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

Jake M Bieber,Lani F Wu,Feng Bao,Heinz Hammerlindl,Megan L Koleske,Laura E Sanman,Maike A Roth,Fran Aweeka,Liusheng Huang,Xiaoxiao Sun,Steven J Altschuler

doi:10.1038/s42003-022-03048-x

Jake M Bieber, Lani F Wu + Show 9 more

Open Access

https://doi.org/10.1038/s42003-022-03048-x

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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.

Highlights

Gastrointestinal toxicity is a major concern in the development of drugs
The primary function of the small intestine is nutrient absorption, while the large intestine is responsible for water absorption[13]; to optimally perform these tasks, a gradient in transporter expression exists across the GI tract
We focused on clinically used oncology drugs, which are known to induce widespread GI toxicity[14,15,16,17]

Summary

Introduction

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. 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. Several in vitro intestinal models have been recently developed that enable systematic investigation of intestinal drug absorption, drug metabolism, and anticancer efficacy[7,8,9] These systems either utilize cancer-derived cells, lack both proliferative and differentiated cell types, or do not model both the small and large intestines. The primary function of the small intestine is nutrient absorption, while the large intestine is responsible for water absorption[13]; to optimally perform these tasks, a gradient in transporter expression exists across the GI tract It remains unclear if biological differences in the small and large intestine, such as transporter expression, metabolism, or cell type composition, cause drugs to exhibit differential toxicity to the small and large intestine. As a proof-ofconcept, we screened 48 clinically used oncology drugs for both small and large intestinal toxicity, revealing that many oncology drugs display differential toxicity across the murine GI tract

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