title: Combination of sulindac and antimicrobial eradication of Helicobacter pylori prevents progression of gastric cancer in hypergastrinemic INS-GAS mice.
abstract: Helicobacter pylori infection causes severe dysplasia manifested as gastrointestinal intraepithelial neoplasia (GIN) after 28 weeks post-H. pylori infection (WPI) in cancer-prone, hypergastrinemic male INS-GAS mice. We examined the efficacy of the nonsteroidal anti-inflammatory drug sulindac (400 ppm in drinking water) alone, the CCK2/gastrin receptor antagonist YM022 (45 mg/kg/wk) alone, and sulindac or YM022 combined with H. pylori eradication therapy to prevent H. pylori-associated gastric cancer in male INS-GAS mice. Treatments started at 22 WPI, and mice were euthanized at 28 WPI. In uninfected mice, all treatments significantly delayed development of spontaneous GIN (P < 0.05). In H. pylori-infected mice, sulindac alone or YM022 alone had no protective effect on H. pylori-associated GIN. Importantly, sulindac exacerbated the severity of H. pylori-associated gastritis despite decreased gastric prostaglandin E(2) levels. However, sulindac combined with H. pylori antimicrobial eradication reduced the incidence of GIN (P < 0.05), whereas YM022 combined with antimicrobial eradication did not reduce GIN. In infected mice, sulindac or YM022 treatment did not alter gastric expression of the proinflammatory cytokines Ifn-gamma and Tnf-alpha and mucosal cell proliferation. Sulindac or YM022 combined with antimicrobial eradication down-regulated mRNA levels of Ifn-gamma and Tnf-alpha and mucosal cell proliferation (P < 0.05). We conclude that sulindac enhances H. pylori gastritis and may promote inflammation-mediated gastric carcinogenesis. The combination of sulindac and antimicrobial H. pylori eradication was beneficial for reducing proinflammatory cytokine mRNA in the stomach and preventing progression from severe dysplasia to gastric cancer in H. pylori-infected INS-GAS mice.
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Chung-Wei
authors.initials: CW
authors.lastname: Lee
authors.forename: Barry
authors.initials: B
authors.lastname: Rickman
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.forename: Shigeo
authors.initials: S
authors.lastname: Takaishi
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005756:Gastritis / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D016481:Helicobacter Infections / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D016480:Helicobacter pylori / Q000302:isolation & purification*; D006727:Hormone Antagonists / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011230:Precancerous Conditions; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D013467:Sulindac / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D006727:Hormone Antagonists; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D001569:Benzodiazepines; C087260:YM 022; D013467:Sulindac; D007371:Interferon-gamma; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone