Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics
| Autor: | Mark T. Schnepper, L. Richard Bridges, Christopher W. McAleer, Christopher J. Long, Michael L. Shuler, Candace Martin, James J. Hickman, Daniel Elbrecht, Adrian Roth, Franz Schuler, Trevor Sasserath, John W. Rumsey, Ying Wang, Christoph Funk |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Diclofenac Metabolite Drug Evaluation Preclinical Antineoplastic Agents 02 engineering and technology Pharmacology 03 medical and health sciences chemistry.chemical_compound Breast cancer Lab-On-A-Chip Devices medicine Humans Cells Cultured Cell Proliferation business.industry Cancer Imatinib General Medicine 021001 nanoscience & nanotechnology medicine.disease Tamoxifen 030104 developmental biology Verapamil chemistry Toxicity Cancer cell Imatinib Mesylate 0210 nano-technology business medicine.drug |
| Zdroj: | Science Translational Medicine. 11 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | A pumpless, reconfigurable, multi-organ-on-a-chip system containing recirculating serum-free medium can be used to predict preclinical on-target efficacy, metabolic conversion, and measurement of off-target toxicity of drugs using functional biological microelectromechanical systems. In the first configuration of the system, primary human hepatocytes were cultured with two cancer-derived human bone marrow cell lines for antileukemia drug analysis in which diclofenac and imatinib demonstrated a cytostatic effect on bone marrow cancer proliferation. Liver viability was not affected by imatinib; however, diclofenac reduced liver viability by 30%. The second configuration housed a multidrug-resistant vulva cancer line, a non-multidrug-resistant breast cancer line, primary hepatocytes, and induced pluripotent stem cell-derived cardiomyocytes. Tamoxifen reduced viability of the breast cancer cells only after metabolite generation but did not affect the vulva cancer cells except when coadministered with verapamil, a permeability glycoprotein inhibitor. Both tamoxifen alone and coadministration with verapamil produced off-target cardiac effects as indicated by a reduction of contractile force, beat frequency, and conduction velocity but did not affect viability. These systems demonstrate the utility of a human cell-based in vitro culture system to evaluate both on-target efficacy and off-target toxicity for parent drugs and their metabolites; these systems can augment and reduce the use of animals and increase the efficiency of drug evaluations in preclinical studies. |
| Databáze: | OpenAIRE |
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