Abstract
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.
Highlights
A significant improvement in the safety of cancer therapies could result from adequate drug timing within the 24 hours, as Authors' Affiliations: 1INSERM UMRS 776 «Rythmes biologiques et cancers», 2Assistance Publique-Ho^pitaux de Paris, Laboratoire d'Anatomie et Cytologie Pathologiques, 3Assistance Publique-Ho^pitaux de Paris, Unite de Chronotherapie, Departement d'Oncologie Medicale, Ho^pital Paul Brousse, Villejuif; 4Universite Paris-Sud, Orsay; 5Laboratoire des Signaux et Systemes, UMR8506 CNRS-SUPELEC-UNIV PARIS-SUD, Gif-surYvette; 6University de Nice-Sophia-Antipolis, Institute de Biologie Valrose, CNRS UMR 7277, INSERM 1091, Nice, France; and 7Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, ItalyNote: Supplementary data for this article are available at Cancer Research Online.Ó2013 American Association for Cancer Research.shown in international randomized trials [1]
We studied clock genes Rev-erba, Per2, and Bmal1 and clock-controlled genes involved in irinotecan metabolism—CES2, Top1, UGT1A1, and DBP; cell cycle—Wee1, Ccna2, Ccnb2, and p21; and apoptosis— Bcl2, Mdm2, Bax, and p53
Our study is the first one that showed that optimal chemotherapy timing could be predicted by clock gene expression
Summary
The timing of best drug tolerability coincided with that of best efficacy [1, 4,5,6] This puzzling finding was best explained both by the disruption of circadian clocks and by cell-cycle variability in cancer cells [7]. The delivery of medications according to circadian timing could shift the current cancer treatment paradigm from "the worse the toxicity, the better the efficacy" toward "the better the tolerability, the better the efficacy" [1, 6, 8]. A molecular clock ticks within most body cells through 3 main interwoven transcriptional/posttranslational feedback loops.
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