Circadian Regulation of Drug Responses: Toward Sex-Specific and Personalized Chronotherapy

The Annual Review of Pharmacology and Toxicology, Journal Year: 2023, Volume and Issue: 64(1), P. 89 - 114

Published: Sept. 19, 2023

Today's challenge for precision medicine involves the integration of impact molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements tolerability and/or medications through proper administration timing have been confirmed over past decade immunotherapy chemotherapy against cancer, as well commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, neurological conditions. Experimental human studies recently revealed sexually dimorphic circadian responses. Dedicated randomized clinical trials should now aim to issue recommendations daily medical practice, integrating innovative technologies remote longitudinal monitoring metrics, statistical prediction clock function from single-timepoint biopsies, multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust function, who would benefit most chronotherapy, need be identified. Conversely, nonchronofit could emerging class chronobiotics targeting clock.

Language: Английский

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Sex‐dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial

Cancer Medicine, Journal Year: 2020, Volume and Issue: 9(12), P. 4148 - 4159

Published: April 22, 2020

Abstract The least toxic time (LTT) of irinotecan varied by up to 8 hours according sex and genetic background in mice. translational relevance was investigated within a randomized trial dataset, where no LTT stood out significantly the whole population. 130 male 63 female eligible patients with metastatic colorectal cancer were receive chronomodulated Irinotecan peak delivery rate at 1 6 clock staggered 4 on day 1, then fixed‐time Fluorouracil‐Leucovorin‐Oxaliplatin for days, q3 weeks. sex‐specific circadian characteristics grade (G) 3‐4 toxicities mapped cosinor time*sex interactions confirmed Fisher's exact test. Baseline or similar six treatment groups. Main over courses diarrhea (males vs females, 39.2%; 46.0%), neutropenia (15.6% 15.0%), fatigue (11.5% 15.9%), anorexia (10.0% 7.8%). They reduced following morning males, but afternoon statistically significant rhythms ( P < .05 from cosinor) sex*timing (Fisher's test, diarrhea, = .023; neutropenia, .015; fatigue, .062; anorexia, .032). timing most critical grades ranging 55.2% (morning) 29.4% (afternoon) 25.9% 0% neutropenia. study results support administration males order minimize adverse events without impairing efficacy.

Language: Английский

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Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling

Molecular Cancer Therapeutics, Journal Year: 2015, Volume and Issue: 14(9), P. 2154 - 2164

Published: July 4, 2015

Abstract Cancer chronotherapy aims at enhancing tolerability and efficacy of anticancer drugs through their delivery according to circadian clocks. However, mouse patient data show that lifestyle, sex, genetics, drugs, cancer can modify both host clocks metabolism pathways dynamics, thus the optimal timing drug administration. The mathematical modeling chronopharmacology could indeed help moderate patient-specific determinants. Here, we combine in vitro silico methods, order characterize critical molecular drive irinotecan, a topoisomerase I inhibitor with complex known activity against colorectal cancer. Large transcription rhythms moderated bioactivation, detoxification, transport, target synchronized cell cultures. These translated into statistically significant changes pharmacokinetics pharmacodynamics timing. top-up multiple coordinated resulted four-fold difference irinotecan-induced apoptosis Irinotecan cytotoxicity was directly linked clock gene BMAL1 expression: least from exposure near mRNA nadir (P &lt; 0.001), whereas silencing siBMAL1 ablated all mechanisms. Mathematical highlighted bioactivation detoxification as most determinants irinotecan chronopharmacology. In vitro–in systems is new powerful methodology for identifying main mechanisms work optimize delivery. Mol Ther; 14(9); 2154–64. ©2015 AACR.

