Optimizing Temporal Patterns of Anticancer Drug Delivery by Simulations of a Cell Cycle Automaton

Determining the optimal temporal pattern of drug administration represents a central issue in chronopharmacology. Given that circadian rhythms profoundly affect the response to a variety of anticancer drugs, circadian chronotherapy is used clinically in cancer treatment. Assessing the relative cytotoxicity of various temporal patterns of administration of anticancer drugs requires a model for the cell cycle, since these drugs often target specific phases of this cycle. Here we use an automaton model to describe the transitions through the successive phases of the cell cycle. The model accounts for the progressive desynchronization of cells due to the variability in duration of the cell cycle phases, and for the entrainment of the cell cycle by the circadian clock. Focusing on the cytotoxic effect of 5-fluorouracil (5-FU), which kills cells exposed to this anticancer drug during the S phase, we compare the effect of continuous infusion of 5-FU with various circadian patterns of 5-FU administration that peak at either 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 a circadian delivery peaking at 4 a.m.-which is the profile used clinically for 5-FU-and is maximum for continuous infusion or a circadian pattern peaking at 4 p.m. These results are explained in terms of the relative temporal profiles of 5-FU and the fraction of cells in S phase. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.