; Pancreatic Neoplasms; Radioimmunoassay; Swine; Trypsin

Topics: Carcinoembryonic Antigen; Cholecystokinin; Duodenum; Humans; Intestinal Secretions; Pancreatic Neoplasms; Secretin

To investigate the relationship between the duodenal outputs of calcium and diseases of the pancreas, we measured calcium secretion into the duodenum (during saline perfusion and after stimulation with an intravenous infusion of cholecystokinin (CCK) or secretin) in healthy controls, patients with chronic alcoholic or idiopathic pancreatitis, and patients with pancreatic cancer. The effects of acute and chronic hypercalcaemia and previous cholecystectomy were also studied. Our results indicate a characteristic increase in duodenal calcium outputs in response to CCK in chronic pancreatitis which is unaffected by the level of serum calcium, aetiology of the pancreatitis, previous cholecystectomy, and the presence or absence of radiological pancreatic calcifications. Although unproven, indirect observations support a pancreatic source for the increased calcium secretion. As we measured the outputs of calcium into the duodenum, previously described increases in calcium concentration are not merely a reflection of reduced volume secretion in chronic pancreatitis. Duodenal calcium outputs were significantly reduced in patients with cancer of the pancreas.

Topics: Calcium; Cholecystectomy; Cholecystokinin; Duodenum; Humans; Pancreatic Neoplasms; Pancreatitis; Perfusion

CEA concentration in juice collected during the Secretin-Pancreozymin test, and cytology were evaluated in order to establish whether they may be used as an aid in the diagnosis of pancreatic carcinoma before resorting to x-ray examinations. Thirty-three subjects were studied: 6 normal subjects, 12 with chronic pancreatitis, 3 after recovery from acute pancreatitis, 8 with gall-stones, 3 with carcinoma of the pancreas and 1 with cancer of the biliary tract. Three duodenal juice samples (at 30, 60 and 90 mins of hormonal infusion) were taken in each subject for CEA, cytology, bicarbonate and trypsin determinations. Although a significant statistical difference was noted between normal subjects and patients with carcinoma of the pancreas in the 30-min-juice sample, CEA concentration in the duodenal juice did not seem a reliable index in the diagnosis of pancreatic carcinoma. The information provided by cytology was also very scanty and sometimes misleading. The clinical picture and radiological investigation still remain the surest basis for the diagnosis of pancreatic cancer.

Topics: Adult; Bile Duct Neoplasms; Carcinoembryonic Antigen; Cholecystokinin; Cholelithiasis; Female; Humans; Male; Middle Aged; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin

With the advent of radioimmunoassay and immunocytochemical methods, the peptides of the gastrointestinal tract have been identified and measured. Gastrinoma and insulinoma syndromes have been wall characterized. The pancreatic cholera syndrome and some of the evidence that the major manifestations of this disease may be mediated by vasoactive intestinal peptide have been re-examined. Pancreatic polypeptide seems to be an ideal peptide for study of vagal-cholinergic mechanisms that regulate hormone release; it also appears to be a tumor marker for several types of pancreatic endocrine tumors, particularly those of pancreatic cholera. Secretin and cholecystokinin are important regulators of pancreatic exocrine secretion and have been used to test pancreatic function, but there is little evidence that they account for clinical disease. Glucagon-secreting tumors produce a clinical syndrome of diabetes mellitus and distinctive skin lesions, which can be cured by tumor resection. Hormone-secreting tumors may provide insight into normal gut physiology.

Topics: Adenoma, Islet Cell; Animals; Apudoma; Cholecystokinin; Diarrhea; Dogs; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Hormones; Humans; Intestines; Pancreas; Pancreatic Neoplasms; Pancreatic Polypeptide; Stomach; Stomach Neoplasms; Vasoactive Intestinal Peptide

Pancreas and gut hormones are involved in many endocrine and gastrointestinal diseases. Radioimmunoassays for these hormones have proved particularly valuable in diagnosis, localisation and control of treatment of endocrine tumours, of which many are mixed. An estimate based on ten years experience in a homogenous population of 5 million inhabitants (Denmark) suggests, that endocrine gut tumour-syndromes on an average appear with an incidence of 1 patient per year/syndrome/million. At present six different syndromes are known: 1) The insulinoma syndrome, 2) The Zollinger-Ellison syndrome.3) The Verner-Morrison syndrome. 4) The glucagonoma syndrome. 5) The somatostatinoma syndrome, and 6) the carcinoid syndrome. Accordingly diagnostically valuable RIAs for pancreas and gut hormones include those for insulin, gastrin, VIP, HPP, glucagon, somatostatin, and presumably also substance P. It is probably safe to predict that the need for gut and pancreas hormone RIAs within the next decade will increase greatly in order to assure proper management of tumours producing gastroentero-pancreatic hormones.

Topics: Adenoma, Islet Cell; Carcinoid Tumor; Cholecystokinin; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Insulin; Intestinal Neoplasms; Motilin; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Secretin; Somatostatin; Substance P; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Gastro-entero-pancreatic (GEP) and bronchial endocrine tumours have been studied by immunohistochemistry using specific antisera against a variety of hormonal and neuronal peptides. In gastrinomas numerous tumour cells were found to contain GH-like immunoreactivity. These cells were identical with those storing gastrin. Gastrinomas as a rule were extremely heterogeneous containing a variety of minority cell populations, including CCK immunoreactive cells and neurotensin immunoreactive cells. Glucagonoma cells were found to store GIP-like material in addition to glucagon. In some insulinomas calcitonin-like material was encountered in the insulin producing tumour cells. In both glucagonomas and insulinomas other pancreatic endocrine cell types constituted minority cell populations. One intestinal somatostatinoma contained gastrin cells as a minority cell population. Bronchial endocrine tumours contained scattered cells displaying ACTH-like or enkephalin-like immunoreactivity. Two such tumours in addition contained cells displaying neurophysin immunoreactivity.

