دورية أكاديمية
Mouse organoids as an in vitro tool to study the in vivo intestinal response to cytotoxicants.
| العنوان: | Mouse organoids as an in vitro tool to study the in vivo intestinal response to cytotoxicants. |
|---|---|
| المؤلفون: | Jardi F; Preclinical Sciences & Translational Safety, Janssen Pharmaceutica NV, Beerse, Belgium. fjardi@its.jnj.com., Kelly C; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK., Teague C; GlaxoSmithKline, Non-Clinical Safety, Ware, UK., Fowler-Williams H; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK., Sevin DC; Omics Sciences, Genomic Sciences, GlaxoSmithKline, Heidelberg, Germany., Rodrigues D; Department of Toxicogenomics, GROW School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands., Jo H; Certara UK Limited, Simcyp Division, Sheffield, UK., Ferreira S; Certara UK Limited, Simcyp Division, Sheffield, UK., Herpers B; Crown Bioscience Netherlands, Leiden, The Netherlands., Van Heerden M; Preclinical Sciences & Translational Safety, Janssen Pharmaceutica NV, Beerse, Belgium., de Kok T; Department of Toxicogenomics, GROW School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands., Pin C; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK., Lynch A; GlaxoSmithKline, Non-Clinical Safety, Ware, UK., Duckworth CA; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK., De Jonghe S; Preclinical Sciences & Translational Safety, Janssen Pharmaceutica NV, Beerse, Belgium., Lammens L; Preclinical Sciences & Translational Safety, Janssen Pharmaceutica NV, Beerse, Belgium., Pritchard DM; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. |
| المصدر: | Archives of toxicology [Arch Toxicol] 2023 Jan; Vol. 97 (1), pp. 235-254. Date of Electronic Publication: 2022 Oct 06. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Springer-Verlag Country of Publication: Germany NLM ID: 0417615 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0738 (Electronic) Linking ISSN: 03405761 NLM ISO Abbreviation: Arch Toxicol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Berlin, New York, Springer-Verlag. |
| مواضيع طبية MeSH: | Fluorouracil*/toxicity , Apoptosis*, Humans ; Animals ; Mice ; Caspase 3/metabolism ; Diarrhea/chemically induced ; Organoids ; Intestinal Mucosa |
| مستخلص: | Cross-species comparison of drug responses at the organoid level could help to determine the human relevance of findings from animal studies. To this end, we first need to evaluate the in vitro to in vivo translatability of preclinical organoids. Here, we used 5-fluorouracil (5-FU) as an exemplar drug to test whether the in vivo gut response to this cytotoxicant was preserved in murine intestinal organoids. Mice treated with 5-FU at 20 or 50 mg/kg IV (low and high dose, respectively) displayed diarrhea at clinically relevant exposures. 5-FU also induced intestinal lesions, increased epithelial apoptosis, and decreased proliferation in a dose-dependent manner. To enable comparison between the in vitro and in vivo response, top nominal in vitro drug concentrations that caused significant cytotoxicity were chosen (dose range 1-1000 µM). The inferred intracellular concentration in organoids at 1000 µM was within the tissue exposure range related to intestinal toxicity in vivo. 5-FU at ≥ 100 µM decreased ATP levels and increased Caspase-3 activity in intestinal organoids. In keeping with the in vivo findings, 5-FU increased the percentage of Caspase-3-positive cells and reduced Ki67 staining. At the transcriptome level, there was an overlap in the activity of pathways related to 5-FU's mode of action, lipid and cholesterol metabolism and integrin signaling across in vivo gut and organoids. The predicted activity state of upstream regulators was generally well preserved between setups. Collectively, our results suggest that despite their inherent limitations, organoids represent an adequate tool to explore the intestinal response to cytotoxicants. (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) |
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| معلومات مُعتمدة: | 116030 Innovative Medicines Initiative |
| فهرسة مساهمة: | Keywords: Drug-induced intestinal toxicity; Organoids; PBPK; Preclinical species; Transcriptomics |
| المشرفين على المادة: | EC 3.4.22.- (Caspase 3) U3P01618RT (Fluorouracil) |
| تواريخ الأحداث: | Date Created: 20221006 Date Completed: 20230109 Latest Revision: 20230118 |
| رمز التحديث: | 20230120 |
| DOI: | 10.1007/s00204-022-03374-3 |
| PMID: | 36203040 |
| قاعدة البيانات: | MEDLINE |
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| DOI: | 10.1007/s00204-022-03374-3 |