Elevated gastrin levels in patients with colon cancer or adenomatous polyps

Gastrin has been shown to stimulate the growth of carcinogenic-induced colon cancer in animals, and some human colon cancers grown in vitroor as xenografts in nude mice. We determined fasting plasma gastrin levels in control subjects and patients with adenomatous polyps or adenocarcinoma of the colon to determine whether abnormal levels occurred in either patient group. Blood samples were obtained from 73 patients undergoing colonoscopy, primarily for evaluation of Hemoccult-positive stools. Fasting plasma gastrin was significantly greater in patients with adenomatous polyps (24.2±5.7 pM, N=25) or colon cancer (84.5±28.5 pM, N=20) than in controls (9.9±0.9 pM, N=28). Elevations were due to gastrin values greater than control mean + 2 sd in nine patients with polyps (19.5–150.2 pM) and eight with cancer (20.7–403.2 pM). None of the patients had identifiable causes (drugs, prior surgery) for elevated gastrin levels. Our results indicate that elevated plasma gastrin occurs in subgroups of patients with adenomatous polyps or adenocarcinoma of the colon. The cause and potential role of elevated gastrin for polyp and tumor growth in these patients is not known.Work performed at University of Missouri Medical Center and the Harry S. Truman Veterans' Administration Hospital, Columbia, Missouri, Departments of Medicine and Physiology.     

Antral Gastrin Cells and Serum Gastrin in Achlorhydria

Forty-five patients with achlorhydria due to severe atrophic corpus gastritis or gastric atrophy were studied by determination of serum gastrin, histological examination of multiple biopsy specimens from the antrum, and quantitation of gastrin cells revealed by an indirect immunofluorescence technique. In a reference group of 12 persons with normal gastric secretion and without atrophic antral gastritis, the mean number of gastrin cells per field of vision was 52±6.5 (S.E.M.). In a group of achlorhydric patients having normal antral mucosa (n = 24), the serum gastrin level was 324±56 pmol/1 and the number of gastrin cells was 79.6±7.5 cells/field of vision. The corresponding values for a group of achlorhydric patients with chronic superficial antral gastritis (n = 11) were 361±186 pmol/1 and 88.0±14.4 cells/field of vision. In a group of achlorhydric patients with atrophic antral gastritis (n = 10) serum gastrin was 15.0±3.3 pmol/1, and the number of gastrin cells was 6.2±3.3 cells/field of vision. Compared to the subjects in the reference group, the number of gastrin cells was significantly higher in the groups of achlorhydric patients with normal or superficially inflamed antral mucosa and significantly lower in achlorhydric patients with atrophic antral gastritis. It is concluded that serum gastrin in general is a good indicator for the presence or absence of antral atrophic gastritis in achlorhydria.     

Regulation of gastric function by endogenous gastrin releasing peptide in humans: studies with a specific gastrin releasing peptide receptor antagonist

BACKGROUND AND AIMS: The main goal of our study was to characterise the activity of BIM26226 as a peripheral gastrin releasing peptide (GRP) receptor antagonist in healthy human subjects and to determine if endogenous GRP is a physiological regulator of gastric acid secretion and gastrin release. METHODS: Our study consisted of three parts. In part I, subjects received saline or BIM26226 followed by graded doses of intravenous human GRP in a four period crossover design. In part II, subjects received BIM26226 or saline during oral meal ingestion or modified sham feeding. In part III, subjects received an acidified meal in the presence and absence of BIM26226 in a two period crossover design. In addition, gastrin and somatostatin mRNA were measured in biopsy specimens during saline and BIM26226 infusion. RESULTS: BIM26226 dose dependently inhibited GRP induced acid output. Acid secretion after oral liquid meal intake and sham feeding was significantly inhibited by BIM26226 (p<0.01) whereas plasma gastrin release remained unchanged. Gastrin and somatostatin mRNAs were not significantly different after saline or BIM26226. CONCLUSIONS: BIM26226 is a potent GRP antagonist in humans. Endogenous GRP may be a physiological regulator of gastric acid secretion. Gastrin release does not seem to be under the control of GRP.     

