Differential toxicity to murine small and large intestinal epithelium induced by oncology drugs
Jake M Bieber1,2, Laura E Sanman1, Xiaoxiao Sun1
1Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
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.
Insights
New gut models using mouse intestine cells can screen oncology drugs for gastrointestinal toxicity. The system revealed significant drug effects, especially in the small intestine, aiding preclinical drug development.
Area of Science:
- Pharmacology
- Gastroenterology
- Drug Development
Background:
- Gastrointestinal (GI) toxicity is a significant challenge in drug development, particularly for oncology therapeutics.
- Existing preclinical models often fail to fully capture the complex GI environment and drug interactions.
Purpose of the Study:
- To establish and validate a novel *in vitro* screening system using murine small and large intestine-derived monolayers to assess drug-induced GI toxicity.
- To evaluate the GI toxicity profiles of approximately 50 clinically used oncology drugs with diverse mechanisms of action.
Main Methods:
- Development of primary intestinal epithelial cell monolayers from murine small and large intestines.
- Application of these monolayers to screen ~50 oncology drugs for toxicity.
- Analysis of differential drug effects and mechanisms (uptake, metabolism, signaling) between small and large intestine models.
Main Results:
- Nearly all tested oncology drugs exhibited deleterious effects on the gut monolayers.
- The small intestine models demonstrated increased sensitivity to drug toxicity compared to the large intestine.
- Differential toxicity identified specific mechanisms, including drug uptake (antifolates), metabolism (cyclophosphamide), and cell signaling (EGFR inhibitors).
Conclusions:
- Murine intestinal monolayers provide a robust platform for predicting drug-induced GI toxicity.
- Distinct small and large intestine properties significantly modulate drug toxicity, an under-appreciated factor in preclinical development.
- This system accelerates preclinical drug development by accurately predicting drug effects on the gut.
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