A cell cycle automaton model for probing circadian patterns of anticancer drug delivery

Abstract

To optimize the temporal patterning of drug delivery used in cancer chronotherapy, we resort to an automaton model describing the transitions through the successive phases of the cell cycle. The model accounts for the progressive desynchronization of cells due to the variability of the durations of the cell cycle phases, and for the entrainment of the cell cycle by the circadian clock. Focusing on the cytotoxic effect of the anticancer drug 5-fluorouracil (5-FU), which kills cells in the S phase, we compare the effect of continuous infusion of 5-FU with various circadian patterns of 5-FU administration that peak either at 4 a.m., 10 a.m., 4 p.m., or 10 p.m. The model indicates that the cytotoxic effect of 5-FU is minimum for the circadian delivery peaking at 4 a.m., and maximum for the continuous infusion or the circadian pattern peaking at 4 p.m. These results fit well with experimental observations and illustrate how the modeling approach based on the cell cycle automaton may help to predict the cytotoxic effect of anticancer drugs affecting various phases of the cell cycle.