Implications of circadian clocks for the rhythmic delivery of cancer therapeutics

The circadian timing system (CTS) controls drug metabolism and cellular proliferation over the 24 hour day through molecular clocks in each cell. These cellular clocks are coordinated by a hypothalamic pacemaker, the suprachiasmatic nuclei, that generates or controls circadian physiology. The CTS plays a role in cancer processes and their treatments through the downregulation of malignant growth and the generation of large and predictable 24 hour changes in toxicity and efficacy of anti-cancer drugs. The tight interactions between circadian clocks, cell division cycle and pharmacology pathways have supported sinusoidal circadian-based delivery of cancer treatments. Such chronotherapeutics have been mostly implemented in patients with metastatic colorectal cancer, the second most common cause of death from cancer. Stochastic and deterministic models of the interactions between circadian clock, cell cycle and pharmacology confirmed the poor therapeutic value of both constant-rate and wrongly timed chronomodulated infusions. An automaton model for the cell cycle revealed the critical roles of variability in circadian entrainment and cell cycle phase durations in healthy tissues and tumours for the success of properly timed circadian delivery schedules. The models showed that additional therapeutic strategy further sets the constraints for the identification of the most effective chronomodulated schedules.