A Circadian Clock Transcription Model for the Personalization of Cancer Chronotherapy

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-erb alpha 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-erba and Bmal1 mRNA expressions and for irinotecan chronotoxicity in clock-altered Per2(m/m) mice. The application of a maximum-aposteriori Bayesian inference method identified a linear model based on Rev-erba and Bmal1 circadian expressions that accurately predicted for optimal irinotecan timing. The assessment of the Rev-erba 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. (C) 2013 AACR.