Gastric Functions in Gastrin Gene Knock‐Out Mice

Abstract: The gastric hormone gastrin was the 2nd hormone to be identified and was initially recognized for its ability to induce acid secretion. Following the purification and subsequent development of specific radioimmunoassays for gastrin, it was also shown to be a regulator of oxyntic mucosal growth. To explore the importance of gastrin or its receptors for gastric development and gastric physiology both have been knocked out. The knock‐out mice are viable, develop with any gross abnormalities, and are fertile. Even though gastrin acts as a growth factor during hypergastrinaemia there was no general atrophy of the gastrin mucosa in the knock‐out mice. But the maturation of both parietal and ECL cells were disturbed and the number of parietal cells reduced. Furthermore, lack of gastrin impaired basal acid secretion and rendered the parietal cells unresponsive to histamine and acetylcholine, the other two major stimulators of gastric acid secretion. Despite the major changes in gastric physiology, the number of genes down‐regulated in the gastrin knock‐out mice is modest. The achlorhydria due to lack of gastrin also leads to bacterial overgrowth of the stomachs of the gastrin knock‐out mice, which could facilitate the development of gastric ulcer disease and cancer.     

Gastric phenotypic abnormality in cholecystokinin 2 receptor null mice

Gastrin, released from antral G-cells, plays an important role in the regulation of gastric acid secretion and is trophic for the stomach. The cholecystokinin type 2 (CCK)2 receptor (previously referred to as CCK-B/gastrin receptors) is expressed in both parietal cells and ECL cells in the oxyntic mucosa of stomach. Gastric phenotypic abnormality has been observed in CCK2 receptor null (gene knock-out) mice. Such mice displayed markedly impaired gastric acid secretion, atrophy of the oxyntic mucosa and hypergastrinaemia. The impaired acid secretion may be the result of a reduced parietal cell mass, a reduced proportion of actively secreting parietal cells (with secretory canaliculi), and a replacement of ECL cells by histamine-free ECL-like cells. The ECL-like cells, observed in the CCK2 receptor null mice, lacked the hallmark features of wild-type ECL cells, i.e. histamine and cytoplasmic secretory vesicles. However, they had the features of endocrine cells, such as the content of pancreastatin (a fragment of chromogranin A), with cytoplasmic small dense-core granules and microvesicles. We propose that the replacement of ECL cells by ECL-like cells in the mutant mice reflects an altered differentiation of the same precursors that develop into ECL cells in wild-type mice. Thus, studies of CCK2 receptor null mice demonstrate the importance of the receptor in the regulation of gastric acid secretion and in the differentiation of ECL cells in the oxyntic mucosa of stomach.     

Targeting gastrin for the treatment of gastric acid related disorders and pancreatic cancer

Gastrin, acting through peripheral cholecystokinin (CCK) 2 receptors, is a major hormonal regulator of gastric acid secretion. The effects of gastrin on acid secretion occur both acutely and chronically because gastrin directly stimulates gastric acid secretion and also exerts trophic effects on the enterochromaffin-like and parietal cells that together constitute the acid secretory apparatus of the stomach. Several antagonists that target the CCK2 receptor have been identified and investigated for the treatment of gastroesophageal reflux disease and pancreatic cancer. In this paper, we discuss the contribution of gastrin to these disease pathologies and the data generated to date from clinical studies investigating CCK2 receptor antagonists.     

The relationship between blood gastrin levels and gastric secretion in conscious dogs

1 In conscious dogs with gastric fistulae and Heidenhain pouches, acid and pepsin secretion, immunoreactive plasma pancreatic polypeptide (PP) and gastrin were measured following intravenously administered pentagastrin, cholinomimetics, and intragastric administration of milk. 2 Pentagastrin did not raise endogenous plasma gastrin. There was a significant positive dose-response relationship between pentagastrin and acid and fistula pepsin secretions, but not between plasma gastrin of endogenous origin and gastric secretion. 3 Carbachol raised plasma gastrin immunoreactivity; but in no instance was there a significant relationship between gastric secretion and plasma gastrin immunoreactivity. Gastric acid secretion faded, but plasma gastrin concentrations did not. 4 PP plasma immunoreactivity was elevated by methacholine and carbachol. Its levels correlated significantly with gastric acid secretion. Pentagastrin did not raise PP and its levels did not, therefore, correlate with gastric acid secretion. 5 Intragastric milk raised plasma gastrin immunoreactivity; but the acid secretion per pg of plasma gastrin was much smaller than with the cholinomimetics. Ganglionic blocking agents depressed both plasma gastrin and acid and pepsin secretion. 6 The results suggest that cholinomimetics sensitize parietal cells to the stimulating action of gastrin.     

