title: A circadian clock transcription model for the personalization of cancer chronotherapy.
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 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.
authors.affiliation: 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.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Li
authors.forename: Ali
authors.initials: A
authors.lastname: Mohammad-Djafari
authors.forename: Mircea
authors.initials: M
authors.lastname: Dumitru
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dulong
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Filipski
authors.forename: Sandrine
authors.initials: S
authors.lastname: Siffroi-Fernandez
authors.forename: Ali
authors.initials: A
authors.lastname: Mteyrek
authors.forename: Francesco
authors.initials: F
authors.lastname: Scaglione
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.forename: Franck
authors.initials: F
authors.lastname: Delaunay
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019454:Chronotherapy / Q000379:methods*; D057906:Circadian Clocks / Q000235:genetics*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000077146:Irinotecan; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008954:Models, Biological; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics; D056950:Period Circadian Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D057285:Precision Medicine / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin