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Cancer Res. 2013 Dec 15;73(24):7176-88. doi: 10.1158/0008-5472.CAN-13-1528. Epub 2013 Oct 23.

A circadian clock transcription model for the personalization of cancer chronotherapy.

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Authors' Affiliations: INSERM UMRS 776 «Rythmes biologiques et cancers», Assistance Publique-Hôpitaux de Paris, Laboratoire d'Anatomie et Cytologie Pathologiques, Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département d'Oncologie Médicale, Hôpital Paul Brousse, Villejuif; Université Paris-Sud, Orsay; Laboratoire des Signaux et Systèmes, UMR8506 CNRS-SUPELEC-UNIV PARIS-SUD, Gif-sur-Yvette; University de Nice-Sophia-Antipolis, Institute de Biologie Valrose, CNRS UMR 7277, INSERM 1091, Nice, France; and Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.


Circadian timing of anticancer medications has improved treatment tolerability and efficacy several fold, yet with intersubject variability. Using three C57BL/6-based mouse strains of both sexes, we identified three chronotoxicity classes with distinct circadian toxicity patterns of irinotecan, a topoisomerase I inhibitor active against colorectal cancer. Liver and colon circadian 24-hour expression patterns of clock genes Rev-erbα and Bmal1 best discriminated these chronotoxicity classes, among 27 transcriptional 24-hour time series, according to sparse linear discriminant analysis. An 8-hour phase advance was found both for Rev-erbα and Bmal1 mRNA expressions and for irinotecan chronotoxicity in clock-altered Per2(m/m) mice. The application of a maximum-a-posteriori Bayesian inference method identified a linear model based on Rev-erbα and Bmal1 circadian expressions that accurately predicted for optimal irinotecan timing. The assessment of the Rev-erbα and Bmal1 regulatory transcription loop in the molecular clock could critically improve the tolerability of chemotherapy through a mathematical model-based determination of host-specific optimal timing.

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