Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics - PubMed (original) (raw)

. 2019 Jun 19;11(497):eaav1386.

doi: 10.1126/scitranslmed.aav1386.

Christopher J Long 1, Daniel Elbrecht 1, Trevor Sasserath 1, L Richard Bridges 1, John W Rumsey 1, Candace Martin 2, Mark Schnepper 2, Ying Wang 2, Franz Schuler 3, Adrian B Roth 3, Christoph Funk 3, Michael L Shuler 1, James J Hickman 4 2

Affiliations

• PMID: 31217335
• DOI: 10.1126/scitranslmed.aav1386

Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics

Christopher W McAleer et al. Sci Transl Med. 2019.

Abstract

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.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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Comment in

• Mimicking multi-organ drug effects.
  Harjes U. Harjes U. Nat Rev Cancer. 2019 Aug;19(8):417. doi: 10.1038/s41568-019-0175-z. Nat Rev Cancer. 2019. PMID: 31289373 No abstract available.

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