Differential Response to Cytotoxic Drugs Explains the Dynamics of Leukemic Cell Death: Insights from Experiments and Mathematical Modeling

Abstract

This study presents a framework whereby cancer chemotherapy could be improved through collaboration between mathematicians and experimentalists. Following on from our recently published model, we use A20 murine leukemic cells transfected with monomeric red fluorescent proteins cells (mCherry) to compare the simulated and experimental cytotoxicity of two Federal Drug Administration (FDA)-approved anticancer drugs, Cytarabine (Cyt) and Ibrutinib (Ibr) in an in vitro model system of Chronic Lymphocytic Leukemia (CLL). Maximum growth inhibition with Cyt (95%) was reached at an 8-fold lower drug concentration (6.25 μM) than for Ibr (97%, 50 μM). For the proposed ordinary differential equations (ODE) model, a multistep strategy was used to estimate the parameters relevant to the analysis of in vitro experiments testing the effects of different drug concentrations. The simulation results demonstrate that our model correctly predicts the effects of drugs on leukemic cells. To assess the closeness of the fit between the simulations and experimental data, RMSEs for both drugs were calculated (both RMSEs < 0.1). The numerical solutions of the model show a symmetrical dynamical evolution for two drugs with different modes of action. Simulations of the combinatorial effect of Cyt and Ibr showed that their synergism enhanced the cytotoxic effect by 40%. We suggest that this model could predict a more personalized drug dose based on the growth rate of an individual’s cancer cells.

Keywords

• A20 cells
• cytarabine
• ibrutinib
• combination therapy
• in vitro experiments
• logistic cancer growth rate