Circadian timing of anticancer medications has improved treatment tolerability and efficacy several-fold, yet with inter-subject 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-h expression patterns of clock genes Rev-erbα and Bmal1 best discriminated these chronotoxicity classes, among 27 transcriptional 24-h 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 Per2m/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. Major findings: The optimal circadian timing of an anticancer drug was predicted despite its variation by up to 8-h along the 24 h among six mouse categories. This prediction relied on a mathematical model using liver circadian expression of clock genes Rev-erbα and Bmal1 as input data and treatment tolerability as output parameter.

A circadian clock transcription model for the personalization of cancer chronotherapy / X. Li, A. Mohammad-Djafari, M. Dumitru, S. Dulong, E. Filipski, S. Siffroi-Fernandez, A. Mteyrek, F. Scaglione, C. Guettier, F. Delaunay, F. Lévi. - In: CANCER RESEARCH. - ISSN 0008-5472. - 73:24(2013 Dec 15), pp. 7176-7188.

A circadian clock transcription model for the personalization of cancer chronotherapy

F. Scaglione;
2013

Abstract

Circadian timing of anticancer medications has improved treatment tolerability and efficacy several-fold, yet with inter-subject 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-h expression patterns of clock genes Rev-erbα and Bmal1 best discriminated these chronotoxicity classes, among 27 transcriptional 24-h 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 Per2m/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. Major findings: The optimal circadian timing of an anticancer drug was predicted despite its variation by up to 8-h along the 24 h among six mouse categories. This prediction relied on a mathematical model using liver circadian expression of clock genes Rev-erbα and Bmal1 as input data and treatment tolerability as output parameter.
Settore BIO/14 - Farmacologia
15-dic-2013
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/229967
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