Unraveling the complexity of cell cycle effects of anticancer drugs in cell populations

Cell cycle perturbations occur after treatment with all anticancer drugs. The perturbations are usually classified as cytostatic (cell cycle arrest) or cytotoxic (cell killing). Our approach for analysis of cell cycle perturbations in vitro was to consider all the data provided by different experimental tests and interpret them through a mathematical formulation of the problem. The model adopted for data analysis and interpretation is the result of merging two models, one for the cell cycle and the other for the drug effects. The first exploits the results of the theory of age-structured cell population dynamics while the second is based on distinct parameters ("effect descriptors") directly linked to cell cycle arrest, damage repair or cell death in G(1) and G(2)M and to inhibition of DNA synthesis and death in S. The set of values of the effect descriptors which are coherent with all experimental data are used to estimate the cytostatic and cytotoxic effects separately. Applying the procedure to data from in vitro experiments, we found complex but biologically consistent patterns of time and dose dependence for each cell cycle effect descriptor, opening the way for a link to the parallel changes in the molecular pathways associated with each effect.