Humoral control of gut function.
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Aging↗
Biomedical subjects
J C Thompson
Publications and source records attributed to J C Thompson.
Pancreatic regeneration after partial pancreatectomy.
The ability of the pancreas to regenerate and the effects of trophic hormones on regeneration of the pancreas after partial pancreatectomy are not completely understood. We investigated the effects of the trypsin inhibitor FOY-305 (an agent that stimulates endogenous cholecystokinin) on pancreatic regeneration after partial pancreatectomy in rats. FOY-305 or water was administered for either 13 days or 27 days by gavage feeding, after sham operation or partial pancreatectomy (n = 6 to 8 animals per group). FOY-305 stimulated hypertrophy of the pancreatic remnant at 13 days; prolonged treatment for 27 days produced both hypertrophy and hyperplasia. The magnitude of pancreatic growth after FOY-305 administration was significantly greater at 27 days in the pancreatic remnant than growth of the equivalent pancreatic segment (duodenal and parabiliary) in sham-operated rats treated with FOY-305. Our results suggest that endogenous cholecystokinin released by FOY-305 stimulates regeneration after partial pancreatectomy. The pancreatic remnant is more sensitive to trophic stimulation in comparison to the normal pancreas. FOY-305 may be a useful agent in the treatment of pancreatic insufficiency after extensive subtotal pancreatectomy or chronic pancreatitis.
Animals↗
Establishment and characterization of a human carcinoid in nude mice and effect of various agents on tumor growth.
The authors have established a long-term tissue culture cell line (BON) derived from a metastatic human carcinoid tumor of the pancreas. The cells have been in continuous passage for 46 months. Tissue culture cells produce tumors in a dose-dependent fashion after SC inoculation of cell suspensions in athymic nude mice. BON tumors, grown in nude mice, are histologically identical to the original tumor; they possess gastrin and somatostatin receptors, synthesize serotonin and chromogranin A, and have a doubling time of approximately 13 days. The antiproliferative effects of the long-acting somatostatin analogue, SMS 201-995 (300 micrograms/kg, t.i.d.), and 2% alpha-difluoromethylornithine on BON xenografts in nude mice were examined. Tumor size was significantly decreased by day 14 of treatment with either agent and at all points of analysis thereafter until the animals were killed (day 33). In addition, tumor weight, DNA, RNA, and protein contents were significantly decreased in treated mice compared with controls. Establishment of this human carcinoid xenograft line, BON, provides an excellent model to study further the biological behavior of carcinoid tumors and the in vivo effect of chemotherapeutic agents on tumor growth.
Animals↗
Somatostatin and analogues in the treatment of cancer. A review.
Somatostatin is a naturally occurring cyclic tetradecapeptide that inhibits release of growth hormone and all gastrointestinal hormones. The beneficial effect of somatostatin in the treatment of certain hypersecretory disorders of hormone excess in well recognized; however its clinical usefulness has been limited in the past by its extremely short plasma half-life. The development of long-acting somatostatin analogues has provided clinically useful agents for treatment of hormone-producing tumors. In addition to well-known inhibiting effects on hormone release and actions, recent studies using experimental tumor models have demonstrated an antiproliferative effect of somatostatin and its analogues on growth of a variety of neoplasms. The exact role of somatostatin analogues in cancer therapy has yet to be established; however studies suggest that these agents could provide a useful and relatively nontoxic adjuvant therapy in the treatment of certain tumors. In this review, the oncologic application of somatostatin and possible mechanism of action are examined and current clinical and experimental studies are summarized.
Breast Neoplasms↗
Novel therapy for the treatment of human carcinoid.
