Abstract
Although studies of cell cycle perturbation and growth inhibition are common practice, they are unable to properly measure the activity of cell cycle checkpoints and frequently convey misinterpretation or incomplete pictures of the response to anticancer treatment. A measure of the strength of the treatment response of all checkpoints, with their time and dose dependence, provides a new way to evaluate the antiproliferative activity of the drugs, fully accounting for variation of the cell fates within a cancer cell line. This is achieved with an interdisciplinary approach, joining information from independent experimental platforms and interpreting all data univocally with a simple mathematical model of cell cycle proliferation. The model connects the dynamics of checkpoint activities at the molecular level with population-based flow cytometric and growth inhibition time course measures. With this method, the response to five drugs, characterized by different molecular mechanisms of action, was studied in a synoptic way, producing a publicly available database of time course measures with different techniques in a range of drug concentrations, from sublethal to frankly cytotoxic. Using the computer simulation program, we were able to closely reproduce all the measures in the experimental database by building for each drug a scenario of the time and dose dependence of G(1), S, and G(2)-M checkpoint activities. We showed that the response to each drug could be described as a combination of a few types of activities, each with its own strength and concentration threshold. The results gained from this method provide a means for exploring new concepts regarding the drug-cell cycle interaction.
Highlights
Pharmacodynamics, intended in a broad sense as the study of the efficacy of a drug in cancer or in cancer biological models, is object of research from the molecular scale, focused on inhibition of specific targets, up to large-scale tumor growth inhibition in vivo
Time course plots of absolute cell number, %G1, %S, and %G2-M for each drug were reported in Supplementary Figure, together with their best-fit model
We adopted an interdisciplinary approach to measure the dynamics of checkpoint activities, joining information from independent experimental platforms and interpreting all data univocally with a simple mathematical model of cell cycle proliferation
Summary
Pharmacodynamics, intended in a broad sense as the study of the efficacy of a drug in cancer or in cancer biological models, is object of research from the molecular scale, focused on inhibition of specific targets, up to large-scale tumor growth inhibition in vivo. Studies of the proliferation of a cancer cell population are done at an intermediate scale, distinct from the molecular level, because the behavior of a group of cells is not a straightforward consequence of how a single (or “typical” or “average”) cell functions, as studied in molecular research. This intermediate level is where in vitro toxicity tests are done and “probabilistic” quantities, such as the percentage of surviving cells, are measured. Rough data depend on, but do not provide a direct measure of, the activities of the molecular networks regulating G1, S, and G2-M checkpoints, which in turn are the results of complex molecular interactions studied by systems biology
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