elastase Interestingly all three antihistamines emerging as

Interestingly, all three antihistamines emerging as putative anti-cancer drugs in our studies have extremely high apparent volumes of distribution (VD) ranging from 48 to over 100L/kg for astemizole (Tillement, 2000), loratadine (Tillement, 2000) and ebastine (Del Cuvillo et al., 2006) (Table 3). High VD values reflect the efficient distribution of drugs to tissues. Accordingly, the reported concentrations of astemizole in e.g. lungs, kidneys, liver and pancreas of Beagle dogs treated for six weeks with 1mg/kg astemizole are over 1000-fold higher than the corresponding plasma concentrations (Tillement, 2000, Michiels et al., 1986). Notably, astemizole and other CADs, which per definition are weak bases, are likely to accumulate in acidic tumors even more efficiently than in healthy tissues with neutral pH. Data for tissue distribution of loratadine and ebastine are unfortunately not available, but their higher VD values suggest even more efficient tissue distribution than observed for astemizole. On the other hand, the approximately 50-fold lower VD (Tillement, 2000) and less efficient tissue distribution of terfenadine (Leeson et al., 1982) may explain the discrepancy between its potent anti-cancer activity in vitro and lack of effect in the pharmacoepidemilogical study. Contrary to the other CADs studied here, clemastine use was associated with increased cancer mortality. Notably, clemastine is commonly used in prevention and treatment of hypersensitivity reactions associated with cancer therapy at Danish hospitals and its use increased over six-fold after cancer diagnosis in our patient cohort. Such a prescription bias towards high-risk patients may thus explain the poor prognosis associated with the use of clemastine. It should also be noted that clemastine has a relatively low VD value (Schran et al., 1996) (Table 3), and its ability to augment chemotherapy in parental and MDR cancer elastase in vitro is inferior to that of astemizole, loratadine and ebastine. Over-the-counter sale of loratadine (<35% of the total sale) and ebastine (<25%) could create another potential source of bias. Such exposure misclassification is, however, considered negligible.
Funding Sources
This work was supported by grants from the European Research Council (Advanced grant number 340751), the Danish National Research Foundation (grant number DNRF125), the Danish Cancer Society (grant number R90-A5783), the Danish Medical Research Council (grant number DFF4004-00465), the Novo Nordisk Foundation (grant number NNF12OC0001341) and the Danish Cancer Research Foundation (project grant from 2011) to MJ.

Conflict of Interest Statement

Author Contributions
A.M.E. designed and performed most of the cell culture experiments, analyzed the data and contributed to the writing of the manuscript. C.D. designed and performed the analyses of all registry-based data. A.C.V. performed experiments presented in Fig. 3c and Fig. S2e. A.A. designed and performed the experiment presented in Fig. S1b. L.C. assisted in the design of the registry-based studies, N.H.T.P. and J.N. contributed to the design of cell culture experiments, J.S. designed the experiments and analyzed the data presented in Fig. 3c and Fig. S2e. A.M. and K.Ø. provided important insight into the clinical practice and possible confounding factors. S.F. designed the epidemiological analyses, analyzed the data and contributed to the writing the manuscript. M.J. designed the study, analyzed the biological data and wrote the first draft of the manuscript. All authors contributed to the final text and approved it.

Acknowledgements

Introduction
Almost one million new cases of gastric cancer were estimated to have occurred throughout the world in 2012 (952,000 cases, 6.8% of total new cancer cases), making RNA transcript the fifth most common malignancy after cancers of the lung, breast, colorectum and prostate (GLOBOCAN, 2012). Gastric cancer is the third leading cause of death from cancer among both sexes worldwide (723,000 deaths, 8.8% of total cancer deaths). Most patients with gastric cancer are diagnosed at an advanced stage, with an overall 5-year survival rate of approximately 28% (American Cancer Society. Cancer facts and figures, 2014). Early detection is the key to improving the survival of gastric cancer patients (Leung et al., 2008). Upper gastrointestinal endoscopy is a widely accepted procedure for early detection of gastric cancer. However, in many countries, endoscopists have limited opportunities to acquire the techniques, knowledge and experience which are imperative for the endoscopic detection of early gastric cancer (EGC) when only subtle mucosal morphology is apparent (Veitch et al., 2015). In contrast, endoscopists in Japan have more such opportunities thereby enabling them to detect subtle lesions that suggest EGC.