Development of effective treatment for patients with carcinoid tumors has been hampered by lack of an experimental model. The authors have established the only long-term cell line of a functioning human pancreatic carcinoid tumor (BON) that produces tumors in nude mice. In this study the authors examined the effect of three agents, alpha-interferon (IFN), a somatostatin analog, SMS 201-995 (SMS), and an inhibitor of polyamine biosynthesis, alpha-difluoromethylornithine (DFMO), on the growth of BON tumors. BON was implanted bilaterally as 3-mm2 pieces (subcutaneously [sc]) into male BALB/c nude mice. In the first study, 23 mice were randomized to four groups: control, IFN (1 x 10(6) units, sc, four times a day), IFN + SMS (300 micrograms/kg, intraperitoneally, three times a day), and IFN + 3% DFMO in drinking water. Treatments were initiated on day of tumor implantation. In the second study, mice were randomized to six groups: control, IFN, SMS, DFMO, IFN + SMS, IFN + DFMO, and IFN + SMS + DFMO. Treatments were started on day 15 after tumor implantation. Tumor area and body weights were measured weekly. In both studies mice were killed on day 28 after BON implantation and tumors removed, weighed, and analyzed for DNA and RNA content. In the first study, IFN either alone or in combination with SMS or DFMO suppressed BON tumor growth. When treatment was initiated after established tumor growth (study 2), however, the only effective treatments for suppression of growth of BON were IFN + DFMO and IFN + DFMO + SMS.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The economic burden of gallstone lithotripsy. Will cost determine its fate?
Gallstone lithotripsy (LITHO) was performed on 52 patients who underwent 107 procedures. Two hundred sixty-seven gallstone patients were screened and 215 (81%) were excluded. Excessive stone burden and nonvisualization by oral cholecystogram (OCG) were the most common reasons for exclusion. The hospital course of 100 excluded patients who later underwent elective cholecystectomy was evaluated for length of hospital stay (2.3 days) and total cost of treatment ($3685.00). Successful fragmentation to less than 5 mm was achieved in 43 LITHO patients (83%). Five LITHO patients (10%) required conversion to operative management. Complications of LITHO included acute cholecystitis (1 of 52 patients) and biliary colic (17 of 52 patients, or 33%). Multiple procedures in one patient were common. Costs for LITHO were calculated in two ways: first the individual cost for each of the 52 candidates; second the cost for successful LITHO was calculated by excluding five patients who required operation as well as five patients (10%) who are predicted failures of LITHO. Including the preoperative evaluation, treatment, recovery room, and follow-up, the individual LITHO cost for 52 patients was $8275.00. If the same total expenditure is calculated after excluding patients who required operation and those predicted to fail, the cost per 'successful' LITHO procedure was $10,245. The cost of 1 year of bile acid therapy is $1949.00 or $2413.00 per 'successful' procedure. Follow-up costs were $1232.00 per patient or $1525.00 per 'successful' procedure. The added LITHO cost incurred by screening eventual noncandidates was $904.00 per successful procedure. The sum of these individual costs was $15,087.00 per success, as compared to $3685.00 for cholecystectomy. No allowance was made for cost of stone recurrence. Lithotripsy costs appear to be sufficiently high to render the procedure unlikely to emerge as the treatment of choice.
Adult↗
Expression of neurotensin messenger RNA in a human carcinoid tumor.
Neurotensin (NT), a distal gut peptide, has important regulatory and trophic effects throughout the gut; however the intracellular mechanisms that regulate the gene expression and release of human NT are not known. The purpose of this endeavor was to study a functioning human pancreatic carcinoid cell line (called BON) in vitro that expresses the NT gene, and to study the effect of the cyclic adenosine monophosphate (cAMP) signal-transduction pathway on the expression and release of human NT. RNA was prepared from BON cell line (which has been established in this laboratory); the RNA was analyzed for NT mRNA expression by Northern hybridization with a complementary DNA probe. RNA blot analysis demonstrated that the NT gene is expressed in BON and is transcribed to two mRNAs of 1.0- and 1.5-kb sizes. In the second part of this study, BON cells were treated with either forskolin (FSK), which increases intracellular levels of cAMP, or with serotonin (5-HT), which reduces cAMP in BON cells. Forskolin produced a dose-dependent increase in NT peptide release and, furthermore, FSK (10(-6) mol/L) rapidly increased NT mRNA abundance 1 hour after addition; conversely, 5-HT (10(-5) mol/L) decreased NT mRNA at 1 hour. Neurotensin mRNA levels returned to control values by 3 hours after either FSK or 5-HT, which suggests that the transcript half-life for NT is relatively short. These findings show that the expression and peptide release of human NT is mediated, in part, by the cAMP signal-transduction pathway. Our human carcinoid cell line will provide a useful model to study the in vitro regulation of NT gene expression and peptide release.
