The circadian timing system controls cell cycle, apoptosis,
drug bioactivation, and transport and detoxification mechanisms in healthy tissues. As a consequence, the tolerability of
cancer chemotherapy varies up to several folds as a function of circadian timing of
drug administration in experimental models. Best antitumor efficacy of single-agent or
combination chemotherapy usually corresponds to the delivery of anticancer drugs near their respective times of best tolerability. Mathematical models reveal that such coincidence between chronotolerance and chronoefficacy is best explained by differences in the circadian and cell cycle dynamics of host and
cancer cells, especially with regard circadian entrainment and cell cycle variability. In the clinic, a large improvement in tolerability was shown in international randomized trials where
cancer patients received the same sinusoidal
chronotherapy schedule over 24h as compared to constant-rate infusion or wrongly timed
chronotherapy. However, sex, genetic background, and lifestyle were found to influence optimal
chronotherapy scheduling. These findings support systems biology approaches to
cancer chronotherapeutics. They involve the systematic experimental mapping and modeling of chronopharmacology pathways in synchronized cell cultures and their adjustment to mouse models of both sexes and distinct genetic background, as recently shown for
irinotecan. Model-based personalized circadian
drug delivery aims at jointly improving tolerability and efficacy of anticancer drugs based on the circadian timing system of individual patients, using dedicated circadian
biomarker and
drug delivery technologies.