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Published on: March 10, 2015
Evaluation of interspecies differences in DS-2087b-induced gastrointestinal toxicity using mouse and monkey
Yuji Shirai1, Takuma Iguchi1, Kazunori Fujimoto1
1Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
Abstract:
Gastrointestinal (GI) toxicity is a common adverse event induced by anti-cancer drugs; however, the information of the correlations in vitro to in vivo regarding GI toxicity is limited. The objective of this study was elucidating the usefulness of animal small intestinal organoids using DS-2087b, a novel epidermal growth factor receptor/human epidermal growth factor receptor 2 exon 20 insertion inhibitor. Mice showed no DS-2087b-related GI toxicities up to 100 mg/kg in 28-day repeated oral toxicity studies, while monkeys exhibited diarrhea at 10 mg/kg, along with histopathological changes including intestinal atrophy/erosion at 30 and 100 mg/kg. To clarify the mechanisms involved in interspecies differences, cell viability and transcriptomic analysis were performed using mouse and monkey small intestinal organoids generated from adult stem cells treated with DS-2087b at 0-10,000 nM for 3 days. Cell viability in monkey small intestinal organoids treated with DS-2087b at 1000 and 10,000 nM was significantly decreased compared to that of mice. In the transcriptomic analysis, expression of stem- and Paneth-cell marker genes was markedly decreased in the monkey small intestinal organoids. In conclusion, the intestinal organoids are valuable in vivo-in vitro translation of drug-induced GI toxicity and the changes in specific cell-type composition induced by DS-2087b may be important factors for contributing the interspecies differences.
Insights
Animal small intestinal organoids effectively predict in vivo drug-induced gastrointestinal toxicity. Monkey organoids showed decreased cell viability and altered gene expression, explaining interspecies differences in toxicity from DS-2087b.
Area of Science:
- Pharmacology
- Toxicology
- Gastroenterology
Background:
- Gastrointestinal (GI) toxicity is a frequent side effect of anti-cancer drugs.
- Limited in vitro-in vivo correlation data exists for drug-induced GI toxicity.
Purpose of the Study:
- To evaluate the utility of animal small intestinal organoids for predicting in vivo GI toxicity.
- To investigate interspecies differences in GI toxicity using DS-2087b, an EGFR/HER2 exon 20 insertion inhibitor.
Main Methods:
- In vivo oral toxicity studies in mice and monkeys with DS-2087b.
- Generation of mouse and monkey small intestinal organoids from adult stem cells.
- In vitro assessment of cell viability and transcriptomic analysis of organoids treated with DS-2087b.
Main Results:
- Mice showed no GI toxicity; monkeys exhibited diarrhea and histopathological changes (atrophy/erosion) at higher doses.
- Monkey small intestinal organoids demonstrated significantly reduced cell viability compared to mouse organoids when treated with DS-2087b.
- Transcriptomic analysis revealed decreased expression of stem and Paneth cell markers in monkey organoids.
Conclusions:
- Small intestinal organoids serve as valuable tools for in vitro-in vivo translation of drug-induced GI toxicity.
- Interspecies differences in DS-2087b-induced GI toxicity may be attributed to changes in specific cell-type composition within the intestine.