Animals↗
Bacterial translocation and its relationship to visceral blood flow, gut mucosal ornithine decarboxylase activity, and DNA in pigs.
The relationship of bacterial translocation to gut blood flow and mucosal integrity was studied in pigs. Three groups of miniature pigs were studied: sham injured (controls) (n = 7), 50% mechanical reduction in blood flow to the superior mesenteric artery (SMA) and celiac artery (CA) (n = 6), and a 40% third-degree cutaneous flame burn (n = 9). Forty-eight hours after injury, animals were killed and organ samples obtained for analysis. Bacteria of the same biotype as that found in the intestinal lumen were present in the mesenteric lymph nodes (MLN) of 9 of 9 burned pigs and 5 of 6 pigs undergoing partial vascular occlusion. The DNA content and ornithine decarboxylase (ODC) activity were increased in the colon mucosa of animals from both the reduced-flow and burn-injured groups compared with control animals. Decreased blood flow to the gut may contribute to the development of bacterial translocation. In addition, intestinal regenerative capacity remains intact 48 hours after injury.
Animals↗
Aging and the trophic effects of cholecystokinin, bombesin and pentagastrin on the rat pancreas.
We examined the effect of age on the trophic response of the pancreas to chronic treatment with cholecystokinin (CCK), bombesin, or pentagastrin. Three age groups (3-, 12-, and 24-months) male F344 rats received saline; CCK-8 (5 ng/kg), bombesin (10 micrograms/kg), or pentagastrin (100 micrograms/kg) by intraperitoneal injection t.i.d. for 2 weeks. Rats were then killed and the pancreases excised, weighed, and assayed for DNA, RNA, protein, and polyamine (putrescine, spermidine, and spermine) concentrations and contents. We found that none of the treatments altered body weight at any age. All three hormones increased pancreas size and cell number in 3-month old rats, but by 12 months, all three had increased only pancreatic RNA content. Pancreatic spermidine concentration was decreased by all three hormone regimens in 3- but not in 12-month old rats, and pancreatic putrescine concentration and content were increased in 12-month old rats receiving all three hormones. There was no change in any parameter following any of the three hormones, tested at 24 months of age. We conclude that, at the dosages tested, the trophic response of pancreas to chronic administration of CCK, bombesin, and pentagastrin, which is normally present in young adult rats, is lost with aging.
Aging↗
Intracolonic infusion of bile salt stimulates release of peptide YY and inhibits cholecystokinin-stimulated pancreatic exocrine secretion in conscious dogs.
The purpose of this study was to examine the effect of transanal (intracolonic) infusion of bile acid on release of peptide YY (PYY) and cholecystokinin (CCK)-stimulated pancreatic exocrine secretion in seven conscious dogs. CCK-8 (50 ng/kg/h) was given intravenously for 120 min and either taurocholic acid (TA, 1 or 2 mmol/h) or saline was infused transanally (150 ml/h) during the 0-60-min period of CCK infusion. Transanal infusion of TA (1 or 2 mmol/h) significantly inhibited output of CCK-8-stimulated pancreatic protein, compared to transanal infusion of saline during the first 60 min. On the average, the magnitude of inhibition was approximately 45%. Plasma concentrations of PYY increased significantly in response to intracolonic infusion of TA or saline. Transanal infusion of TA (1 or 2 mmol/h) significantly increased plasma levels of PYY when compared with transanal infusion of saline during the first 60 min. The magnitude of the increase of plasma PYY levels was approximately 50 pg/ml (p less than 0.05). Plasma levels of pancreatic polypeptide were not altered significantly by transanal infusion of TA. Our results suggest that release of endogenous PYY by TA in the colon plays a role in the inhibition of CCK-stimulated pancreatic exocrine secretion. Bile salts in the hindgut may participate in the physiologic regulation of pancreatic exocrine secretion by stimulation of release of ilealcolonic PYY.