Language: Английский

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The utility of Apc-mutant rats in modeling human colon cancer

Disease Models & Mechanisms, Journal Year: 2014, Volume and Issue: unknown

Published: Jan. 1, 2014

Prior to the advent of genetic engineering in mouse, rat was model choice for investigating etiology cancer. Now, recent advances manipulation genome, combined with a growing recognition physiological differences between mice and rats, have reignited interest as human Two recently developed models, polyposis colon (Pirc) Kyoto Apc Delta (KAD) strains, each carry mutations intestinal-cancer-associated adenomatous coli (Apc) gene. In contrast mouse models carrying mutations, which cancers develop mainly small intestine rather than there is no gender bias, these exhibit colonic predisposition gender-specific susceptibility, seen The also provides other experimental resources organism that are not provided by mouse: structure its chromosomes facilitates analysis genomic events, size permits longitudinal tumor growth, biological samples from animal multiplexed molecular analyses host. Thus, underlying biology provide important avenues investigation. We anticipate disease modeling will synergize being deeper understanding

Language: Английский

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Clock gene Per2 as a controller of liver carcinogenesis

Oncotarget, Journal Year: 2016, Volume and Issue: 7(52), P. 85832 - 85847

Published: Aug. 3, 2016

// Ali Mteyrek 1 , Elisabeth Filipski Catherine Guettier 2 Alper Okyar 3 Francis Lévi 1, 2, 4 INSERM and Paris Sud University, UMRS 995, Team « Cancer Chronotherapy Postoperative Liver », Campus CNRS, Villejuif F-94807, France Assistance Publique-Hopitaux de Paris, Department of Medical Oncology Laboratory Anatomy Pathologic Cytology, Hôpital Paul Brousse, F-94800, Istanbul University Faculty Pharmacy, Pharmacology, Beyazit TR-34116, Istanbul, Turkey Warwick School, Unit, Coventry, CV4 7AL, United Kingdom Correspondence to: Lévi, email: [email protected] Keywords: Circadian rhythm, Per2 gene, Hepatocellular carcinoma, Molecular clock, Cell cycle genes Received: May 12, 2016     Accepted: July 13, Published: August 03, 2016 ABSTRACT Environmental disruption molecular clocks promoted liver carcinogenesis accelerated cancer progression in rodents. We investigated the specific role clock gene Period (Per2) for clock-controlled cellular proliferation, genomic instability inflammation. assessed histopathology, determined physiology circadian patterns mice on chronic diethylnitrosamine (DEN) exposure according to constitutive mutation. First, we found that m/m displayed profound alterations proliferation expression, including c-Myc derepression, phase-advanced Wee1, arrhythmic Ccnb1 K-ras mRNA expressions, as well deregulated inflammation, through IL-6 protein concentration, absence any DEN exposure. These changes could then make more prone subsequently develop cancers DEN. Indeed, primary were nearly fourfold frequent compared wild-type (WT), months after The was severely disrupted throughout whole process, initiation stage, i.e. within initial 17 days further exhibited increased mean 24h lack P53 response, ATM, Wee1 expressions. DEN-induced tumor related inflammation concentrations TNF-α WT during initiation. mutation or expressions three hallmarks, uncontrolled instability, promoting several-fold. Clock acted here a suppressor from progression.

Language: Английский

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Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A

EBioMedicine, Journal Year: 2019, Volume and Issue: 45, P. 139 - 154

Published: July 1, 2019

The identification of new biomarkers and the development novel, targetable contexts vulnerability are urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression genes involved angiogenesis tumour progression. We hypothesised that BMAL1 increases vascular endothelial growth A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), clinically used antibody for neutralization VEGFA.PCR immunohistochemistry were employed assess mice (C57BL/6 J Apcmin/+; BALB/c nu/nu xenografts) CRC patients under combination chemotherapy Beva. single nucleotide polymorphisms (SNPs) analysed by DNA-microarray samples. functions studied human cell lines using colorimetric growth, DNA-binding reporter assays.In murine CRCs, high correlated poor preclinical response Beva treatment. In patients' tumours (n = 74), was associated non-response (*p .0061) reduced progression-free survival (PFS) [*p .0223, Hazard Ratio (HR) 1.69]. SNPs also shorter PFS (rs7396943, rs7938307, rs2279287) overall (OS) [rs11022780, *p .014, HR 1.61]. Mechanistically, Nuclear-Receptor-Subfamily-1-Group-D-Member-1 (NR1D1/REVERBA) bound - 672 bp Retinoic-Acid-Receptor-Related-Orphan-Receptor-Alpha-responsive-element (RORE) adjacent motif (E-box) promoter, resulting increased synthesis proliferation lines.BMAL1 CRC. Inhibition REVERBA-BMAL1 signalling may prevent therapy. FUND: This work part supported European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]).