Hypergastrinemia is associated with decreased gastric acid secretion in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) produces a delayed onset hypergastrinemia in rats. The purpose of the present study was to determine if the increased serum gastrin concentrations were caused by decreased gastric acid secretion, decreased plasma clearance of gastrin, and/or decreased gastric emptying. It was found that TCDD treatment decreased gastric acid secretion as determined by decreases in gastric secretory volume, acidity, and total acid output in pylorus-ligated rats. Also, both dose-response and time-course curves for decreased gastric acid secretion in TCDD-treated rats were similar to those for hypergastrinemia. These findings, as well as a significant inverse correlation between serum gastrin concentrations and total gastric acid output in rats treated with graded doses of TCDD (5-100 micrograms/kg), suggest that TCDD-induced decreases in gastric acid production cause elevated serum gastrin concentrations. Neither hypergastrinemia nor decreased gastric acid secretion were observed in pair-fed control rats, demonstrating that neither effect was secondary to undernutrition. The TCDD-induced decrease in gastric acid secretion was not caused by a decrease in the number of acid-secreting parietal cells in the stomach, but rather was associated with a decrease in parietal cell responsiveness to gastrin-elicited acid secretion. This was evidenced by both elevated serum gastrin concentrations and a pharmacological dose of pentagastrin failing to stimulate gastric acid secretion in TCDD-treated rats. The disappearance of iv-administered gastrin-17 from the serum was not affected by TCDD treatment, suggesting that reduced serum gastrin clearance is not responsible for the TCDD-induced hypergastrinemia. Although a marked decrease in gastric emptying of a 51Cr-labeled liquid test meal was also observed in TCDD-treated rats, the lowest dose of TCDD required to produce this effect was greater than that needed to cause hypergastrinemia. This suggests that the hypergastrinemic effect of TCDD is not secondary to a decrease in gastric emptying. We conclude that the most probable cause of hypergastrinemia in TCDD-treated rats is decreased gastric acid secretion.     

Structural and functional characterization of gastric mucosa and central nervous system in histamine H2 receptor-null mice

To examine the physiological role of the histamine H(2) receptor, histamine H(2) receptor-null mice were generated by homologous recombination. Histamine H(2) receptor-null mice, which developed normally and were fertile and healthy into adulthood, exhibited markedly enlarged stomachs and marked hypergastrinemia. The former was due to hyperplasia of gastric gland cells (small-sized parietal cells, enterochromaffin-like cells and mucous neck cells which were rich in mucin), but not of gastric surface mucous cells, which were not increased in number as compared with those in wild-type mice despite the marked hypergastrinemia. Basal gastric pH was slightly but significantly higher in histamine H(2) receptor-null mice. Although carbachol but not gastrin induced in vivo gastric acid production in histamine H(2) receptor-null mice, gastric pH was elevated by both muscarinic M(3) and gastrin antagonists. Thus, both gastrin and muscarinic receptors appear to be directly involved in maintaining gastric pH in histamine H(2) receptor-null mice. Interestingly, gastric glands from wild-type mice treated with an extremely high dose of subcutaneous lansoprazole (10 mg/kg body weight) for 3 months were very similar to those from histamine H(2) receptor-null mice. Except for hyperplasia of gastric surface mucous cells, the findings for gastric glands from lansoprazole-treated wild-type mice were almost identical to those from gastric glands from histamine H(2) receptor-null mice. Therefore, it is possible that the abnormal gastric glands in histamine H(2) receptor-null mice are secondary to the severe impairment of gastric acid production, induced by the histamine H(2) receptor disruption causing marked hypergastrinemia. Analyses of the central nervous system (CNS) of histamine H(2) receptor-null mice revealed these mice to be different from wild-type mice in terms of spontaneous locomotor activity and higher thresholds for electrically induced convulsions. Taken together, these results suggest that (1) gastrin receptors are functional in parietal cells in histamine H(2) receptor-null mice, (2) abnormal gastric glands in histamine H(2) receptor-null mice may be secondary to severe impairment of gastric acid production and secretion and (3) histamine H(2) receptors are functional in the central nervous system.     

Unique roles of G protein-coupled histamine H2 and gastrin receptors in growth and differentiation of gastric mucosa

Disruption of histamine H2 receptor and gastrin receptor had different effects growth of gastric mucosa: hypertrophy and atrophy, respectively. To clarify the roles of gastrin and histamine H2 receptors in gastric mucosa, mice deficient in both (double-null mice) were generated and analyzed. Double-null mice exhibited atrophy of gastric mucosae, marked hypergastrinemia and higher gastric pH than gastrin receptor-null mice, which were unresponsive even to carbachol. Comparison of gastric mucosae from 10-week-old wild-type, histamine H2 receptor-null, gastrin receptor-null and double-null mice revealed unique roles of these receptors in gastric mucosal homeostasis. While small parietal cells and increases in the number and mucin contents of mucous neck cells were secondary to impaired acid production, the histamine H2 receptor was responsible for chief cell maturation in terms of pepsinogen expression and type III mucin. In double-null and gastrin receptor-null mice, despite gastric mucosal atrophy, surface mucous cells were significantly increased, in contrast to gastrin-null mice. Thus, it is conceivable that gastrin-gene product(s) other than gastrin-17, in the stimulated state, may exert proliferative actions on surface mucous cells independently of the histamine H2 receptor. These findings provide evidence that different G-protein coupled-receptors affect differentiation into different cell lineages derived from common stem cells in gastric mucosa.     

Extragastric effects of gastrin gene knock-out mice

Gastrin is a peptide hormone that regulates both acid secretion and growth of the gastric oxyntic mucosa. Recent studies suggest that gastrin, in both its amidated, and less processed forms (glycine-extended gastrin and progastrin) may also exert biological activity in other organs in the gastrointestinal tract. This article will review the studies performed to date addressing the physiological role of gastrin outside of the gastric mucosa, with particular emphasis on the information gleaned from gastrin-deficient mice. Most of these studies address the potential role for the less processed forms of gastrin in regulating the proliferation of the colonic mucosa and colon cancers. There is also some data to support a potential role for gastrin in the regulation of the pancreas and the kidney, although the effects of gastrin deficiency on the function of these organs in mice have not yet been rigorously studied.     

Cellular localization of cholecystokinin receptors as the molecular basis of the periperal regulation of acid secretion

Gastrin stimulates gastric acid secretion through direct activation of CCK-B/gastrin receptors on parietal cells and indirectly through release of histamine from ECL cells. Cholecystokinin (CCK) is structurally closely related to gastrin and shares high affinity for CCK-B/gastrin receptors. In contrast to gastrin, CCK also recognizes CCK-A receptors. While CCK appears to be a negative regulator of gastric acid secretion and postprandial release of gastrin in the normal human gastrointestinal tract, its impact on the pathogenesis of acid hypersecretion in Helicobacter pylori-infected individuals remains uncertain. This article will review the endocrine and paracrine regulatory pathways which are activated by CCK/gastrin peptides and which appear relevant in the pathogenesis of peptic ulcer disease in man.     

The cellular localization of the cholecystokinin 2 (gastrin) receptor in the stomach

The role of the gastric acid secretagogues acetylcholine, gastrin and histamine has been debated for decades. Initially, the mast cell was considered the source of acid stimulatory histamine. Later, H?kanson & Owman (1969) showed that the entero-chromaffinlike (ECL) cell produces and stores histamine in several species, including rat and man. Kahlson et al. (1964) showed that food and gastrin stimulated oxyntic mucosal histamine synthesis and release, Berglindh et at. (1976) that histamine and cholinergics but not gastrin induced acid secretion in isolated oxyntic glands and parietal cells, and Rangachari (1995) that acetylcholine or gastrin released histamine in isolated mucosa. These findings suggested that gastrin stimulates acid secretion through release of ECL cell histamine. Studying simultaneous histamine release and acid secretion in isolated oxyntic mucosal cells, we found that gastrin stimulated acid secretion only in preparations releasing histamine. Moreover, in the isolated rat stomach, gastrin stimulated both histamine release and acid secretion. Maximal acid output was higher with histamine than with gastrin, and augmented by acetylcholine but not by gastrin. These findings strongly suggested that gastrin acts by releasing histamine. Finally, a fluorescein-labelled gastrin analogue bound to the ECL cell, not to the parietal or stem cell regions. This is interesting, recalling that gastrin has a potent and specific trophic effect on the ECL cell and only a general effect on all other oxyntic cell types. In conclusion, physiological observations are best explained by localising the CCK2 receptor only to the ECL cell, the other effects of gastrin on the gastric mucosa being secondary to the release of mediators from the ECL cell.     