Animals↗
Inhibitory action of islet amyloid polypeptide and calcitonin gene-related peptide on release of insulin from the isolated perfused rat pancreas.
Islet (or insulinoma) amyloid polypeptide (IAPP) is a 37-residue peptide recently purified from amyloid deposits in the pancreas of patients with type 2 diabetes and from amyloid deposits of a human insulinoma. IAPP immunoreactivity has been identified in islet B cells of diabetic and nondiabetic humans. IAPP is structurally similar to calcitonin gene-related peptide (CGRP). The purpose of this study was to examine the effects of IAPP and CGRP on glucose- and carbachol-stimulated release of insulin and pancreatic polypeptide (PP) from the isolated perfused rat pancreas. IAPP and CGRP, at 10(-7) M, failed to inhibit glucose-stimulated (16.7 mM) release of insulin. At the same concentration, however, IAPP significantly (p less than 0.05) inhibited carbachol-stimulated (10(-7) M) release of insulin by 30%, and CGRP significantly inhibited carbachol-stimulated release of insulin by 33% when compared with the control group. IAPP also significantly decreased carbachol-stimulated release release of PP. IAPP and CGRP, at 10(-8) M, did not inhibit carbachol-stimulated release of insulin and PP. These results suggest that IAPP and CGRP may have roles in the regulation of secretion of insulin. IAPP may inhibit secretion of insulin, at least in part, by blocking cholinergic mechanisms.
Amyloid↗
Myo-inositol and D-glucose transport in rat glomerular and cultured mesangial cells.
Myo-inositol (MI) is the precursor of membrane-bound phosphoinositides important for transmembrane signaling. This study examines whether freshly isolated whole glomeruli can be used to characterize intact cell transport kinetics for MI and D-glucose. Transport properties of cultured mesangial cells are compared. Glomeruli greater than 95% tubule free were isolated from Sprague-Dawley rat kidney cortex by means of selective sieving. Scanning electron microscopy revealed substantial damage of glomerular epithelial cells, whereas endothelial and mesangial cells remained intact. Specific [3H]MI uptake (7-180 min, 37 degrees C) was observed in presence of 5.5 mM D-glucose when L-[14C]glucose was used as a marker of nonspecific uptake. With ouabain (3 mM), or when Na was replaced with N-methyl-D-glucamine, choline, or Li, specific MI uptake was reduced by 95%. A single high-affinity, Na-dependent MI transport site on glomerular cells with Km of 16.5 +/- 1.4 (SE) microM and Vmax of 947 +/- 56 (SE) fmol.mg protein-1.min-1 was observed for 0.75-100 microM MI. D-glucose competitively inhibited MI transport. Specific D-[3H]-glucose transport was Na independent. Phlorizin inhibition of D-glucose and MI uptake was in keeping with Na-independent D-glucose transport. Km and Vmax for MI uptake in cultured mesangial cells were 42.7 +/- 7.1 microM and 1,474 +/- 192 fmol.mg protein-1.min-1, respectively. We conclude that freshly isolated glomeruli can be used to study cellular transport function that may be modified in disease states.
Animals↗
Regulation of pancreastatin release from a human pancreatic carcinoid cell line in vitro.
