The circadian timing system, a coordinator of life processes. implications for the rhythmic delivery of cancer therapeutics

Cell physiology is regulated along the 24-h time scale by a circadian timing system composed of molecular clocks within each cell and a central coordination system in the brain. The mammalian molecular clock is made of interconnected molecular loops involving at least 12 circadian genes. The cellular clocks are coordinated by the suprachiasmatic nucleus, a hypothalamic pacemaker which also helps the organism adjust to environmental cycles. The rest- activity rhythm is a reliable marker of the circadian system function in both rodents and Man. It can be monitored non-invasively through several devices or systems. The circadian organization is responsible for predictable changes in the tolerability and efficacy of anticancer agents, and also controls tumor promotion and growth. The clinical relevance of the chronotherapy principle, i.e. treatment administration as a function of rhythms, has been demonstrated in randomized multicenter trials, using programmable-in-time drug delivery systems. Chronotherapeutic schedules first documented the safety and the activity of oxaliplatin-based combination chemotherapy in patients with metastatic colorectal cancer. The chronotherapy concept offers further promises for improving current cancer treatment options as well as for optimizing the development of new anticancer or supportive agents. Technological developments of chronotherapeutics in daily practice are essential in order to non invasively assess dynamic changes in biological functions and to insure temporally-adjusted therapeutics interventions.