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

Science translational medicine (2019-06-21)
Christopher W McAleer, Christopher J Long, Daniel Elbrecht, Trevor Sasserath, L Richard Bridges, John W Rumsey, Candace Martin, Mark Schnepper, Ying Wang, Franz Schuler, Adrian B Roth, Christoph Funk, Michael L Shuler, James J Hickman
RESUMEN

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.

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Sigma-Aldrich
Diclofenac sodium salt
Sigma-Aldrich
(±)-Verapamil hydrochloride, ≥99% (titration), powder
Sigma-Aldrich
Imatinib mesylate, ≥98% (HPLC)
Sigma-Aldrich
Imatinib