促胃液素及其受体拮抗剂丙谷胺对人胃癌细胞系生长的影响

目的观察和分析五肽促胃液素ＰＧ及其受体拮抗剂丙谷胺ＰＧＭ对人胃癌细胞系ＭＧＣ生长的影响,为临床应用促胃液素受体拮抗剂协助治疗胃癌提供依据．方法选用５ｍｇ／Ｌ,１０ｍｇ／Ｌ,１５ｍｇ／Ｌ,２０ｍｇ／Ｌ４种浓度的ＰＧ和３０ｍｇ／Ｌ的ＰＧＭ分别作用于体外培养的浓度为２５×１０８／Ｌ的ＭＧＣ,分别培养２４,４８,７２ｈ,于酶标仪上选用波长５４０ｎｍ测定吸光值Ａ,并对数据进行比较分析．结果４种浓度的ＰＧ作用于ＭＧＣ,ＭＧＣ连续３ｄ的生长状态与对照组无明显差异,而ＭＧＣ在ＰＧＭ作用下,其连续３ｄ的平均Ａ值分别为００２９,００４６和００８４,而未被ＰＧＭ作用的ＭＧＣ的平均Ａ值分别是０１０１,０１１５和０１８２,ＭＧＣ在ＰＧＭ作用下生长明显低于对照组（Ｐ＜００５）．结论外源性的ＰＧ对ＭＧＣ无营养促进作用,而ＰＧＭ能抑制ＭＧＣ的生长     

Gastrin as an autocrine growth factor in colorectal carcinoma: implications for therapy

Ｔｈｅｒｅｉｓｎｏｗｃｏｎｓｉｄｅｒａｂｌｅｅｘｐｅｒｉｍｅｎｔａｌｓｕｐｐｏｒｔｆｏｒｔｈｅｈｙｐｏｔｈｅｓｉｓｔｈａｔｐｒｏｇａｓｔｒｉｎｄｅｒｉｖｅｄｐｅｐｔｉｄｅｓｓｔｉｍｕｌａｔｅｐｒｏｌｉｆｅｒａｔｉｏｎｏｆｔｈｅｎｏｒｍａｌｃｏｌｏｎ...     

Effect of gastrin on protein kinase C and its subtype in human colon cancer cell line SW480

INTRODUCTION Gastrin is a trophic gastrointestinal hormone which is secreted by G cell. Gastrin has long been considered a growth stimulatory hormone for mucosa of the gastrointestinal tract[1]. The growth responses of certain colorectal cancer cells, and xenografts, can be stimulated by endogenous gastrin[2]. Protein kinase C (PKC) is a family of isozymes that plays a crucial role in transducing signals of many hormones, growth peptides,neurotransmitters, and its activation is crucial in tumor promotion[3]. PKC is also involved in regulating cellular proliferation[4].     

Gastrin and Acid Studies in the Pouch Dog

Serum gastrin and pouch acid secretion were measured in dogs with either innervated (Pavlov) or denervated (Heidenhain) pouches in the basal state and following a meat meal or insulin hypoglycaemia. The gastrin response to meat was consistently greater than to insulin hypoglycaemia and pouch acid output followed the changes in serum gastrin in both groups. These studies confirm that gastrin is the secretagogue responsible for acid secretion from a denervated pouch. They also indicate that intact vagal innervation is essential for the optimal effect of gastrin on acid secretion to be observed.     

Hypothesis on the existence of an adenoma-carcinoma sequence in the small intestine

An analysis of a literature survey of 104 adenomas of the ampulla of Vater, 94 of the duodenum and 20 of the jejunum and ileum, as well as 735 carcinomas of Vater's ampulla, 180 carcinomas of the duodenum and 72 carcinomas of the jejunum and ileum, demonstrated, in spite of small case collectives, that there is probably a similar close relationship between adenomas and carcinomas in the small intestine, as in the large intestine. In adenomas of the small intestine signs of malignancy sometimes can be seen, as well as in some case of carcinoma of the small intestine rests of adenomas have been described. The age and sex distribution of the epithelial neoplasms of the small intestine permits an adenoma-carcinoma-sequence. The relative distribution of the adenomas over the different parts of the small intestine corresponds with that of the carcinomas. The adenomas and carcinomas of the small intestine in patients with adenomatosis coli have the same relationship to the neoplasms of the small intestine in patients without adenomatosis coli, as it is valid in the large intestine. The hypothesis of an adenoma-carcinoma-sequence in the small bowel with a great significance, which explains the results best, is therefore proposed. As the distribution of adenomas and carcinomas of the small bowel in patients with and without familial polyposis is equal, the theory is suggested, that the principle of the adenomatosis intestine disease is a general increase of the overall liability to adenomas in the large and small intestine.     

