Circadian timing in cancer treatments.
The circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments.
Lévi
Francis
F
INSERM, U Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, France. francis.levi@inserm.fr
Okyar
Alper
A
Dulong
Sandrine
S
Innominato
Pasquale F
PF
Clairambault
Jean
J
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis; D001683:Biological Clocks; D002453:Cell Cycle; D002940:Circadian Rhythm / Q000187:drug effects; D004260:DNA Repair; D016503:Drug Delivery Systems; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy*; D057285:Precision Medicine; D013997:Time Factors
D000970:Antineoplastic Agents