Host: The Japanese Society of Toxicology
Drug-induced gastrointestinal (GI) toxicity is commonly observed as clinical adverse effects of therapeutic agents targeting intracellular effectors in cancer treatment. The adverse effects include diarrhea, colitis, and other drug-induced GI toxicity influencing safety and tolerability of the agents. GI toxicity prediction of candidate molecules during drug discovery and development has been challenging due to limitation of in vitro models to recapitulate key structures and functions of human GI tract. Over the past decade more physiologically relevant models have been developed using three-dimensional (3D) cultures for better cell polarization and characteristics of tissues and organs. This talk will highlight our recent experiences of trans-well formatted 3D GI microtissues, which consist of primary human small intestinal cells and recapitulate structural features such as villi. GI toxicity is assessed by informative readouts such as molecular signatures by whole-transcriptome profiling for better understanding the mechanisms of GI toxicity, and transepithelial electrical resistance (TEER) for barrier integrity. In particular, TEER may provide better prediction of test articles to induce diarrhea, which is correlated to intestinal barrier dysfunction. The talk will provide examples from our studies with the GI model demonstrating the effect of a known class of drugs that cause transcriptional disruption of the cell cycle and autophagy pathways, and influence barrier integrity in a target-dependent manner. We will also discuss the benefits and challenges of the GI model for drug safety assessment.
