Chemoprevention of Helicobacter pylori-associated gastric carcinogenesis in a mouse model: is it possible?
Although debates still exist whether Helicobacter pylori infection is really class I carcinogen or not, H. pylori has been known to provoke precancerous lesions like gastric adenoma and chronic atrophic gastritis with intestinal metaplasia as well as gastric cancer. Chronic persistent, uncontrolled gastric inflammations are possible basis for ensuing gastric carcinogenesis and H. pylori infection increased COX-2 expressions, which might be the one of the mechanisms leading to gastric cancer. To know the implication of long-term treatment of antiinflammatory drugs, rebamipide or nimesulide, on H. pylori-associated gastric carcinogenesis, we infected C57BL/6 mice with H. pylori, especially after MNU administration to promote carcinogenesis and the effects of the long-term administration of rebamipide or nimesulide were evaluated. C57BL/6 mice were sacrificed 50 weeks after H. pylori infection. Colonization rates of H. pylori, degree of gastric inflammation and other pathological changes including atrophic gastritis and metaplasia, serum levels and mRNA transcripts of various mouse cytokines and chemokines, and NF-kappaB binding activities, and finally the presence of gastric adenocarcinoma were compared between H. pylori infected group (HP), and H. pylori infected group administered with long-term rebamipide containing pellet diets (HPR) or nimesulide mixed pellets (HPN). Gastric mucosal expressions of ICAM-1, HCAM, MMP, and transcriptional regulations of NF-kappaB binding were all significantly decreased in HPR group than in HP group. Multi-probe RNase protection assay showed the significantly decreased mRNA levels of apoptosis related genes and various cytokines genes like IFN-gamma, RANTES, TNF-alpha, TNFR p75, IL-1beta in HPR group. In the experiment designed to provoke gastric cancer through MNU treatment with H. pylori infection, the incidence of gastric carcinoma was not changed between HP and HPR group, but significantly decreased in HPN group, suggesting the chemoprevention of H. pylori-associated gastric carcinogenesis by COX-2 inhibition. Long-term administration of antiinflammatory drugs should be considered in the treatment of H. pylori since they showed the molecular and biologic advantages with possible chemopreventive effect against H. pylori-associated gastric carcinogenesis. If the final concrete proof showing the causal relationship between H. pylori infection and gastric carcinogenesis could be obtained, that will shed new light on chemoprevention of gastric cancer, that is, that gastric cancer could be prevented through either the eradication of H. pylori or lessening the inflammation provoked by H. pylori infection in high risk group.
Hahm
Ki Baik
KB
Chemoprevention Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Song
Young Joon
YJ
Oh
Tae Young
TY
Lee
Jeong Sang
JS
Surh
Young-Joon
YJ
Kim
Young Bae
YB
Yoo
Byung Moo
BM
Kim
Jin Hong
JH
Han
Sang Uk
SU
Nahm
Ki Taik
KT
Kim
Myung-Wook
MW
Kim
Dae Yong
DY
Cho
Sung Won
SW
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D016481:Helicobacter Infections / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D016480:Helicobacter pylori; D006801:Humans; D008770:Methylnitrosourea / Q000009:adverse effects; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000382:microbiology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D016328:NF-kappa B; D015363:Quinolones; D013449:Sulfonamides; D008770:Methylnitrosourea; C052785:rebamipide; D000409:Alanine; C012655:nimesulide