Topics: Adenoma, Islet Cell; Adrenocorticotropic Hormone; Bronchial Neoplasms; Cholecystokinin; Enkephalins; Fluorescent Antibody Technique; Gastrins; Glucagon; Growth Hormone; Humans; Insulin; Insulin Secretion; Neurophysins; Pancreatic Neoplasms; Serotonin; Somatostatin; Stomach Neoplasms; Zollinger-Ellison Syndrome

Studies on exfoliative cytology of the pancreatic-duodenal juice in the diagnosis of pancreas neoplasia are not numerous and the data reported are not uniform. The present study examines 176 patients, 18 of them suffering from carcinoma of the pancreas. In these latter patients there were no advanced signs of the disease. Cytology gave a correctly negative result in 46.8% of the normal subjects and in those with non-neoplastic pancreatic or digestive conditions, correctly positive in 66.6% of the pancreas neoplasias, falsely negative in 2,2% of the total series and in 33.3% of the pancreatic cancers, and falsely positive in 1,1% of the series. In 47.7% of cases, the study proved useless owing to the absence of material in the collected juice.

Topics: Cholecystokinin; Cytodiagnosis; Duodenum; Evaluation Studies as Topic; False Negative Reactions; False Positive Reactions; Humans; Pancreatic Juice; Pancreatic Neoplasms; Secretin

Plasma CEA concentration before and after administration of secretin and cholecystokinin-pancreozymin has been determined in 89 patients with neoplastic or inflammatory pancreatric disease and other neoplastic and nonneoplastic disorders. The purpose of the study was to expore the specificity and sensitivity of such a provocation tests. Some rise of the plasma CEA concentration after hormonal stimulation could be observed in several patients in the various groups. However, none of the 37 patients with nonpancreatic disease who had a basal CEA concentration of 6 micrograms/l or less had a maximal CEA concentration above 13 micrograms/l after the stimulation whereas 7 out of 31 patients with pancreatic disease (3 with pancreatic carcinoma and 4 with chronic pancreatitis) showed such an elevation of plasma CEA concentration. Thus, the provocation test showed a satisfactory specificity for pancreatic disease but a low sensitivity. It is suggested that the possibility of an effect of physiologically released gastrointestinal hormones should be considered when "unexplained" high CEA values are found in plasma samples from nonfasting patients.

Topics: Animals; Carcinoembryonic Antigen; Cholecystokinin; Evaluation Studies as Topic; Male; Pancreatic Neoplasms; Pancreatitis; Secretin

Pancreas scintigraphy with 75selenomethionine, pancreocimine-secretin test and selective abdominal angiography was carried out in patients with chronic pancreatitis, pancreas carcinoma and subjects without any pancreas diseases. Scintigraphic changes in pancreas were found in 95.6 per cent of the patients with chronic pancreatitis (136 patients) in 92 per cent of them with pancreas carcinoma (25 patients) and in 53.4 per cent from the subjects without pancreas diseases (30 examined). Pathological changes in pancreatic secretion was found in 93.4 per cent of the patients with chronic pancreatitis (105 patients) in 93.8 per cent of the subjects with pancreas carcinoma (32 patients) and only in 3.3 per cent from the examined without pancreatic diseases. The angiographic examination is informative mainly in case of tumours and cysts of the pancreas. The diagnostic potentialities of the separate methods for pancreas examination were critically assessed. The basic diagnostic problems, in pancreas diseases are solved to a great extent with the combined examination with scintigraphy, pancreocimine-secretin test and angiography (76 patients).

Topics: Angiography; Cholecystokinin; Chronic Disease; Humans; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Radionuclide Imaging; Secretin; Selenomethionine

Topics: Adolescent; Adult; Aged; Cholecystokinin; Chronic Disease; Duodenum; Female; Humans; Male; Middle Aged; Pancreatic Diseases; Pancreatic Neoplasms; Secretin; Thailand

In animal studies, DL-[carboxyl-14C]tryptophan [DL-Try(C-14)] showed a high specificity for the pancreas, which suggested the potential of DL-[carboxyl-11C]tryptophan [DL-Try(C-11)] for clinical pancreatic inaging. The blood clearance and tissue uptake of the amino acid were very rapid, and no carrier effect was observed through a dose of 5 mg/kg. None of three transplanted hamster pancreatic adenocarcinomas that we studied showed a selective uptake of DL-Try(C-14) by the tumor, and none of the three enzymatic regimens investigated gave significant enhancement of the pancreatic specificity. Commercial L-Try(C-14) gave slightly better pancreatic specificity than the analogous racemic compound but without enough improvement to warrant attempts at optical resolution. DL-Try(C-11) was synthesized in amounts up to 325 mCi using a rapid, high-temperature, high-pressure modification of the Bücherer-Strecker amino acid synthesis. Yields ranged from 30--60%, and a total of 40 min was required for synthesis and chromatographic purification. DL-Try(C-11) thus appears to have significant potential as a clinical pancreas-imaging agent, particularly when used in conjunction with positron computerized transaxial tomography.

Topics: Adenocarcinoma; Animals; Carbon Radioisotopes; Cholecystokinin; Cricetinae; Dogs; Female; Isotope Labeling; Male; Mesocricetus; Neoplasm Transplantation; Neoplasms, Experimental; Pancreas; Pancreatic Neoplasms; Rabbits; Radionuclide Imaging; Rats; Secretin; Stimulation, Chemical; Tissue Distribution; Transplantation, Homologous; Tryptophan

In medical practice, diagnostic and therapeutic aspects of gastrointestinal hormones attract interest. Gastrin--in the form of pentagastrin--can be used for gastric secretory analysis and, in the analysis of exocrine pancreatic function, secretin and cholecystokinin-pancreozymin can be employed as stimulants. Diagnosis of hormone-producing tumors is possible by radioimmunological determination of serum levels of the hormone in question: so, dramatically high gastrin levels can be found in the Zollinger-Ellison syndrome while in the Verner-Morrison syndrome, VIP (vasoactive intestinal peptide) values are significantly elevated.--The therapeutic use of gastrointestinal hormones (gastrin, secretin) is waiting in the wings.

Topics: Cholecystokinin; Duodenal Ulcer; Gastrointestinal Diseases; Gastrointestinal Hormones; Humans; Pancreatic Diseases; Pancreatic Neoplasms; Pentagastrin; Secretin; Vasoactive Intestinal Peptide

Pancreatic exocrine secretion was studied in 22 patients with pancreas cancer. In 17 of patients the diagnosis was made at operation. In all patients examined the pancreocymine-secretin test according to Herfort was performed. The results were compared with those of a control group of 30 healthy subjects. In 95.5 per cent of the examined a statistically significant decreased hydrobicabonate and enzyme secretion was found. The changes in the pancreatic secretion are characterized by the presence of a total secretory deficiency, with a significant diminution ( p less than 0.001) of all parameters of pancreatic secretion.

Topics: Carcinoma; Cholecystokinin; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Secretin

The purpose of this study was to compare the diagnostic efficacy of endoscopic retrograde pancreatography (ERP) and secretin-CCK test for the diagnosis of pancreatic disease. The bicarbonate output after the secretin stimulation was low in 26 out of 30 patients (87%) with pancreatitis, whereas ERP revealed an abnormal duct in 21 (70%) of these patients. In all 7 patients with pancreatic carcinoma, ERP showed major abnormalities, whereas the bicarbonate output was reduced only in four of them. Thus, the secretin test appears to be at least as efficient as the ERP in disclosing pancreatitis. On the other hand, ERP seems to be a more reliable method for the diagnosis of pancreatic carcinoma.

Topics: Adult; Aged; Bicarbonates; Cholecystokinin; Endoscopy; Evaluation Studies as Topic; Humans; Middle Aged; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Radiography; Secretin

A comparison has been made between a modified Lundh test and the secretin-CCK test. Thirty-four patients with pancreatic disease (chronic pancreatitis, n = 25; recurrent pancreatitis, n = 5; and pancreatic carcinoma, n = 4) and 20 patients with other gastrointestinal disorders were studied. The results showed that estimation of trypsin secretion, irrespective of the mode of stimulation, had a low sensitivity in detecting pancreatic disease. Estimation of bicarbonate secretion after secretin stimulation provided a more sensitive test, especially for disclosing chronic pancreatitis.

Topics: Adult; Aged; Bicarbonates; Cholecystokinin; Duodenum; Food; Gastrointestinal Diseases; Humans; Intubation, Gastrointestinal; Methods; Middle Aged; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Recurrence; Secretin; Secretory Rate; Trypsin

Eighy cases with carcinoma of the pancreas were divided into 10 groups according to the location and size of the tumor. Drip infusion cholangiography, percutaneous transphepatic cholangiography, hypotonic duodenography and endoscopic retrograde cholangiopancreatography were employed for this classification. Comparison of cholangiopancreatograms (ERCP) with results of the biliary and pancreatic secretory function assessed by pancreozymin secretin test (PS test clarifies secretory capacity of the exocrine pancreas. But combination of ERCP and PS test with cytology is necessary for the correct diagnosis of the pancreatic cancer and it is hoped that the combination may excavate the disease in the early stage.

Topics: Bile; Cholangiography; Cholecystokinin; Endoscopy; Humans; Methods; Pancreas; Pancreatic Neoplasms; Secretin

There is no agreement in the literature as regards the carrying out of the Secretin-Pancreozymin test in order to achieve the greatest accuracy in the diagnosis of pancreatic insufficiency. In this study the results obtained by bolus i.v. injection of Secretin and Pancreozymin GIH are compared with those obtained by i.v. infusion of the hormones. The test - always prolonged for one hour - was done in 125 subjects, divided into two groups matched for sex, age and pancreatic or digestive disease. Volume, pH, bicarbonates, calcium and amylase were measured in the juice collected. The results showed that bolus i.v. injection of Secretin and Pancreozymin has greater diagnostic sensitivity (94%) than the infusion method (84%). If infusion is used, it is necessary to protract the test for more than one hour.

Topics: Adult; Cholecystokinin; Chronic Disease; Drug Synergism; Female; Humans; Injections, Intravenous; Male; Middle Aged; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Cholecystokinin; Humans; Pancreas; Pancreatic Neoplasms; Pancreatitis; Secretin; Stimulation, Chemical

The pancreatic excretion test with a weak acid of 5, 5-dimethyl-2,4-oxazolidinedione (DMO) was performed concomitantly with the pancreozymin-secretin test in 28 patients with pancreatolithiasis, 14 patients with pancreatic carcinoma, and 67 healthy subjects. The DMO concentration and total output of duodenal content after secretin stimulation, when corrected to the simultaneously determined plasma DMO concentration, were significantly reduced in the patients. While the pancreozymin-secretin test was abnormal in 96% of patients with pancreatolithiasis and in 86% of those with pancreatic carcinoma, the pancreatic DMO excretion test gave abnormal results in 100% of the patients. This suggests that the new test may well become effective in detecting early stages of pancreatic disease including carcinoma and chronic pancreatitis.

