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Combination of Sulindac and Antimicrobial Eradication of Helicobacter pylori Prevents Progression of Gastric Cancer in Hypergastrinemic INS-GAS Mice
- Source :
- PMC
- Publication Year :
- 2009
- Publisher :
- American Association for Cancer Research (AACR), 2009.
-
Abstract
- Author Manuscript: 2010 October 15<br />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 E2 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-γ and Tnf-α and mucosal cell proliferation. Sulindac or YM022 combined with antimicrobial eradication down-regulated mRNA levels of Ifn-γ and Tnf-α 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. [Cancer Res 2009;69(20):8166–74]<br />National Institutes of Health (U.S.) (Grant R01AI37750)<br />National Institutes of Health (U.S.) (Grant P01CA26731)<br />National Institutes of Health (U.S.) (Grant P30ES02109)<br />National Institutes of Health (U.S.) (Grant R01CA093405-07A1)
- Subjects :
- Male
Cancer Research
medicine.medical_specialty
Blotting, Western
Antineoplastic Agents
Biology
Gastroenterology
Article
Dinoprostone
Helicobacter Infections
Proinflammatory cytokine
Benzodiazepines
Interferon-gamma
Mice
Hormone Antagonists
Sulindac
Anti-Infective Agents
Stomach Neoplasms
Internal medicine
medicine
Animals
RNA, Messenger
Stomach cancer
Cell Proliferation
Gastrin
Helicobacter pylori
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha
Stomach
Membrane Proteins
Cancer
Hydrogen-Ion Concentration
medicine.disease
biology.organism_classification
digestive system diseases
Disease Models, Animal
medicine.anatomical_structure
Oncology
Cyclooxygenase 2
Gastritis
Immunology
Cyclooxygenase 1
Drug Therapy, Combination
medicine.symptom
Precancerous Conditions
medicine.drug
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 69
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....7e64e16c5982726664f313502e4b1676