Luminal Nalpha-methyl histamine stimulates gastric acid secretion in duodenal ulcer patients via releasing gastrin

Nalpha-methyl histamine is an unusual histamine metabolite which is produced in the stomach infected by Helicobacter pylori and which was shown in animals to stimulate gastric acid secretion and to release gastrin in vitro isolated G-cells, but no information is available regarding its influence on gastric secretion and gastrin release in duodenal ulcer patients before and after H. pylori eradication. In this study, we compared the effects of intragastric administration of single or graded doses of Nalpha-methyl histamine on gastric acid secretion and plasma gastrin levels in 16 male duodenal ulcer patients (aging from 35 to 48 years and weighing 65-82 kg) before and after the eradication of H. pylori. Furthermore, the gastric luminal histamine and gastrin contents were determined before and after H. pylori eradication. In H. pylori-infected duodenal ulcer patients, the intragastric application of Nalpha-methyl histamine failed to affect gastric acid secretion or plasma gastrin levels. Following eradication of H. pylori, gastric luminal histamine and gastrin, and both basal gastric acid secretion and plasma gastrin levels, were significantly reduced. Nalpha-methyl histamine given intragastrically in graded doses to such H. pylori-eradicated duodenal ulcer patients was found to increase dose-dependently gastric acid output reaching at a dose of 5 mg, about 80% of histamine maximum induced by i.v. infusion of 25 microg/kg h of histamine dihydrochloride. We conclude that Nalpha-methyl histamine is a potent luminally active stimulant of gastrin release and gastric acid secretion in H. pylori-eradicated patients when luminal histamine is low but is not effective in H. pylori infected patients when luminal histamine is enhanced, possibly due to desensitization of gastrin (G-cells) and acid-producing (parietal) cells by Nalpha-methyl histamine produced excessively in H. pylori-infected stomach.     

Continuing development of acid pump inhibitors: site of action of pantoprazole.

Both receptor antagonists and acid pump inhibitors are clinically useful suppressants of acid secretion. The latter class of drugs, the substituted benzimidazoles, inhibit acid secretion more effectively and, therefore, provide superior symptom relief and healing in all acid- related diseases. The H2-receptor antagonists competitively block the action of histamine on the H2-receptors of parietal cells. This histamine is released from enterochromaffin-like cells (ECL cells) due to gastrin, acetylcholine or epinephrine stimulation. In addition, parietal cells have M3-receptors which can function independently of H2- receptors. Hence, there is no single common pathway for parietal cell stimulation. Stimulation of acid secretion by parietal cells requires activation of the acid pump, the gastric H+,K(+)-ATPase. The target site for the benzimidazoles is the activated gastric H+,K(+)-ATPase, and, in particular, the cysteines of the pump that are exposed to the acid space of the secretory canaliculus of the parietal cells. Pantoprazole in its protonated form selectively reacts with cysteines present in both the fifth and sixth membrane segments of the ATPase, explaining its mechanism of inhibiting proton transport by this enzyme.     

Genetic dissection of the signaling pathways that control gastric acid secretion

Gastric acid secretion is regulated by endocrine, paracrine and neurocrine signals via at least three pathways, the gastrin-histamine pathway, the CCK-somatostatin pathway and the neural pathway. Genetically-engineered mice, subjected to targeted gene disruption (i.e., knockout mice), have been used to dissect the signaling pathways that are responsible for the complexity of the regulation of acid secretion in vivo. Both gastrin knockout and gastrin/CCK₂ receptor knockout mice displayed greatly impaired acid secretion, presumably because of the loss of the gastrin-histamine pathway. Gastrin/CCK double-knockout mice had a relatively high percentage of active parietal cells with a maintained ability to respond with copious acid secretion to pylorus ligation-evoked vagal stimulation and to a histamine challenge. The low acid secretion in gastrin knockout mice and gastrin/CCK₂ receptor knockout mice and the restoration of acid secretion in gastrin/CCK double-knockout mice suggest that CCK plays an important role as inhibitor of the parietal cells via the CCK-somatostatin pathway by stimulating the CCK₁ receptor of the D cell. In the absence of both the gastrin-histamine and the CCK-somatostatin pathway (as in gastrin/CCK₂ receptor double-knockout mice), the control of acid secretion is probably taken over by neural pathways, explaining the high acid output. The observations illustrate the complexity and plasticity of the acid regulatory mechanisms. It seems that one pathway may be suppressed or allowed to dominate over the others depending on the circumstances.     