胃泌素及其受体拮抗剂对BGC－823细胞系生长的调节

本文用液闪测定和细胞计数观察了胃泌素及其受体拮抗剂丙谷胺和Ｌ－３６５２６０对体外培养的人胃腺癌ＢＧＣ－８２３细胞系的生长调节作用。结果表明不同浓度胃泌素对ＢＧＣ－８２３细胞系的生长均有显著促进作用，而这种作用可被其受体拮抗剂丙谷胺和Ｌ－３６５２６０所抑制，且发现在胃泌素浓度衡定时，Ｌ－３６５２６０对ＢＧＧ－８２３细胞系的生长抑制作用明显强于丙谷胺。这一结果也提示，Ｌ－３６５２６０对胃泌素受体的亲合力可能明显高于丙谷胺。     

Factors affecting the serum gastrin 17 level: an evidence-based analysis of 3906 serum samples among Chinese

OBJECTIVE: To investigate the influence of gender, age, site of lesion, disease type and Helicobacter pylori (H. pylori) infection on the human serum gastrin‐17 level and to study the diagnostic value of serum gastrin‐17 in gastric precancerous lesions and gastric cancer. METHODS: Serum gastrin‐17 and serum H. pylori IgG antibody were detected by the ELISA method. The different gastric disease groups were confirmed by endoscopy and histopathology. RESULTS: Among the 3906 serum samples according to the gender, age, site of lesion and the data of different gastric disease groups, the serum gastrin‐17 level was markedly higher in people ≥60 years old than that in younger age groups. The serum gastrin‐17 level increased progressively in the following order: healthy control group, nonatrophic gastritis group, gastric ulcer group, and the serum gastrin‐17 level was higher in the atrophic gastritis with dysplasia group than that without it, the lowest level being in the gastric cancer group. Among the 2946 serum samples matched with the site of the lesion, the serum gastrin‐17 level was higher in those with antral diseases than in those with gastric corpus diseases. Among the 3805 serum samples matched with the H. pylori infection data, the serum gastrin‐17 level was higher in the H. pylori‐positive group than in the H. pylori‐negative group. CONCLUSIONS: In people over 60 years of age, the serum gastrin‐17 level tends to increase. In subjects with precancerous gastric lesions, it may increase significantly with the progression of gastric disease, and ultimately decrease in gastric cancer. Serum gastrin‐17 is a good biomarker to differentiate benign from malignant gastric diseases. The site of the gastric lesions is an important factor affecting the serum gastrin‐17 level, whereas H. pylori infection is usually associated with its increment.     

Circadian rhythms in the number of gastrin cells,DNA synthesizing cells and labelling index of gastrin cells in the antral mucosa of the rat

Circadian variations of the gastrin cell (G-cell) number, the DNA synthesizing cell (S phase cell) number and labelling index of G-cell in antral mucosa were studied using the simultaneous double immunoenzymatic labelling method of gastrin and bromodeoxyuridine (BrdU) both in fed and 24 h fasted rats. No significant change was observed in the G-cell number. The S phase cell number and labelling index of G-cell showed significant circadian rhythms. Labelling index of G-cell markedly decreased in 24 h fasted rats in comparison to that in fed rats. These results suggest that DNA synthesis in G-cells has a circadian rhythm and that the activity is influenced by food ingestion.     

Gastric acid secretion and gastrin release in the baboon

Significant species differences have been demonstrated in gastric physiology, a factor that limits extrapolation of animal data to man. Primate physiology is thought to be similar to that of man; however, gastric function has not been adequately documented in the primate. In the present study six baboons (body weight 25.5±1.8 kg) were trained to sit in a chair and gastric acid secretion and gastrin release was studied in conscious animals. Mean basal acid secretion was 1.3±0.1 mmol (H⁺)/hr. Maximum output after pentagastrin (12 g/kg/hr) was 9.5±0.9 mmol (H⁺)/hr and 11.0±0.4 mmol (H⁺)/hr after histamine (40 g/kg/hr). A statistically significant (by cosinor analysis) circadian rhythm was demonstrated for intragastric pH over 24 hr in fasted baboons (P<0.001). Mean basal serum gastrin level was 37.7±8.3 pg/ml. The integrated gastrin response after administration of a protein rich meal was 2.52±0.07 ng×min/ml and this increased to 5.17±0.18 ng×min/ml (P<0.05) following simultaneous administration of a meal with atropine (0.2 mg/kg) (P<0.05). Our results suggest that there is significant basal and stimulated acid secretion in the baboon; the amount of acid secreted is similar to that reported in man. Gastric pH demonstrated a circadian rhythm. Postprandial gastrin release was significantly enhanced by cotreatment with atropine. As the present findings are similar to those previously reported in man, the baboon may be a useful model for further studies in gastric physiology and experimental peptic ulceration.     

