Cancer Chronotherapeutics: Experimental, Theoretical, and Clinical Aspects

  • E. Ortiz-Tudela
  • A. Mteyrek
  • A. Ballesta
  • P. F. Innominato
  • F. LéviEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 217)


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.


Cancer Circadian rhythms Chronotherapy Survival Chronotolerance Chronoefficacy Mathematical models Clinical trials 


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • E. Ortiz-Tudela
    • 1
    • 2
  • A. Mteyrek
    • 1
    • 3
  • A. Ballesta
    • 1
    • 3
    • 4
  • P. F. Innominato
    • 1
    • 3
    • 5
  • F. Lévi
    • 1
    • 3
    • 5
    Email author
  1. 1.INSERM, UMRS776 “Rythmes biologiques et cancers”Paul Brousse HospitalVillejuifFrance
  2. 2.Department of Physiology, Chronobiology LaboratoryUniversity of MurciaMurciaSpain
  3. 3.ParisSud UniversityOrsayFrance
  4. 4.INRIA Rocquencourt, BANG Project TeamLe Chesnay CedexFrance
  5. 5.Department of Oncology, APHP, Chronotherapy UnitPaul Brousse HospitalVillejuifFrance

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