Gastroenterology

Gastroenterology

Volume 128, Issue 7, June 2005, Pages 1965-1983
Gastroenterology

Basic-alimentary tract
Synergistic Inhibitory Effects of Gastrin and Histamine Receptor Antagonists on Helicobacter-Induced Gastric Cancer

https://doi.org/10.1053/j.gastro.2005.03.027Get rights and content

Background & Aims: Apart from its importance as an acid secretogogue, the role of histamine as a downstream target of gastrin has not been fully explored. Previous studies have shown that the combination of hypergastrinemia and Helicobacter infection resulted in accelerated gastric cancer in mice. We used this model to examine the role of cholecystokinin 2 (CCK2)/gastrin receptor and histamine H2-receptor signaling in the development of gastric atrophy and cancer. Methods: Male hypergastrinemic mice (INS-GAS mice) were infected with Helicobacter felis and given the CCK2/gastrin receptor antagonist YF476 and/or the histamine H2-receptor antagonist loxtidine for 3 or 6 months. In addition, mice were treated with omeprazole alone or in combination with either YF476 or loxtidine for 3 months. Results: Mice treated with YF476 or loxtidine alone showed partial suppression of both gastric acid secretion and progression to neoplasia. The combination of YF476 plus loxtidine treatment resulted in nearly complete inhibition of both parameters. YF476 and/or loxtidine treatment did not alter the overall level of H felis colonization but did result in significant down-regulation of the growth factors regenerating gene I and amphiregulin. Loxtidine treatment, with or without YF476, induced a mild shift in T-helper cell polarization. In contrast, omeprazole treatment resulted in mild progression of gastric hyperplasia/dysplasia, which was ameliorated by the addition of YF476 or loxtidine. Conclusions: The combination of CCK2/gastrin- and histamine H2-receptor antagonists has synergistic inhibitory effects on development of gastric atrophy and cancer in H felis/INS-GAS mice, while the proton pump inhibitor showed no such effects. These results support an important role for the gastrin-histamine axis in Helicobacter-induced gastric carcinogenesis.

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Animals

The INS-GAS transgenic mice (FVB/N background) have been described previously7, 21 and were free of specific murine pathogens. Animals were housed in microisolator, solid-bottomed polycarbonate cages, fed a commercially prepared pelleted diet, and given water ad libitum. A total of 124 male INS-GAS mice at 2 or 3 months of age were inoculated with H felis (ATCC 49179) 3 times every other day in 1 week with a dose of about 1 billion colony-forming units per mouse each time.7 Infection status was

YF476 and/or Loxtidine Treatment for 3 Months Resulted in Synergistic Inhibition of Gastric Acid Output and Gastric Atrophy, Hyperplasia, and Dysplasia in H felis-Infected INS-GAS Mice

While the highly specific CCK2/gastrin receptor antagonist YF476 and the irreversible histamine H2-receptor antagonist loxtidine have previously been shown to inhibit acid secretion in mice, they have not been studied in models of chronic Helicobacter infection. In addition, they have not previously been examined in a mouse model of gastric cancer such as the hypergastrinemic INS-GAS mouse model. Previous studies have shown that young (<6 months of age) INS-GAS mice have substantially elevated

Discussion

In this study, we have investigated in our H felis-infected INS-GAS mouse model the effect of 3 distinct acid-suppressive reagents: the CCK2/gastrin receptor antagonist YF476, the histamine H2-receptor antagonist loxtidine, and the PPI omeprazole. All 3 drugs strongly inhibit gastric acid secretion and were initially developed as antiulcer or anti-gastroesophageal reflux disease drugs. Our results strongly suggest that the gastrin-histamine axis contributes to the development of gastric atrophy

References (60)

  • L.H. Tang et al.

    Gastrin receptor expression and function during rapid transformation of the enterochromaffin-like cells in an African rodent

    Regul Pept

    (1997)
  • D. Chen et al.

    Differentiation of gastric ECL cells is altered in CCK(2) receptor-deficient mice

    Gastroenterology

    (2002)
  • D. Poynter et al.

    Neuroendocrine cell hyperplasia and neuroendocrine carcinoma of the rodent fundic stomach

    Mutat Res

    (1991)
  • H. Fukui et al.

    Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats

    Gastroenterology

    (1998)
  • H. Fukui et al.

    Effects of Helicobacter pylori infection on the link between regenerating gene expression and serum gastrin levels in Mongolian gerbils

    Lab Invest

    (2003)
  • Y. Murayama et al.

    Localization of heparin-binding epidermal growth factor-like growth factor in human gastric mucosa

    Gastroenterology

    (1995)
  • S. Tsutsui et al.

    Induction of heparin binding epidermal growth factor-like growth factor and amphiregulin mRNAs by gastrin in the rat stomach

    Biochem Biophys Res Commun

    (1997)
  • M. Garcia-Caballero et al.

    Histamine synthesis and content in benign and malignant breast tumours. Its effects on other host tissues

    Surg Oncol

    (1994)
  • H. Tonnesen et al.

    Effect of cimetidine on survival after gastric cancer

    Lancet

    (1988)
  • C.R. Haigh et al.

    Gastrin induces proliferation in Barrett’s metaplasia through activation of the CCK2 receptor

    Gastroenterology

    (2003)
  • Gastric cancer and Helicobacter pyloria combined analysis of 12 case control studies nested within prospective cohorts

    Gut

    (2001)
  • N. Uemura et al.

    Helicobacter pylori infection and the development of gastric cancer

    N Engl J Med

    (2001)
  • Infection with Helicobacter pylori

    IARC Monogr Eval Carcinog Risks Hum

    (1994)
  • J. Houghton et al.

    Gastric cancerlaboratory bench to clinic

    J Gastroenterol Hepatol

    (2002)
  • J.G. Fox et al.

    Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces Helicobacter-induced gastric atrophy

    Nat Med

    (2000)
  • J.G. Fox et al.

    Helicobacter pylori-associated gastric cancer in INS-GAS mice is gender specific

    Cancer Res

    (2003)
  • G.J. Dockray et al.

    The gastrinstheir production and biological activities

    Annu Rev Physiol

    (2001)
  • M. Asahara et al.

    Gastrin receptor genes are expressed in gastric parietal and enterochromaffin-like cells of Mastomys natalensis

    Dig Dis Sci

    (1994)
  • E.C. Klinkenberg-Knol et al.

    Long-term treatment with omeprazole for refractory reflux esophagitisefficacy and safety

    Ann Intern Med

    (1994)
  • E.J. Kuipers et al.

    Increase of Helicobacter pylori-associated corpus gastritis during acid suppressive therapyimplications for long-term safety

    Am J Gastroenterol

    (1995)
  • Cited by (0)

    G.C.’s current affiliation is: Laboratory of Gastroenterology, University of Tromso, Tromso, Norway.

    Supported in part by National Institutes of Health grants CA93405 and DK48077 (to T.C.W) and AI37750 and RR07036 (to J.G.F.).

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