Accurately quantifying drug response is essential to designing effective anti-cancer agents. Though agents such as chemotherapies have known effects on the cell cycle, these have not been comprehensively characterized or analyzed using a unified quantitative model of pharmacologic response. Here, we used a breast cancer cell line with a stably expressed fluorescent translocation cell cycle phase reporter. Nuclear or cytoplasmic expression indicates cells in G1 or S/G2 phase, respectively. The dynamic response of cells to four types of chemotherapy drugs was quantified. Drug treatment causes oscillations in the number of cells in different cell-cycle phases. A simple ordinary differential equation model of division and cell death, though consistent with measurements of just cell number, could not show oscillations under any parametrization. By examining the distribution of cell cycle phase lengths, we observed that cell cycle phases were gamma-distributed and that drugs necessarily lead to oscillations due to “pseudo-synchronization” when these lengths are extended. A delay differential equation model, in contract, was able to recapitulate this oscillation behavior. A Hill model was then applied to examine the overall dose-response behavior across drug concentrations. In total, we identify that many more drugs including targeted agents have strong cell cycle-specific effects, that nearly all agents cause cell cycle synchronization, and that a dynamic model with a fluorescent reporter can help to analyze the influence of any drug on the dynamics of cell cycle phases. These findings could lead to new optimized chemotherapy protocols using both timing and drug combinations.
Authors: Farnaz Mohammadi 1, Sean Gross 2, Laura M. Heiser2, Aaron S. Meyer1
1Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
2Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, USA