Data from A Circadian Clock Transcription Model for the Personalization of Cancer Chronotherapy

Abstract

<div>Abstract<p>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 <i>Rev-erbα</i> and <i>Bmal1</i> 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 <i>Rev-erbα</i> and <i>Bmal1</i> mRNA expressions and for irinotecan chronotoxicity in clock-altered <i>Per2<sup>m/m</sup></i> mice. The application of a maximum-<i>a</i>-posteriori Bayesian inference method identified a linear model based on <i>Rev-erbα</i> and <i>Bmal1</i> circadian expressions that accurately predicted for optimal irinotecan timing. The assessment of the <i>Rev-erbα</i> and <i>Bmal1</i> 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. <i>Cancer Res; 73(24); 7176–88. ©2013 AACR</i>.</p></div>