Language: Английский

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Impact of Shift Work on the Circadian Timing System and Health in Women

Sleep Medicine Clinics, Journal Year: 2018, Volume and Issue: 13(3), P. 295 - 306

Published: Aug. 8, 2018

Language: Английский

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Optimizing circadian drug infusion schedules towards personalized cancer chronotherapy

PLoS Computational Biology, Journal Year: 2020, Volume and Issue: 16(1), P. e1007218 - e1007218

Published: Jan. 27, 2020

Precision medicine requires accurate technologies for drug administration and proper systems pharmacology approaches patient data analysis. Here, plasma pharmacokinetics (PK) of the OPTILIV trial in which cancer patients received oxaliplatin, 5-fluorouracil irinotecan via chronomodulated schedules delivered by an infusion pump into hepatic artery were mathematically investigated. A pump-to-patient model was designed order to accurately represent solution dynamics from blood. It connected semi-mechanistic PK models analyse inter-patient variability parameters. Large time delays up 1h41 between actual start detection blood predicted confirmed data. Sudden delivery spike due glucose rinse after accounted 10.7% total dose. New model-guided profiles precisely lead exposure intended clinicians. Next, complete mathematical framework achieved a very good fit individual time-concentration concluded that inter-subject differences parameters lowest irinotecan, intermediate oxaliplatin largest 5-fluorouracil. Clustering according their parameter values revealed subgroups each largely decreased compared population. This study provides optimize pumps inform on variability, step towards precise personalized chronotherapy.

Language: Английский

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Role of the Immune System and the Circadian Rhythm in the Pathogenesis of Chronic Pancreatitis

Pancreas, Journal Year: 2020, Volume and Issue: 49(8), P. 1024 - 1032

Published: Aug. 20, 2020

Pancreatitis, in both acute and chronic forms, poses a major therapeutic challenge is associated with great morbidity several complications. The nature of pancreatic injury pancreatitis (CP) the wide range causative processes that lead to CP have made effective therapy true unmet need. Multiple physiological, genetic, environmental, behavioral factors contribute development CP. As result, fields research are aimed at identifying addressing injury. In this article, we review current understanding pathogenesis natural history We focus on autonomous nervous system, immune role chronobiological approach alleviate symptoms prevent or reverse aim demonstrate individualizing chronopharmacological treatments for promising direction future treatment using immune, nervous, circadian systems.

Language: Английский

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A mathematical model of the circadian clock and drug pharmacology to optimize irinotecan administration timing in colorectal cancer

Computational and Structural Biotechnology Journal, Journal Year: 2021, Volume and Issue: 19, P. 5170 - 5183

Published: Jan. 1, 2021

Scheduling anticancer drug administration over 24 h may critically impact treatment success in a patient-specific manner. Here, we address personalization of timing using novel mathematical model irinotecan cellular pharmacokinetics and –dynamics linked to representation the core clock predict toxicity colorectal cancer (CRC) model. The is fitted three different scenarios: mouse liver, where metabolism mainly occurs, two human cell lines representing an vitro experimental system for progression. Our successfully recapitulates quantitative circadian datasets mRNA protein expression together with timing-dependent cytotoxicity data. also discriminates time-dependent between cells, suggesting that can be optimized according their clock. results show degradation mediating activation, as well oscillation death rate play important role variations toxicity. In future, this used support personalized scheduling by predicting optimal based on patient's gene profile.

Language: Английский

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