Biologic and Immunologic Gastrin Activity in Serum of Patients with Gastrinoma. Bioassay of Gastrin Activity in Serum

The biologic gastrin activity in serum from 14 patients with the Zollinger-Ellison syndrome was assessed by the stimulation of histamine release and acid secretion from the isolated vascularly perfused rat stomach and compared with the immunologic activity as determined by radioimmunoassay using an antibody directed towards the active site of the gastrin molecule. Biologic gastrin activity assessed by the stimulation of histamine release was more closely correlated to immunologic gastrin activity than biologic activity assessed by the stimulation of gastrin acid secretion. This study does not contradict the concept that gastrin stimulates acid secretion at least partly by releasing histamine and also shows that the immunologic gastrin activity determined with the help of an antibody directed towards the active site reflects biologic activity.     

Effect of aging on gastric acid secretion,serum gastrin,and antral gastrin content in rats

The purpose of this study was to characterize the effects of aging on gastric acid secretion and on serum and antral concentrations of gastrin in rats. Young and old Fischer 344 rats were prepared with gastric fistulas. Twenty-four hours after surgery, graded doses of human synthetic gastrin-17 (SHG-17) (2, 5, 10, 20, and 40 g/kg) were given intravenously in random order. Gastric secretions were collected for gastric acid measurement before and at 15-min intervals after each dose of gastrin. In a separate study, blood was collected and the stomachs were removed for antral gastrin extraction from fed young and old rats. Serum and antral gastrin was measured by radioimmunoassay. The basal and gastrin-stimulated acid secretions were significantly decreased in aged rats compared to the young rats. The basal acid output was 0.4±0.2 eq/15 min in the aged rats and 1.5±0.5 eq/15 min in the young. The maximal acid output stimulated by gastrin was 11.1±1.8 eq/15 min in the aged rats and 24.2±2.8 eq/15 min in the young. Both serum and antral concentrations of gastrin were significantly decreased in aged rats. Serum gastrin concentration was 114.8±7.4 pg/ml in the aged rats and 192.0±14.4 pg/ml in the young. Antral gastrin concentration was 3.9±0.5 g/g tissue in the aged rats, which was significantly less than the concentration in the young (6.5±0.4 g/g tissue). Antral gastrin content did not change with aging. Gastric acid secretion in aged rats is significantly decreased compared to the young in both the basal condition and in response to fixed doses of exogenous gastrin. Diminished concentrations of circulating gastrin may well be responsible, at least in part, for the diminished acid secretion in the aged rats.Part of this work was presented at the special session on aging during the Digestive Disease Week held by the American Gastroenterology Association (AGA) in New York, May 14, 1985, and has been published in abstract form (Gastroenterology 88:1445, 1985).Supported by grants from the National Institutes of Health (RO1 DK 15241, PO1 DK 35608, RCDA CA 00854, CA 38651) and a grant from the American Cancer Society (PDT-220).     

Basal and Postprandial Serum Levels of Gastrin in Normotensive and Hypertensive Adults

Gastrin is a peptide hormone, which acts not only to regulate gastric acid secretion, but also to exert physiological actions such as the regulation of sodium balance. From a case (n = 95)–control (n = 82) study in Fuyang People’s Hospital, Anhui Province, China, we found that the fasting serum gastrin levels are similar in normotensive and hypertensive adults but increased to higher levels in the latter group than in the former group after a mixed meal. We suggest that gastrin is involved in the regulation of blood pressure, possibly via the regulation of sodium and water metabolism and/or renin–angiotensin–aldosterone system. However, the mechanism remains to be determined.     

Helicobacter pylori Infection and Exaggerated Gastrin Release: Effects of Inflammation and Progastrin Processing

Helicobacter pylori infection is associated with exaggerated gastrin release. We investigated whether this abnormality was due to the bacteria or the immune response. Fasting and meal-stimulated ‘total’ and amidated gastrin were measured in 10 H. pylori-infected volunteers before eradication therapy, after 2 and 14 days of therapy, and 4 weeks after completion of therapy. The exaggerated meal-stimulated gastrin concentration remained unchanged after 2 days of therapy, although the polymorphonuclear cell infiltrate and H. pylori bacteria were no longer evident. The expected fall in gastrin concentration after 14 days of therapy was associated with a reduction in the density of mucosal mononuclear cells, suggesting exaggerated gastrin release was related to chronic inflammation or to H. pylori or its products. The effect of H. pylori on normal progastrin processing was also assessed; 2 control groups were included: 10 H. pylori-uninfected volunteers and 13 patients with H. pylori peptic ulcers. There was a significant difference in the proportion of circulating gastrins that were biologically active amidated gastrins between ulcer patients and uninfected controls (56.7 ± 4% versus 33.8 ± 4%, p < 0.001). The proportion of amidated to total gastrins did not increase after successful eradication.     

