title: Long-term high-dose proton pump inhibitor administration to Helicobacter pylori-infected Mongolian gerbils enhances neuroendocrine tumor development in the glandular stomach.
abstract: Proton pump inhibitors (PPIs) are routinely used for control of upper gastrointestinal disorders, often with long-term application. However, there has been some concern about the long-term safety and the possibility of cancer induction and development of neuroendocrine tumors (NET) in the stomach. We therefore analyzed the influence of PPI use on tumor development histologically, immunohistochemically, and serologically in the glandular stomachs of Helicobacter pylori (Hp)-infected and uninfected Mongolian gerbils (MGs). 53 MGs were divided into 6 groups: Hp+25PPI, Hp+5PPI, Hp, 25PPI, 5PPI, and controls. The high-dose Hp+25PPI and 25PPI groups received the PPI (lansoprazole) at 25mg/kg/day, and the low-dose Hp+5PPI and 5PPI groups were given 5mg/kg/day. After 50 or 100 weeks, animals were sacrificed humanely, and the glandular stomach samples were evaluated histologically and phenotypically, using antibodies against chromogranin A (CgA), gastrin and gastric inhibitory polypeptide (GIP). Serum gastrin levels were also examined. NETs occurred in the Hp+25PPI, Hp+5PPI, Hp, and 25PPI groups, but there was no synergistic effect between Hp-infection and high-dose PPI administration. Serum gastrin was increased statistically by Hp infection and high-dose PPI administration, but not influenced by the low-dose. The NETs featured expression of CgA, but not gastrin or GIP. In conclusions, PPI at low dose had no influence on development of carcinomas and NETs in the Hp-infected and uninfected glandular MG stomach, suggesting clinical safety. However, PPI at high dose increased NET development and serum gastrin in the MG model.
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Mizoshita
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Mizushima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanida
authors.forename: Keiji
authors.initials: K
authors.lastname: Ozeki
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Takaya
authors.initials: T
authors.lastname: Shimura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kamiya
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nojiri
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Masae
authors.initials: M
authors.lastname: Tatematsu
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000633:toxicity; D000818:Animals; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D053379:Chromogranin A / Q000235:genetics; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics; D005755:Gastrins / Q000097:blood / Q000235:genetics; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000235:genetics / Q000473:pathology*; D016480:Helicobacter pylori; D064747:Lansoprazole; D008297:Male; D009375:Neoplasms, Glandular and Epithelial / Q000139:chemically induced* / Q000473:pathology / Q000821:virology; D018358:Neuroendocrine Tumors / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000821:virology; D054328:Proton Pump Inhibitors / Q000633:toxicity*; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000821:virology*
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D053379:Chromogranin A; D005755:Gastrins; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D005749:Gastric Inhibitory Polypeptide