Sustained Cholecystokinin–B/Gastrin Receptor Blockade Does Not Impair Basal or Histamine–Stimulated Acid Secretion in Chronic Gastric Fistula Rats

Abstract: Gastrin is a physiologically important secrelagogue. It is thought to stimulate parietal cells indirectly by mobilizing histamine from enterochromaffin–like (ECL) cells in the oxyntic mucosa. Gastrin stimulates the secretory activity and growth of the ECL cells via an action on cholecystokinin–B/gastrin receptors. Acute cholecystokinin–B/gastrin receptor blockade is known to inhibit gastrin–stimulated acid secretion but whether sustained cholecystokinin–B/gastrin receptor blockade will impair basal, gastrin– and histamine–stimulated acid secretion remains uncertain. The present study was designed to study the effect of long–term (4 weeks) cholecystokinin–B/gastrin receptor blockade on basal and stimulated acid secretion in conscious rats. The selective cholecystokinin–B/gastrin receptor antagonist YM022 (3 μmol kg^–1 hr^–l) was given to gastric fistula rats by continuous subcutaneous infusion via osmotic minipumps for various times from 2 hr to 4 weeks. Basal, gastrin– and histamine– stimulated acid secretion were examined during and after cessation of treatment. Basal and histamine–stimulated acid secretion was not affected by YM022 during the 4 week period of administration, whereas gastrin–induced acid secretion was inhibited. YM022 induced hypergastrinaemia in freely fed rats but did not affect the serum gastrin level in fasted rats. The serum gastrin concentration and gastrin–induced acid secretion returned to control levels 3–7 days after termination of YM022 administration.     

Review article: the pharmacological inhibition of gastric acid secretion—tolerance and rebound

During the last decade our understanding of the regulation of gastric acid secretion has changed considerably. The recognition that gastrin acts mainly by releasing histamine from the enterochromaffin-like (ECL) cell is of major importance. It is now necessary to review and seek new explanations for the development of tolerance and for the post-treatment acid hypersecretion that may be observed when treatment with acid-secretory inhibitors is discontinued. Tolerance and rebound related to H₂-receptor antagonists has previously been explained as upregulation of gastrin and/or histamine H₂-receptors, and/or an increased parietal cell mass. Experimental evidence for these theories is scarce. On the other hand, tolerance can now be explained by a gastrin-induced increase in ECL cell-derived histamine at the parietal cell H₂-receptor competing with the antagonist. The lack of tolerance to proton pump inhibitors may be explained by their mode of action, being non-competitive and acting at the H⁺, K⁺-ATPase rather than at stimulatory receptors. Post-treatment rebound acid hypersecretion can be understood as gastrin upregulating and/or stimulating growth of the ECL cell, leading to increased amounts of releasable histamine post-treatment. Novel experimental data strongly support this view of the development of tolerance and post-treatment rebound acid hypersecretion.     

Effect of potassium chloride on gastric acid secretion and gastrin release in humans

The effect of potassium chloride on gastric acid secretion and gastrin release was studied in 6 healthy human beings. On 3 separate days and in random order, subjects received an intragastric infusion of 0.5 L of a glucose-saline solution to which had been added 40 mmol KCl, 40 mmol NaCl, or no additional salts. All test solutions stimulated acid secretion and gastrin release to a similar degree. While potassium ions play a critical role in acid secretion by parietal cells (via the H+, K(+)-ATPase), KCl administered into the gastric lumen at a concentration of 80 mmol/L has no effect on acid secretion in man.     

Review article: current perspectives on hypergastrinaemia and enterochromaffin-like-cell hyperplasia

Rabeprazole, a new benzimidazole proton pump inhibitor (PPI), is among a class of agents known to be very potent inhibitors of gastric acid secretion. PPIs inhibit hydrogen-potassium adenosine triphosphatase activity on the luminal surface of the parietal cell, effectively blocking the final common pathway for gastric acid secretion. Raising gastric pH stimulates the production of gastrin by G cells in the antrum of the stomach, which can lead to enterochromaffin-like (ECL)-cell hyperplasia. In the past, these changes have been viewed with concern, particularly in the light of studies in rats indicating that hypergastrinaemia and ECL-cell hyperplasia induce gastric carcinoid tumour formation. All available clinical data indicate that long-term PPI use does not lead to carcinoid tumour formation in humans. In fact, both serum gastrin elevation and ECL-cell hyperplasia are now generally viewed as normal physiological responses to gastric acid suppression. Serum gastrin concentrations, in particular, correlate well with gastric acid suppression, which has led to the use of gastrin response by some investigators as a surrogate marker of antisecretory effectiveness. Long-term tolerability data indicate that PPIs have a favourable side-effect profile. Data obtained from patients receiving acute or long-term maintenance rabeprazole therapy support this conclusion. Furthermore, neither animal nor human data obtained with rabeprazole suggest a significant risk for neoplastic changes secondary to hypergastrinaemia.     

Regulatory mechanism of gastric acid secretion and mucosal integrity--an analysis with various gene deficient mice

Mechanisms for gastric acid secretion have been elucidated through invention of new methods and new drugs. Current genetic technology have generated knockout (KO) mice lacking receptors such as CCK2, histamine H2, muscarinic M3 and M1, or enzymes such as histidine decarboxylase (HDC) and H+,K(+)-ATPase. Here, we review the functional and morphological changes in the gastric mucosa of such KO mice. In M3R-KO mice (intragastric pH 5.9), carbachol, histamine and gastrin stimulated acid secretion like they did in wild-type mice. Carbachol-stimulated acid secretion was significantly inhibited by famotidine and pirenzepine. The serum gastrin level in M3R-KO mice was increased, yet the stomach weight and the gastric mucosa remained unchanged. In H2R-KO mice (intragastric pH 3.0), serum gastrin and mucosal histamine levels significantly increased. Carbachol significantly stimulated acid secretion, yet histamine and gastrin had little or no effect on acid secretion. The stomach wet weight increased with time after birth and the serum albumin level was decreased. In the gastric mucosa with hyperplasia, numerous enlarged cysts and a marked expression of TGF-alpha were observed, indicating the occurrence of Menetrier's disease like mucosal changes. G/D cell ratio was greatly increased, providing evidence of the increased serum gastrin level. In HDC-KO mice (intragastric pH 4.5), the stomach weight was also increased 6 mo after birth, with no enlarged cysts in the gastric mucosa. CONCLUSION: The above results indicate that KO mice can be used to yield many important findings that selective antagonists cannot reveal.     

Acid secretory effect of extracted guinea-pig gastrin on isolated guinea-pig parietal cells

It was confirmed that histamine, cholinergic drugs and gastrin separately produce acid secretory effects of isolated parietal cells. However, the acid secretory response of isolated parietal cells to gastrin stimulation is known to be weaker than that to histamine or cholinergic drugs, which is different from the acid secretory response found in vivo studies. Tetragastrin and pentagastrin were less potent than histamine and carbachol in stimulating acid secretion in our previous study performed using parietal cells isolated from guinea-pigs. In this study, the effect of gastrin extracted from the pyloric antrum of the guinea-pig on parietal cells isolated from the guinea-pig was investigated based on the assumption that the acid secretory response of isolated parietal cells to gastrin stimulation will be especially good if gastrin isolated from the same species is used.     

Development of XPA067.06, a potent high affinity human anti-gastrin monoclonal antibody

The peptide hormone gastrin is a key factor in regulation of gastric acid secretion. It has also been implicated in the development or maintenance of various types of cancer, such as pancreatic and stomach carcinoma. Inhibition of gastrin activity has potential for therapeutic use as a suppressor of acid secretion as well as an inhibitor of gastrin-responsive tumors. XPA067.06 is an affinity matured, 30 pM fully human anti-gastrin monoclonal antibody that was generated. The antibody was tested in a mouse gastric pH model to determine its effect on acid secretion. In this model, animals were treated with human gastrin, XPA067.06, and H2R or M1 receptor antagonists. Gastric fluid was collected and acid output was measured as a function of pH. XPA067.06 was shown to significantly inhibit gastrin-17-stimulated acid output for at least 48h. These results demonstrate that XPA067.06 effectively binds and neutralizes human gastrin-17 in vivo with rapid onset and prolonged duration of efficacy.