Gastrin Produces an Immediate and Dose-Dependent Histamine Release Preceding Acid Secretion in the Totally Isolated,Vascularly Perfused Rat Stomach

Increasing doses of gastrin 1–17 (Gl-17) were administered to totally isolated, vascularly perfused rat stomachs prestimulated with the phosphodiesterase inhibitor isobutyl methylxanthine (IMX). Vascular and luminal histamine outputs and luminal acid output were monitored at short intervals. (31–17 induced an immediate histamine release to the vascular perfusate, preceding the increase in acid secretion by approximately 10 min. Vascular histamine output increased from a base line (IMX only) of 4.0 ± 0.4 to a maximum of 34.5 ± 7.3 nmol/60 min (mean ± SEM) after 1040 pM G1–17, and acid output from 8.0 ± 2.8 to 61.5 ± 7.0 μmo1/60 min after 520 pM GI-17. Acid output was correlated to vascular histamine release (r = 0.64. p < 0,001). Gastrin produced a histamine release giving gastric venous concentrations of the same magnitude as the concentration of histamine necessary to induce a comparable acid response. Histamine release to the lumen, on the other hand, paralleled the acid secretion in time, suggesting it to be a passive phenomenon secondary to acid secretion. Thus, the present study for the first time shows that gastrin induces vascular histamine release of such a magnitude that this substance could be the mediator of the gastrin effect on acid secretion.     

幽门螺杆菌、胃泌素与慢性胃炎的关系

目的：对慢性浅表性胃炎（ＣＧＳ）患者行幽门螺杆菌（ＨＰ）及空腹血清胃泌素（ＳＧ）检测,对ＨＰ（＋）组和ＨＰ（－）组ＳＧ作对比,抗ＨＰ治疗前后ＳＧ、病理组织学作比较,探讨两者与ＣＳＧ的关系。方法：患者先行空腹作ＳＧ测定,再作胃镜检查,取胃罕粘膜３块,分另作快速尿素酶试验、Ｇｉｅｍｓａ染色及病理组织学检查。ＨＰ（＋）组抗ＨＰ治疗,１月后重复上述检查。结果：ＨＰ（＋）且ＳＧ明显高于ＨＰ（－）组（Ｐ〈０．     

Secretory and biosynthetic responses of gastrin and somatostatin to acute changes in gastric acidity

The activity of gastric parietal cells in terms of hydrochloric acid (HCl) secretion is regulated by the interaction of stimulatory substances (e.g. gastrin) and inhibitors (e.g. somatostatin) acting in an endocrine and paracrine mode, as well as luminal factors. In the present study the following parameters were measured: the synthesis (mRNA), storage (tissue peptide concentration) and secretion (plasma peptide concentration) of somatostatin and gastrin following short-term treatment of rats with pentagastrin (acid stimulant), secretin, omeprazole (reduces gastric acidity by inactivating gastric H/K ATPase) and the somatostatin analogue octreotide (reduces gastric acidity by inhibiting both the parietal cell and gastrin). The mRNA coding for H/K ATPase and carbonic anhydrase II (CA II), the two enzymes responsible for the generation of hydrogen ions from the parietal cell, were also quantitated. In response to octreotide, somatostatin peptide and mRNA levels in the fundus rose to 180 ± 16% (P < 0.001) and 1073 ± 356% (P < 0.05) of control, respectively. In contrast, octreotide caused a decrease in antral somatostatin peptide and its mRNA did not change significantly. No significant changes in synthesis, secretion or storage of gastrin were observed except for omeprazole induced hypergastrinaemia (580 ± 76%, P < 0.001). H/K ATPase and CA II mRNA were largely unaffected except for an increase in CA II mRNA following octreotide and a decrease in H/K ATPase mRNA after pentagastrin. These data support the concept of the differential control of antral and fundic somatostatin synthesis and provide evidence for a regulatory loop by which somatostatin can influence its own synthesis. H/K ATPase and CA II mRNA were not regulated in concert, as reported to occur in isolated canine parietal cells, a result that reiterates the need for these type of whole animal studies.