Synergistic inhibitory effects of gastrin and histamine receptor antagonists on Helicobacter-induced gastric cancer.
OBJECTIVE
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.
Takaishi
Shigeo
S
Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Cui
Guanglin
G
Frederick
Dana M
DM
Carlson
Jane E
JE
Houghton
Jeanmarie
J
Varro
Andrea
A
Dockray
Graham J
GJ
Ge
Zhongming
Z
Whary
Mark T
MT
Rogers
Arlin B
AB
Fox
James G
JG
Wang
Timothy C
TC
D000126:Achlorhydria / Q000150:complications; D000818:Animals; D001284:Atrophy; D001570:Benzodiazepinones / Q000494:pharmacology*; D004195:Disease Models, Animal; D005755:Gastrins / Q000502:physiology*; D016481:Helicobacter Infections; D044922:Helicobacter felis; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010671:Phenylurea Compounds / Q000494:pharmacology*; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000502:physiology*; D013274:Stomach Neoplasms / Q000382:microbiology*; D014230:Triazoles / Q000494:pharmacology*
D001570:Benzodiazepinones; D005755:Gastrins; D006635:Histamine H2 Antagonists; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D011970:Receptors, Histamine H2; D014230:Triazoles; C039993:loxtidine; C104428:YF 476