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Cancer Chronotherapeutics: Experimental, Theoretical, and Clinical Aspects

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Circadian Clocks

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 217))

Abstract

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.

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Authors and Affiliations

  1. INSERM, UMRS776 “Rythmes biologiques et cancers”, Paul Brousse Hospital, Villejuif, France

    E. Ortiz-Tudela, A. Mteyrek, A. Ballesta, P. F. Innominato & F. Lévi

  2. Department of Physiology, Chronobiology Laboratory, University of Murcia, Murcia, Spain

    E. Ortiz-Tudela

  3. ParisSud University, UMR-S0776, Orsay, France

    A. Mteyrek, A. Ballesta, P. F. Innominato & F. Lévi

  4. INRIA Rocquencourt, BANG Project Team, Le Chesnay Cedex, France

    A. Ballesta

  5. Department of Oncology, APHP, Chronotherapy Unit, Paul Brousse Hospital, Villejuif, France

    P. F. Innominato & F. Lévi

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  1. E. Ortiz-Tudela
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  2. A. Mteyrek
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  3. A. Ballesta
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  4. P. F. Innominato
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  5. F. Lévi
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Correspondence to F. Lévi .

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  1. , Laboratory of Chronobiology, Charité Universiätsmedizin Berlin, Hessische Str. 3-4, Berlin, 10115, Germany

    Achim Kramer

  2. Ludwig-Maximilians-Universität München, Institute of Medical Psychology, Goethestrasse 31/ I, München, 80336, Germany

    Martha Merrow

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Ortiz-Tudela, E., Mteyrek, A., Ballesta, A., Innominato, P.F., Lévi, F. (2013). Cancer Chronotherapeutics: Experimental, Theoretical, and Clinical Aspects. In: Kramer, A., Merrow, M. (eds) Circadian Clocks. Handbook of Experimental Pharmacology, vol 217. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-25950-0_11

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