The circadian timing system controls drug metabolism and cellular proliferation over the 24 h through molecular clocks in each cell, circadian physiology, and the suprachiasmatic nuclei--a hypothalamic pacemaker clock that coordinates circadian rhythms. As a result, both the toxicity and efficacy of over 30
anticancer agents vary by more than 50% as a function of dosing time in experimental models. The circadian timing system also down-regulates malignant growth in experimental models and possibly in
cancer patients. Programmable-in-time
infusion pumps and rhythmic physiology monitoring devices have made possible the application of chronotherapeutics to more than 2000
cancer patients without hospitalization. This strategy first revealed the antitumor efficacy of
oxaliplatin against
colorectal cancer. In this disease, international clinical trials have shown a five-fold improvement in patient tolerability and near doubling of antitumor activity through the chronomodulated, in comparison to constant-rate, delivery of
oxaliplatin and 5-fluorouracil-leucovorin. Here, the relevance of the peak time, with reference to circadian rhythms, of the chemotherapeutic delivery of these
cancer medications for achieving best tolerability was investigated in 114 patients with metastatic
colorectal cancer and in 45 patients with
non-small cell lung cancer. The incidence of severe adverse events varied up to five-fold as a function of the choice of when during the 24 h the peak dose of the medications was timed. The optimal chronomodulated schedules corresponded to peak delivery rates at 1 a.m. or 4 a.m. for 5-fluorouracil-leucovorin, at 1 p.m. or 4 p.m. for
oxaliplatin, and at 4 p.m. for
carboplatin. Sex of patient was an important determinant of
drug schedule tolerability. This finding is consistent with recent results from a
chronotherapy trial involving 554 patients with metastatic
colorectal cancer, where sex also predicted survival outcome from
chronotherapy, but not conventional
drug delivery. Ongoing translational studies, mathematical modeling, and technology developments are further paving the way for tailoring
cancer chronotherapeutics to the main rhythmic characteristics of the individual patient. Targeting therapeutic delivery to the dynamics of the cross-talk between the circadian clock, the cell division cycle, and pharmacology pathways represents a new challenge to concurrently improve the quality of life and survival of
cancer patients through personalized
cancer chronotherapeutics.