Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
[Background, Objective] Gastrointestinal toxicity, such as the injury to the mucosal epithelial cells in the gastrointestinal tract, is a common adverse event among cytotoxic anticancer drugs and has become one of the dose-limiting factors for many drugs. Evaluation of gastrointestinal toxicity in humans is extremely important from the viewpoint of selecting compounds and predicting side effects. However, since the primary culture of gastrointestinal epithelial cells was very difficult, cell-based model system mimicking physiological condition that stably and universally evaluates gastrointestinal toxicity had not been established. Recently, an intestinal organoids culture method has been established that is capable of culture maintenance in a state close to an in vivo tissue using intestinal epithelial stem cells or iPS cells. In this study, we evaluated the in vitro gastrointestinal toxicity of cytotoxic anticancer drugs using intestinal organoids derived from mouse small intestine and human iPS cells.
[Methods] The mouse intestinal organoids were prepared from the small intestine of C57BL/6 mice, and the human intestinal organoids were differentiated from human iPS cells. SN-38 (active metabolite of irinotecan) and cisplatin were used as the evaluation compounds. On day 3 after seeding, intestinal organoids were treated with various concentrations of each compound. After treatment (2, 6, 24, 48 and 72 hours), cytotoxicity was evaluated by LDH assay.
[Results] SN-38 and cisplatin did not show any harmful effects after short time exposure, and showed a significant damaging effect as the exposure time became longer. In comparison of human and mouse injury responsiveness, cisplatin was similar in human and mouse intestinal organoids, but SN-38 showed a strong damaging effect in human intestinal organoids, and there were species differences in sensitivity.
[Conclusions] This method was considered to be useful as an in vitro system for evaluating the damaging effects and species differences in sensitivity of cytotoxic anticancer drugs on gastrointestinal toxicity.