The objective of these experiments was to investigate the influence of activation of three second messenger systems (protein kinase-C, adenylate cyclase-cAMP, and calcium mobilization) on the secretion of pancreastatin (PST) and chromogranin-A (CGA) by a human pancreatic carcinoid cell line (BON) in tissue culture. Stimulation of protein kinase-C by a phorbol ester (0.025-7.5 microM) caused a significant dose-related release of PST (186 +/- 22-4271 +/- 228% over controls). Treatment of BON cells with graded doses of 8-bromo-cAMP (0.14-3.0 mM) and isobutylmethylxanthine (IBMX; 0.01-1.0 mM) also stimulated a dose-related release of PST (107 +/- 22-284 +/- 28 and 16 +/- 12-1076 +/- 100% over controls, respectively). Incubation of BON cells with ionomycin (0.134-13.4 microM) increased the release of PST (102 +/- 15-554 +/- 21% over controls) in a dose-related manner. A combination of IBMX and ionomycin resulted in an additive effect, whereas treatment with a phorbol ester plus IBMX resulted in a synergistic effect on PST release. Pretreatment of BON cells with monensin, an agent that prevents processing of precursors to smaller peptides, significantly decreased PST, but not CGA, secretion in response to phorbol ester or ionomycin. These findings indicate that protein kinase-C, cAMP, and Ca2+ mobilization participate in CGA and PST secretion. Although the observation that secretions of PST and CGA in response to theophylline are quantitatively associated, the absence of a quantitative relationship in the release patterns of PST and CGA in response to phorbol ester and ionomycin do not support a simple precursor-product relationship between CGA and PST. The monensin experiments are consistent with the notion that PST is derived from CGA in BON cells.
1-Methyl-3-isobutylxanthine↗
The effect of tumor burden on ornithine decarboxylase activity in mice.
Polyamines are essential for cell growth of normal and neoplastic tissue, alpha-Difluoromethylornithine (DFMO) is a known irreversible inhibitor or ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. The purpose of this study was to examine the effects of tumor burden on ODC in tissues of tumor-bearing compared with tumor-free mice. Twenty-eight male Balb/c mice were divided into four groups of 7 each. Groups 1 and 2 were inoculated subcutaneously with 10 x 10(6) MC-26 mouse colon adenocarcinoma cells. Groups 3 and 4 were kept as tumor-free controls. Ten days after inoculation, groups 2 and 4 were injected with DFMO (200 mg/kg) intraperitoneally (IP) while Groups 1 and 3 received saline. Two hours after the injection of DFMO the animals were sacrificed. The tumor, pancreas, kidney, and liver were excised and analyzed for ODC activity. DFMO caused a significant reduction (compared with controls that did not receive DFMO) in the ODC activity of tumors; however, ODC activity of the kidney, pancreas, and liver of tumor-bearing mice was not affected. Additionally, the basal ODC activity in the kidney, liver, and pancreas of tumor-bearing mice was significantly lower compared with tumor-free controls. DFMO lowered ODC activity in the kidney, pancreas, and liver of tumor-free mice. These results suggest that the presence of MC-26 tumor causes systemic effects that alter ODC activity and the response to a known inhibitor of ODC.
Animals↗
Vasoactive intestinal polypeptide inhibits c-myc expression and growth of human gastric carcinoma cells.
Vasoactive intestinal polypeptide (VIP) is a gut neuroendocrine polypeptide that increases cyclic adenosine monophosphate (cAMP) production in cells with VIP receptors. Some gastrointestinal cancer cells possess functional receptors for VIP; however, the role of VIP in regulation of growth of gastric cancer cells has not been determined. The purpose of this study was to determine whether VIP and other agents that increase cAMP regulate growth of a human gastric cancer cell line (AGS) and whether these agents regulate expression of c-myc proto-oncogene, which is required for cell proliferation. We measured levels of cAMP by radioimmunoassay, and we used Northern blot analysis to examine c-myc messenger RNA expression. Cell-growth studies were carried out in media supplemented with 3% serum, and cells were counted with a Coulter counter. We found that VIP significantly increased cAMP production of AGS cells in a dose-dependent manner, whereas secretin, glucagon, and peptide histidine methionine (PHM) did not stimulate cAMP production. Exogenous cAMP (8-bromo-cAMP) inhibited AGS cell growth in a dose-dependent manner. VIP acted synergistically with either isobutylmethyl-xanthine or forskolin to inhibit AGS cell proliferation. The increased c-myc expression, which was induced by serum, was inhibited by simultaneous treatment with VIP and isobutylmethyl-xanthine. We have found that AGS cells have specific, functional VIP receptors (activation of which are negatively correlated with cell growth) and that the mechanism by which VIP acts to inhibit cell growth appears to be due, in part, to cAMP-dependent regulation of c-myc proto-oncogene expression.
