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

An in vitro multi-organ system evaluates the efficacy and potential off-target toxicities of anticancer parent drugs and metabolites. Testing for toxicity Standard methods of in vitro preclinical drug testing can be useful to detect cytotoxicity and evaluate safety pharmacology but fail to capture effects of drug metabolites (including functional effects) that become apparent at the organ systems level. McAleer et al. constructed an in vitro system using multiple human cancer and healthy cell types from different organs and recirculating serum-free medium. Within the system, anticancer drugs including tamoxifen, diclofenac, imatinib, and verapamil demonstrated variable on-target and off-target effects, some of which were dependent on drug metabolism by liver cells. This study supports the use of simple yet versatile multi-organ cell-based systems for efficient preclinical drug testing. 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.