Evaluation of potential gastrointestinal biomarkers in a PAK4 inhibitor-treated preclinical toxicity model to address unmonitorable gastrointestinal toxicity
Autor: | W. Timothy Schaiff, Annette John-Baptiste, Shashi K. Ramaiah, Wes Scott, Cindy J. Gross, Allison Vitsky, Wenhu Huang, Amy H. Yang, Annette Wu, Erick Kindt |
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Rok vydání: | 2012 |
Předmět: |
Oncology
medicine.medical_specialty Gastrointestinal toxicity Pharmacology Toxicology Pathology and Forensic Medicine Bile Acids and Salts Feces Internal medicine Toxicity Tests medicine Animals Biomarker discovery Enzyme Inhibitors Rats Wistar Molecular Biology Preclinical toxicity Kidney business.industry Histocytochemistry Stomach Cell Biology Rats Gastrointestinal Tract Disease Models Animal MicroRNAs medicine.anatomical_structure Jejunum p21-Activated Kinases Gastric Mucosa Toxicity Biomarker (medicine) Citrulline Histopathology Amine Oxidase (Copper-Containing) Calprotectin business Leukocyte L1 Antigen Complex Biomarkers |
Zdroj: | Toxicologic pathology. 40(3) |
ISSN: | 1533-1601 |
Popis: | Although gastrointestinal (GI) toxicity is a significant dose-limiting safety concern noted in multiple therapeutic areas, there are no GI biomarkers that can accurately track, precede, or reliably correlate with histologic evidence of injury. While significant efforts have been made within the pharmaceutical industry, academia, and consortia to address the biomarker gaps in other target organs such as liver, kidney, and muscle (cardiac and skeletal), there have been no concerted efforts in the area of GI biomarkers. Using PAK4 inhibitor as a preclinical rat model of gastric toxicity, selected candidate biomarkers from literature were evaluated to test their usefulness as gastric injury biomarkers in this study. Biomarkers selected in this study include plasma diamino oxidase and citrulline, fecal calprotectin, bile acids, and miRNA. Based on the results, L-citrulline and miR-194 results appear to correlate well with histopathology findings. Although these biomarkers will need additional assay validation and qualification to test if they truly predict the injury prior to histopathology, the results provide promise for further testing using additional GI toxicants. In addition, this article highlights important gaps in GI biomarkers and provides substrate and rationale for additional investments either for further testing of already available biomarkers or to pursue extensive biomarker discovery approaches. |
Databáze: | OpenAIRE |
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