Differential toxicity to murine small and large intestinal epithelium induced by oncology drugs

Abstract

Gastrointestinal toxicity is a major concern in the development of drugs. Here, we establish the ability to use murine small and large intestine-derived monolayers to screen drugs for toxicity. As a proof-of-concept, we applied this system to assess gastrointestinal toxicity of ~50 clinically used oncology drugs, encompassing diverse mechanisms of action. Nearly all tested drugs had a deleterious effect on the gut, with increased sensitivity in the small intestine. The identification of differential toxicity between the small and large intestine enabled us to pinpoint differences in drug uptake (antifolates), drug metabolism (cyclophosphamide) and cell signaling (EGFR inhibitors) across the gut. These results highlight an under-appreciated distinction between small and large intestine toxicity and suggest distinct tissue properties important for modulating drug-induced gastrointestinal toxicity. The ability to accurately predict where and how drugs affect the murine gut will accelerate preclinical drug development.

Core clock gene BMAL1 and RNA-binding protein MEX3A collaboratively regulate Lgr5 expression in intestinal crypt cells

“…The intestine, particularly the upper small intestine, is the major organ that absorb various chemicals, including nutrients and xenobiotics. Moreover, oncology drugs and radiation therapy for gastrointestinal cancers or para-aortic nodes from gynecological cancers have been reported to cause high toxicity in the small intestine, particularly duodenum 28 , 29 . Thus, to cope with such frequent stress and toxic insult, the small intestine must rely on tissue regeneration driven by intestinal stem cells to maintain homeostasis and fitness.…”