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A circadian clock transcription model for the personalization of cancer chronotherapy

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Li, X. -M., Mohammad-Djafari, A., Dumitru, M., Dulong, S., Filipski, E., Siffroi-Fernandez, S., Mteyrek, A., Scaglione, F., Guettier, C., Delaunay, F. and Lévi, Francis A. (2013) A circadian clock transcription model for the personalization of cancer chronotherapy. Cancer Research, Volume 73 (Number 24). pp. 7176-7188. doi:10.1158/0008-5472.CAN-13-1528 ISSN 0008-5472.

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Official URL: http://dx.doi.org/10.1158/0008-5472.can-13-1528

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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 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. Cancer Res; 73(24); 7176–88. ©2013 AACR.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
R Medicine > RC Internal medicine
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Circadian rhythms, Circadian rhythms--Effect of chemicals on, Chemotherapy, Antineoplastic agents
Journal or Publication Title: Cancer Research
Publisher: American Association for Cancer Research
ISSN: 0008-5472
Official Date: 15 December 2013
Dates:
DateEvent
15 December 2013Published
23 October 2013Available
18 October 2013Accepted
31 May 2013Submitted
Volume: Volume 73
Number: Number 24
Number of Pages: 13
Page Range: pp. 7176-7188
DOI: 10.1158/0008-5472.CAN-13-1528
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Funder: European Union (EU), ERASysBio, Association pour la Recherche sur le Temps Biologique et la Chronothérapie (ARTBC)
Grant number: LSHG-CT-2006-037543 (EU), ANR 2009-SYSB-002-01-04 (ERASysBio)

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