1-Methyl-3-isobutylxanthine↗
Posttranscriptional regulation of neurotensin in the gut.
Previous studies have suggested an important role for neurotensin as an enterotrophic factor in the adaptive response of the gut. The purpose of this study was to determine the specific tissue distribution of neurotensin messenger RNA (mRNA) and to examine the molecular mechanisms that regulate intestinal neurotensin gene expression and content. In the first experiment, various segments of gut tissue from three Sprague-Dawley rats were harvested, and polyadenylated RNA was extracted for Northern hybridization with a rat neurotensin probe. In the second experiment, 32 Sprague-Dawley rats were fasted for 72 hours and then killed at 0, 3, 12, and 24 hours after refeeding (n = 8 rats/group). Rats fed ad libitum were killed before fasting (control, n = 8). Distal ileal segments (30 cm) were resected for measurement of neurotensin tissue concentration by radioimmunoassay and extraction of poly (A)+ RNA for Northern hybridization with a rat neurotensin complementary DNA probe. Blots were stripped and reprobed for beta-actin as a control for RNA loading. A nuclear run-on transcription assay was performed to determine the relative rate of neurotensin transcription. In the first experiment, neurotensin messenger RNA transcripts of 1.0 and 1.5 Kb sizes were found throughout the small intestine and proximal colon; the greatest abundance was found in the distal small intestine. In the second experiment, neurotensin tissue concentration was significantly reduced with fasting. Refeeding a diet for 24 hours returned neurotensin concentration to control levels. However, neither the amount of neurotensin messenger RNA nor its rate of transcription were altered by fasting and refeeding. These findings suggest that a posttranscriptional mechanism is responsible for regulation of neurotensin synthesis in gut mucosa.
Animals↗
Pancreastatin: characterization of biological activity.
Pancreastatin (PST) (1-49) was first isolated from the porcine pancreas and can inhibit glucose-induced insulin release. PST (33-49), a PST C-terminal fragment, can also inhibit insulin release. The purpose of this study was to determine the shortest C-terminal biologically active fragment of PST, in terms of inhibition of insulin release from the isolated perfused rat pancreas. Porcine PST (1-49) and C-terminal fragments, PST (33-49), PST (35-49), PST (37-49) and PST (39-49) were synthesized by solid-phase methodology. PST (1-49), PST (33-49) and PST (35-49), at 10 nM, significantly (p less than 0.05) inhibited insulin release from isolated perfused rat pancreas: the first phase was inhibited by 15.6 +/- 2.4, 24.4 +/- 6.5 and 12.5 +/- 1.9% and the second phase, 18.9 +/- 2.7, 25.7 +/- 4.8 and 20.1 +/- 1.9% by PST (1-49), PST (33-49) and PST (35-49), respectively. PST (35-49) shows a dose-dependent inhibition of insulin release. PST (37-49) and PST (39-49) were, however, inactive. Our results indicate that the shortest C-terminal biologically active fragment is PST (35-49). These data further indicate that the C-terminal portion of PST is primarily responsible for the biological activity of PST.
Animals↗
Gastrinoma.
The Zollinger-Ellison syndrome with its main symptom of massive gastric hypersecretion presents problems with both the medical and surgical approaches to treatment. Successful medical treatment depends on a life-long commitment to rigid medication schedules requiring careful ongoing supervision and is subject to pitfalls of compliance, drug side effects, drug resistance, and complications of persistent tumor growth. Surgical therapy carries risks of operative mortality and complications. If a low operative mortality can be maintained and the nutritional results after total gastrectomy are good, then it is the authors' opinion that the permanent relief from dangers of hypersecretion afforded by total gastrectomy makes surgery a worthwhile approach. Based on our operative experience in 34 patients and interpretation of the experience of others, we believe that resection of all tumor that can be resected, combined with total gastrectomy, is safe and dependable. The results compare well with those of long-term medical management.
Gastrinoma↗