Topics: Calculi; Cholecystokinin; Dimethadione; Duodenum; Humans; Oxazoles; Pancreatic Diseases; Pancreatic Neoplasms; Secretin; Trimethadione

Pancreatic secretory abnormalities develop in most persons with pancreatic cancer and have been attributed to ductal obstruction. These experiments investigated whether abnormal secretion results instead from carcinogen-induced changes in the secreting cells. Fifty male Syrian Golden hamsters (40 to 100 grams) received weekly injections of di-isopropyl-nitrosamine (250 mg/kg, subcutaneously), and survivors and age-matched controls were studied after 3.5 to 6.5 months of treatment. Pancreatic secretion was stimulated by secretin or cholecystokinin (2 units/kg, intravenously, as a bolus). After each stimulus four 15-minute collections of pancreatic juice were analyzed for HCO3- and Cl- or total protein, amylase, trypsin, and chymotrypsin. The organs were examined histologically. Pancreatic ductal adenocarcinoma developed in 30% of the animals at 5 months, 56% at 5.5 months, and 100% at 6.5 months. The animals without cancer either had hyperplasia of the duct epithelium or were histologically normal. The histologic appearance of acinar tissue and protein secretion were normal in all groups. The tumors did not obstruct the major ducts. In all treated animals the pancreatic secretory response to secretin was of low volume, low maximal [HCO3-] and HCO3- output, and low [Cl- + HCO3-]; these changes progressed with time. The secretory abnormalities antedated the appearance of the neoplasms and were not caused by obstruction.

Topics: Amylases; Animals; Cholecystokinin; Chymotrypsin; Cricetinae; Electrolytes; Male; Mesocricetus; Pancreas; Pancreatic Ducts; Pancreatic Juice; Pancreatic Neoplasms; Proteins; Secretin; Trypsin

We undertook to test the recent suggestion that measurement of immunoreactive carcinoembryonic antigen (CEA) in pancreatic secretion may be useful in diagnosis of pancreatic cancer. Using duodenal intubation and a perfusion method in 57 cases, we measured the rate of pancreatic CEA secretion into the duodenum under basal saline perfusion, alone and with continuous intravenous infusion of secretin (2 clinical units per kg per hr) and of cholecystokinin-pancreozymin (CCK, 15 Crick-Harper-Raper units per kg per hr); and we compared the CEA output with secretion of trypsin, lipase, and bicarbonate under the same conditions. Subsequent laparotomy revealed pancreatic carcinoma in 25 patients, pancreatitis in 7, other intraabdominal malignancies in 6, and benign nonpancreatic disorders in 19. CEA output rates did not differentiate all pancreatic-cancer patients from other patients in any test condition. However, pancreatic enzyme outputs were abnormal with almost 90% of cancers of the pancreatic head and with 75% of cancers of the pancreatic body and tail. For detection of pancreatic cancer, enzyme and bicarbonate outputs in response to CCK are more accurate than pancreatic CEA or bicarbonate outputs in response to secretin. Since CCK-stimulated enzyme outputs can be related accurately to malabsorption (not reported here), we prefer them to bicarbonate output for assessment of pancreatic function.

Topics: Adult; Bicarbonates; Carcinoembryonic Antigen; Cholecystokinin; Humans; Jaundice; Lipase; Pancreas; Pancreatic Neoplasms; Trypsin

The CEA concentration in duodenal fluid after secretin-CCK stimulation has been investigated in 16 patients with pancreatic disease (6 with pancreatic carcinoma and 10 with chronic pancreatitis), 9 with non-pancreatic disease, and 10 control subjects. The purpose was to study whether the determination of CEA in duodenal fluid during the secretin-CCK test can give any additional information for the diagnosis of pancreatic disease and for differentiation between pancreatitis and carcinoma. We found that high values of CEA in duodenal fluid do not necessarily indicate pancreatic carcinoma. Moreover, the level may be elevated in non-pancreatic disease.

Topics: Carcinoembryonic Antigen; Cholecystokinin; Duodenum; Humans; Pancreatic Neoplasms; Pancreatitis; Secretin

Peritoneoscopic puncture of the gallbladder for transvesical cholecysto-cholangiography and for aspiration of bile for chemical and bacteriological analysis is performed rather rarely because of a seemingly high rate of complications. The risk however is low if an appropriate technique is used. In our series the gallbladder was punctured in 110 cases; a local peritonitis subsiding under conservative treatment occured as a complication in only one case. Peritoneoscopic puncture of the gallbladder is indicated in the following conditions: extrahepatic occlusion of the bile duct system of unknown origin, nonvisualization of the gallbladder during cholangiography, biliary dyskinesia, typical biliary colics with normal X-ray findings. In addition, gallbladder puncture should be done if any suspicion of gallbladder disease arises during peritoneoscopy. The procedure as well as technical variations for cholecysto-cholangiography and for X-ray investigation of the pancreatic duct system are described.

Topics: Bile; Cholangiography; Cholecystokinin; Cholelithiasis; Chronic Disease; Female; Hepatic Duct, Common; Humans; Laparoscopy; Male; Middle Aged; Pancreatic Neoplasms; Pancreatitis

Endoscopic retrograde cholangiopancreatography (ERCP) was carried out in 98 patients with unexplained abdominal pain or known pancreatitis with recurrent pain. Patients with jaundice were excluded from the study. In 38 patients with a clinical diagnosis of pancreatitis, the radiological findings on ERCP were graded according to the criteria of Kasugai et al. Advanced pancreatitis was found in 20 patients (52,5%), moderate changes in 7 (18,4%) and minimal-change pancreatitis in 6 (15,8%). ERCP had normal pancreatic function tests. In 35 patients investigated for unexplained abdominal pain, changes consistent with pancreatitis were found in 7, pancreatic carcinoma in 5, a duodenal ulcer in 2, gallstones in 1 and a duodenal tumour in 1. ERCP was normal in 19 patients. A comparison of the findings on ERCP and the standard secretin-cholecystokinin pancreatic function test was available in 52 patients. There was a good agreement between the two tests in the patients with advanced or moderate pancreatitis as revealed by ERCP, but less agreement in the patients with minimal-change pancreatitis. A few patients with clinical pancreatitis and abnormal ERCP had normal pancreatic function tests. ERCP increases the diagnostic yield in patients suspected of having pancreatitis and is at present the only reliable method of diagnosing pancreatic carcinoma which is not evident by other non-operative techniques. ERCP is also of value in the assessment of the severity of pancreatitis and is a necessary investigation before pancreatic surgery to confirm or exclude cyst formation or the site of duct obstruction. The finding of an unsuspected cyst at ERCP necessitates early operation because of the danger of introducing infection during the procedure.

Topics: Adolescent; Adult; Aged; Child; Cholangiography; Cholecystokinin; Chronic Disease; Endoscopy; Humans; Middle Aged; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Adult; Aged; Cholecystokinin; Chronic Disease; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Cholecystokinin; Endoscopy; Humans; Methods; Pancreas; Pancreatic Neoplasms; Pancreatitis; Radiography; Secretin

Different methods available for investigating patients for pancreatic disease are discussed. They first include measurement of pancreatic enzymes in biological fluids. Basal amylase and/or lipase in blood are truly diagnostic in acute pancreatitis but their utility is low in chronic pancreatic diseases. Evocative tests have been performed to increase the sensitivity of blood enzyme measurement. The procedure is based on enzyme determination following administration of pancreozymin and secretin, and offers a valuable aid in diagnosis of chronic pancreatitis and cancer of the pancreas. They are capable of discerning pancreatic lesions but are not really discriminatory because similar changes are observed in both diseases. The measurement of urinary enzyme levels in patients with acute pancreatitis is a sensitive indicator of disease. The urinary amylase excretion rises to abnormal levels and persists at significant values for a longer period of time than the serum amylase in acute pancreatitis. The fractional urinary amylase escretion seems to be more sensitive than daily urinary measurement. The pancreatic exocrin function can be assessed by examining the duodenal contents after intravenous administration of pancreozymin and secretin. Different abnormal secretory patterns can be determinated. Total secretory deficiency is observed in patients with obstruction of excretory ducts by tumors of the head of the pancreas and in the end stage of chronic pancreatitis. Low volume with normal bicarbonate and enzyme concentration is another typical pattern seen in neoplastic obstruction of escretory ducts. In chronic pancreatitis the chief defect is the inability of the gland to secrete a juice with a high bicarbonate concentration; but in the advanced stage diminution of enzyme and volume is also evident. Diagnostic procedures for pancreatic diseases include digestion and absorption tests. The microscopic examination and chemical estimation of the fats in stool specimens in different conditions of intake are still important screening tests. Isotopic estimates of steatorrhea and distinction between labeled triolein and oleic acid absorption do not provide greater diagnostic discrimination than traditional procedures. 131I labeled proteins permit a good evaluation of a negative nitrogen balance. Sophisticated procedures to estimate exocrine pancreatic insufficiency are based on the study of endoluminal digestive processes at several times and different level of the sm

Topics: Amylases; Cholecystokinin; Clinical Enzyme Tests; Humans; Insulin; Pancreas; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin

After a review of the literature the author's results of testing pancreatic function in 445 patients with different diseases are reported. The activities of serum amylase and lipase were estimated before and after stimulation with secretin and pancreozymin; at the same time exocrine secretions of the pancreas were collected in the duodenum and analyzed. Serum enzyme activity did not change markedly after stimulation in pronounced pancreatic insufficiency. Measuring the enzyme activity thus helped to make the diagnosis only in a few cases with chronic pancreatitis and pancreatic carcinoma. In all other patients there was no correlation between changes of serum enzyme activities and changes of exocrine pancreatic function. Pathological test results, that means an increase in enzyme activity after stimulation, were found not only in patients with established or suspected pancreatic diseases, but also in many other subjects. Thus the diagnostic relevance of these tests seems to be rather limited, since it does not prove or exclude with sufficient specificity or adequate probability the presence of pancreatic diseases; it therefore cannot be recommended for screening purposes.

Topics: Amylases; Cholecystokinin; Chronic Disease; Diabetes Mellitus; Enzymes; Gastrointestinal Diseases; Humans; Kidney Failure, Chronic; Lipase; Liver Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Cholecystokinin; Gastrins; Humans; Pancreas; Pancreatic Diseases; Pancreatic Hormones; Pancreatic Neoplasms; Secretin

The use of multivariate nonlinear discriminant analysis raised the rate of correct classification for 585 pancreatic function tests from 84 percent by the doctor to 93 percent by computer analysis. In addition to the "normal" and "pancreatic" disease groups, a group of 388 patients was found in whom secretion levels were neither normal nor typical of pancreatic disease. For this group, nonpancreatic gastroenterologic disease was established with a diagnostic accuracy of 98 percent. Representation of secretion data by Andrews' method for the differentiation of pancreatitis from carcinoma allows moderately sensitive but highly specific testing.

