No abstract

The spindle assembly checkpoint (SAC) is essential for proper sister chromatid segregation. Defects in this checkpoint can lead to chromosome missegregation and aneuploidy. An increasing body of evidence suggests that aneuploidy can play a causal role in tumorigenesis. However, mutant mice that are prone to aneuploidy have only mild tumor phenotypes, suggesting that there are limiting factors in the aneuploidy-induced tumorigenesis. Here we provide evidence that p53 is such a limiting factor. We show that aneuploidy activates p53 and that loss of p53 drastically accelerates tumor development in two independent aneuploidy models. The p53 activation depends on the ataxia-telangiectasia mutated (ATM) gene product and increased levels of reactive oxygen species. Thus, the ATM-p53 pathway safeguards not only DNA damage but also aneuploidy.

The majority of patients without initial eradication of H pylori had an extensive metabolizer CYP2C19 genotype but were successfully re-treated with high doses of lansoprazole and an antibiotic to which H pylori was sensitive, such as amoxicillin, even when the patients were infected with clarithromycin-resistant strains of H pylori.

Proton pump inhibitors, such as omeprazole (OPZ), lansoprazole and rabeprazole (RPZ), have been widely used as acid inhibitory agents for the treatment of upper gastrointestinal diseases. 1 OPZ is a substituted benzimidazole, which effectively inhibits gastric acid secretion by irreversibly binding to the proton pump (H + ,K + -ATPase) in gastric parietal cells, 2, 3 and is mainly metabolized by a genetically determined enzyme, S-mephenytoin-4¢-hydroxylase (CYP2C19), in the liver to hydroxyomeprazole (OH-OPZ). 4±8 OPZ is partially metabolized by CYP3A4 to omeprazole sulphone (OPZ-SFN), which is then metabolized to hydroxyomeprazole sulphone (OH-OPZ-SFN) by CYP2C19. 9 In individuals with a poor metabolizer (PM) phenotype or genotype of CYP2C19, the SUMMARY Background: Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non-enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual's CYP2C19 status. Aim: To investigate the acid inhibitory effects and plasma levels of omeprazole and rabeprazole with reference to different CYP2C19 genotypes. Methods: Fifteen healthy volunteers took a daily dose of 20 mg of omeprazole or rabeprazole for 8 days. On postdose days 1 and 8, 24-h pro®les of intragastric pH were recorded and plasma concentrations of omeprazole, rabeprazole and their metabolites were determined.