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.
Cancer Res. 2013 Dec 15;73(24):7176-88. doi: 10.1158/0008-5472.CAN-13-1528. Epub 2013 Oct 23.
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.
癌症药物的昼夜节律时间安排已经将治疗耐受性和疗效提高了数倍，但个体间存在差异。使用三种基于 C57BL/6 的雌雄小鼠品系，我们发现伊立替康（一种针对结直肠癌的拓扑异构酶 I 抑制剂）具有三种不同的时间毒性类别，具有不同的昼夜毒性模式。根据稀疏线性判别分析，肝脏和结肠时钟基因 Rev-erbα 和 Bmal1 的 24 小时昼夜表达模式最佳区分了这些时间毒性类别，在 27 个转录 24 小时时间序列中。在 Per2(m/m) 生物钟改变的小鼠中，发现 Rev-erbα 和 Bmal1 mRNA 表达以及伊立替康的时间毒性都提前了 8 小时。最大后验贝叶斯推断方法的应用确定了一个基于 Rev-erbα 和 Bmal1 昼夜表达的线性模型，该模型可以准确预测伊立替康的最佳时间。通过基于数学模型确定宿主特异性最佳时间，评估生物钟中 Rev-erbα 和 Bmal1 的调节转录环，可以显著提高化疗的耐受性。