Topics: Cholecystokinin; Diagnosis, Computer-Assisted; Humans; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin; Stimulation, Chemical

Serum lipase activity was measured in 360 patients with the clinical suspicion of chronic pancreatic disease, 60 of them also having the lipase evocation test (serum lipase activity before and after pancreatic stimulation with secretin and pancreozymin). Of 48 with chronic pancreatitis (40 confirmed at operation) the diagnosis was made by endoscopic retrograde pancretography in all but one. Serum lipase activity was abnormal in 38. Without those cases associated with pancreatic insufficency, serum lipase activity-spontaneously and after the evocation test-was abnormal in 46 patients. Nine of 10 patients with papillary stenosis had the diagnosis confirmed at surgery, the pancretographic findings co-inciding with the surgical ones in all instances. All the five patients with abnormally high serum lipase activity also had chronic pancreatitis on pancreatography. In all of the 18 patients with pancreatic neoplasm pancreatography gave the same results as operation or post-mortem findings. In eight of these serum lipase activity was spontaneously elevated. The lipase evocation test was shown to be most effective if 2 C.H.R.- U/KG-h each of pancreozymin and secretin were administered. Serum lipase results were falsely positive in 17 of 300 patients with clinical suspicion of pancreatic disease but normal pancreatographic findings.

Topics: Adult; Aged; Alcoholism; Cholecystokinin; Chronic Disease; Clinical Enzyme Tests; Duodenal Ulcer; Endoscopy; False Positive Reactions; Gallbladder Diseases; Hepatitis; Humans; Lipase; Liver Cirrhosis; Middle Aged; Pancreatic Neoplasms; Pancreatitis; Radiography; Secretin

The appearance of radioselenium in the protein fraction of duodenal aspirates has been studied after an intravenous injection of 75-Se-selenomethionine. The continuous flow of pancreatic juice was stimulated by pancreozymin at 120 minutes and by secretin at 140 minutes. A good distinction between normal subjects and patients with pancreatic disease was obtained by measuring 75-Se-radioactivity in the protein fraction of duodenal aspirates; either cumulative radioactivity during the combined 80-minute post-pancreozymin-secretin period, or maximum 75-Se-specific activity during the postsecretin period was used as an index. The test presented here might be a useful and sufficiently reliable method for detecting abnormal pancreatic exocrine function. This test can be performed along with the conventional pancreozymin-secretin test, serum enzyme response to pancreozymin and secretin, and pancreatic scintiscanning.

Topics: Amylases; Cholecystokinin; Duodenum; Humans; Pancreas; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Radionuclide Imaging; Secretin; Selenium; Selenomethionine

Topics: Angiography; Bile Duct Neoplasms; Celiac Artery; Cholecystokinin; Gallbladder Neoplasms; Hepatic Artery; Humans; Mesenteric Arteries; Pancreatic Neoplasms

Topics: Carcinoembryonic Antigen; Cholecystokinin; Humans; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Acute Disease; Cholecystokinin; Chronic Disease; Computers; Humans; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Radionuclide Imaging; Secretin; Selenomethionine; Technetium

Topics: Cholecystokinin; Humans; Pancreatic Diseases; Pancreatic Neoplasms; Radionuclide Imaging; Secretin

Topics: Cholecystokinin; Chymotrypsin; Duodenum; Endoscopy; Humans; Intubation, Gastrointestinal; Pancreas; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Radiography; Trypsin

Topics: Adult; Aged; Cholecystokinin; Cholelithiasis; Duodenal Diseases; False Negative Reactions; False Positive Reactions; Female; Humans; Male; Middle Aged; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Parotid Gland; Saliva; Secretin

Topics: Aged; Bicarbonates; Body Weight; Cholecystokinin; Eczema; Erythema; Female; Humans; Pancreatic Neoplasms; Secretin; Syringomyelia

Topics: Animals; Bethanechol Compounds; Cholecystokinin; Female; Glucagon; Humans; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Propantheline; Radioisotopes; Radionuclide Imaging; Rats; Selenium; Stomach Ulcer; Vasopressins

Topics: Cholecystokinin; Clinical Enzyme Tests; Dietary Fats; Glucose Tolerance Test; Humans; Intestinal Absorption; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Secretin

Topics: Adult; Amylases; Cholecystokinin; Cholelithiasis; Chronic Disease; Diagnosis, Differential; Duodenal Diseases; Endoscopy; Female; Glucose Tolerance Test; Humans; Liver Diseases; Male; Middle Aged; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatitis; Radiography; Secretin

Topics: Adenoma; Adrenal Gland Neoplasms; Autopsy; Blood Glucose; Cholecystokinin; Diazoxide; Glucagon; Glucose; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Male; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Parathyroid Neoplasms

Topics: Acute Disease; Adult; Aged; Amylases; Cholecystokinin; Chronic Disease; Clinical Enzyme Tests; Female; Humans; Lipase; Male; Middle Aged; Morphine; Neostigmine; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin; Stimulation, Chemical; Time Factors; Trypsin

The uptake of (75)Se Selenomethionine by the pancreas has been evaluated in 102 patients and compared with the secretin-pancreozymin test of pancreatic function. In groups of patients with chronic pancreatitis and cancer of the pancreas abnormal scans closely parallel the diminished exocrine secretion, especially bicarbonate output, following a submaximal dose of secretin. Thirty per cent of the group with no pancreatic abnormality have abnormal scans, though the secretinpancreozymin test is normal. Though a normal scan excludes the presence of chronic pancreatitis and cancer of the pancreas with a probability greater than 90%, an abnormal scan is found so frequently in normal subjects that it does not provide a reliable index of impaired pancreatic function.

Topics: Bicarbonates; Celiac Disease; Cholecystokinin; Chronic Disease; Humans; Jaundice; Liver Cirrhosis; Liver Cirrhosis, Biliary; Methionine; Pancreas; Pancreatic Neoplasms; Pancreatitis; Radionuclide Imaging; Secretin; Selenium

Topics: Cholecystokinin; Clinical Enzyme Tests; Humans; Methods; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Adolescent; Adult; Aged; Carcinoma; Cholecystokinin; Chronic Disease; Clinical Enzyme Tests; Diagnosis, Differential; Female; Humans; Male; Methods; Middle Aged; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Sarcoma; Secretin

Topics: Amylases; Cholecystokinin; Chronic Disease; Chymotrypsin; Female; Humans; Lipase; Male; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin; Stimulation, Chemical; Trypsin

Topics: Amylases; Bicarbonates; Bile Acids and Salts; Bilirubin; Carcinoma; Cholecystokinin; Chronic Disease; Duodenum; Humans; Infusions, Parenteral; Injections, Intravenous; Intestinal Secretions; Lipase; Pancreas; Pancreatic Neoplasms; Pancreatitis; Secretin; Secretory Rate; Stimulation, Chemical; Trypsin

Topics: Adolescent; Adult; Age Factors; Aged; Alcoholism; Calcinosis; Cholecystokinin; Chronic Disease; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Female; Glucose Tolerance Test; Humans; Japan; Male; Middle Aged; Occupations; Pancreas; Pancreatic Neoplasms; Pancreatitis; Secretin; Sex Factors; Smoking

Topics: Carcinoma; Cholecystokinin; Cholestasis; Duodenum; Gallstones; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Radiography; Secretin

Topics: Adenoma; Blood Glucose; Ceruletide; Cholecystokinin; Gastrointestinal Hormones; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Pancreatic Neoplasms; Peptides

Topics: Acute Kidney Injury; Amylases; Biliary Tract Diseases; Cholecystokinin; Gastrointestinal Diseases; Hepatitis; Humans; Kidney Failure, Chronic; Lipase; Methods; Pancreas; Pancreatic Neoplasms; Pancreatitis; Parotitis; Secretin

Topics: Adult; Aged; Angiography; Biliary Tract Diseases; Blood Flow Velocity; Celiac Artery; Cholecystokinin; Contrast Media; Female; Gallbladder; Humans; Intestine, Small; Liver Circulation; Liver Diseases; Male; Mesenteric Arteries; Middle Aged; Oxygen Consumption; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Regional Blood Flow; Time Factors; Vascular Resistance

Topics: Ascites; Biopsy; Cholecystokinin; Chronic Disease; Diagnosis, Differential; Duodenum; Emaciation; Endoscopy; Humans; Pain; Pancreas; Pancreatectomy; Pancreatic Cyst; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Cholecystokinin; Chymotrypsin; Duodenum; Humans; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin; Trypsin

Topics: Amylases; Bicarbonates; Cholecystokinin; Humans; Methionine; Pancreas; Pancreatic Neoplasms; Pancreatitis; Radionuclide Imaging; Secretin; Selenium

Topics: Cholecystokinin; Diagnosis, Differential; Duodenum; Humans; Pancreas; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Radiography; Radionuclide Imaging; Secretin; Selenium

Topics: Amylases; Bile; Biliary Tract Diseases; Cholecystokinin; Chronic Disease; Duodenal Diseases; Duodenum; Enzymes; Gallbladder Diseases; Gastrointestinal Diseases; Humans; Intestinal Secretions; Lipase; Liver Diseases; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Adenosine Triphosphate; Angiography; Celiac Artery; Cholecystokinin; Epinephrine; Humans; Mesenteric Arteries; Methods; Pancreas; Pancreatic Neoplasms; Secretin; Time Factors; Vasoconstrictor Agents

Topics: Adult; Aged; Calculi; Cholecystokinin; Diabetes Complications; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Male; Middle Aged; Pancreatic Diseases; Pancreatic Neoplasms; Time Factors

Topics: Adult; Bicarbonates; Cholecystokinin; Endopeptidases; Female; Humans; Lipase; Male; Middle Aged; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Acute Kidney Injury; Amylases; Cholecystokinin; Clinical Enzyme Tests; Diagnostic Errors; Female; Humans; Isoenzymes; Kidney Failure, Chronic; Lipase; Ovarian Cysts; Pancreatic Neoplasms; Pancreatitis; Photometry; Pregnancy; Pregnancy, Ectopic; Salivary Gland Diseases; Secretin

Topics: Bicarbonates; Cholecystokinin; Duodenum; Humans; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin; Secretory Rate; Stimulation, Chemical

The interrelationships of proteolytic enzymes and amylase have been studied in the duodenal aspirate obtained from subjects with normal and abnormal pancreatic function during stimulation with secretin and pancreozymin. While the relationship of trypsin to chymotrypsin was independent of stimulus and presence of pancreatic disease the ratio of proteolytic enzymes to amylase rose when the degree of stimulation of the pancreas was increased. Patients with recent acute pancreatitis and with chronic pancreatitis tended to have more severe impairment of secretion of proteolytic enzymes than of amylase. In routine tests of pancreatic function both proteolytic and non-proteolytic enzymes should be measured, both because an abnormal ratio may be of diagnostic significance and because the two different groups of enzymes provide mutual checks of the secretory capacity of pancreatic enzymes.

Topics: Amylases; Cholecystokinin; Chymotrypsin; Duodenal Ulcer; Duodenum; Humans; Pancreas; Pancreatic Neoplasms; Pancreatitis; Peptide Hydrolases; Secretin; Trypsin

Topics: Acute Disease; Amylases; Cholecystokinin; Chronic Disease; Clinical Enzyme Tests; Humans; Lipase; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Recurrence; Secretin

Topics: Acute Disease; Cholecystokinin; Chronic Disease; Humans; Neostigmine; Pancreatic Neoplasms; Pancreatitis

Topics: Angiography; Cholecystokinin; Chronic Disease; Clinical Enzyme Tests; Glucose Tolerance Test; Humans; Iodine Radioisotopes; Lipids; Methods; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Radionuclide Imaging; Secretin

Topics: Amides; Cholecystokinin; Female; Humans; Male; Maltose; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Achlorhydria; Adenoma, Islet Cell; Adult; Animals; Bile; Biological Assay; Cholecystokinin; Diarrhea; Dogs; Female; Gastric Acidity Determination; Glucagon; Histamine; Humans; Hypokalemia; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Secretin; Tissue Extracts

Topics: Adolescent; Adult; Aged; Amylases; Bicarbonates; Bile Duct Neoplasms; Biliary Tract Diseases; Bilirubin; Celiac Disease; Cholecystokinin; Diagnosis, Differential; Duodenum; Female; Hemochromatosis; Humans; Hydrogen-Ion Concentration; Intestinal Secretions; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Pancreatitis; Protein-Losing Enteropathies; Secretin

Topics: Aged; Amylases; Bicarbonates; Blood Glucose; Blood Proteins; Cholecystokinin; Chymotrypsin; Diet Therapy; Female; Humans; Injections, Intravenous; Intestinal Absorption; Intestinal Secretions; Iodine Isotopes; Jejunum; Lipids; Pancreatectomy; Pancreatic Neoplasms; Secretin; Serum Albumin, Radio-Iodinated; Triolein; Trypsin

Topics: Bicarbonates; Cholecystokinin; Duodenum; Humans; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin; Secretory Rate

Topics: Animals; Biliary Tract Diseases; Cholangiography; Cholecystography; Cholecystokinin; Dogs; Intestinal Mucosa; Pancreatectomy; Pancreatic Neoplasms; Pancreatitis

Topics: Adult; Aged; Cholecystokinin; Cholestasis; Diabetes Mellitus; Diagnosis, Differential; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Secretin

Topics: Biopsy; Cholecystokinin; Cytodiagnosis; Female; Humans; Laparotomy; Male; Middle Aged; Pancreatic Neoplasms; Radiography

Topics: Cholecystokinin; Chymotrypsin; Feces; Humans; Pancreatic Neoplasms; Secretin

Topics: Adult; Aged; Cholecystokinin; Chymotrypsin; Feces; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Secretin; Trypsin

Topics: Cholecystokinin; Chronic Disease; Humans; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Cholecystokinin; Cytodiagnosis; Humans; Pancreatic Juice; Pancreatic Neoplasms

Topics: Amylases; Biliary Tract Diseases; Cholecystokinin; Cholestasis; Diagnosis, Differential; Humans; Injections, Intravenous; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Cholecystokinin; Humans; Pancreatic Neoplasms; Radiography; Radionuclide Imaging; Secretin

Topics: Aminopeptidases; Amylases; Blood Chemical Analysis; Body Fluids; Carbohydrates; Cholecystokinin; Clinical Enzyme Tests; Diagnosis; Gastrointestinal Hormones; Humans; Iodine Isotopes; Leucine; Lipase; Metabolism; Pancreatic Neoplasms; Pancreatitis; Secretin; Triolein; Trypsin; Urine

Topics: Bicarbonates; Bile Duct Neoplasms; Biliary Tract; Biliary Tract Diseases; Biomedical Research; Cell Biology; Cholecystokinin; Disease; Duodenal Neoplasms; Humans; Pancreas; Pancreatic Neoplasms; Pancreatitis; Pharmacology; Secretin

Topics: Cholecystokinin; Gastrointestinal Hormones; Humans; Pancreas; Pancreatic Cyst; Pancreatic Fistula; Pancreatic Neoplasms; Pancreatitis

Topics: Amylases; Cholecystokinin; Clinical Enzyme Tests; Diagnosis; Gastrointestinal Hormones; Humans; Lipase; Pancreas; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Adolescent; Amylases; Blood Chemical Analysis; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 1; Gastrointestinal Hormones; Humans; Insulin; Lipase; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Amylases; Bicarbonates; Cholecystokinin; Cystic Fibrosis; Diarrhea; Gastrointestinal Hormones; Hemochromatosis; Humans; Liver Cirrhosis; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Physiology; Secretin

Topics: Amylases; Bicarbonates; Cholecystokinin; Cystic Fibrosis; Diarrhea; Gastrointestinal Hormones; Hemochromatosis; Humans; Liver Cirrhosis; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Pharmacology; Physiology; Secretin

Topics: Amylases; Bicarbonates; Cholecystokinin; Diarrhea; Gastrointestinal Hormones; Hemochromatosis; Humans; Liver Cirrhosis; Pancreas; Pancreatic Neoplasms; Pancreatitis; Pathology; Physiology; Secretin

Topics: Bile Duct Neoplasms; Bile Ducts; Cholecystokinin; Gastrointestinal Hormones; Humans; Pancreas; Pancreatic Neoplasms; Secretin