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The immune system as a chronotoxicity target of the anticancer mTOR inhibitor everolimus

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Ozturk, Narin, Ozturk, Dilek, Pala-Kara, Zeliha, Kaptan, Engin, Sancar-Bas, Serap, Ozsoy, Nurten, Cinar, Suzan, Deniz, Gunnur, Li, Xiao-Mei, Giacchetti, Sylvie, Lévi, Francis A. and Okyar, Alper (2018) The immune system as a chronotoxicity target of the anticancer mTOR inhibitor everolimus. Chronobiology International, 35 (5). pp. 705-718. doi:10.1080/07420528.2018.1432632

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Official URL: http://dx.doi.org/10.1080/07420528.2018.1432632

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Abstract

The circadian timing system controls many biological functions in mammals including xenobiotic metabolism, detoxification, cell proliferation, apoptosis and immune functions. Everolimus is a mammalian target of rapamycin inhibitor, whose immunosuppressant properties are both desired in transplant patients and unwanted in cancer patients, where it is indicated for its antiproliferative efficacy. Here we sought whether everolimus circadian timing would predictably modify its immunosuppressive effects so as to optimize this drug through timing. C57BL/6J mice were synchronized with light-dark 12h:12h, with L onset at Zeitgeber Time (ZT) 0. Everolimus was administered orally to male (5 mg/kg/day) and female mice (15 mg/kg/day) at ZT1, during early rest span or at ZT13, during early activity span for 4 weeks. Body weight loss, as well as hematological, immunological and biochemical toxicities, were determined. Spleen and thymus were examined histologically. Everolimus toxicity was less severe following dosing at ZT13, as compared to ZT1, as shown with least body weight inhibition in both genders; least reductions in thymus weight both in males (p < 0.01) and females (p < 0.001), least reduction in female spleen weight (p < 0.05), and less severe thymic medullar atrophy both in males (p < 0.001) and females (p < 0.001). The mean circulating counts in total leukocytes, total lymphocytes, T-helper and B lymphocytes displayed minor and non-significant changes following dosing at ZT13, while they were decreased by 56.9% (p < 0.01), 45.5% (p < 0.01), 43.1% (p < 0.05) and 48.7% (p < 0.01) after everolimus at ZT1, respectively, in only male mice. Chronotherapy of everolimus is an effective way to increase the general tolerability and decrease toxicity on the immune system.

Item Type: Journal Article
Divisions: Faculty of Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine
Faculty of Medicine > Warwick Medical School
Journal or Publication Title: Chronobiology International
Publisher: Informa Healthcare
ISSN: 0742-0528
Official Date: 5 February 2018
Dates:
DateEvent
5 February 2018Published
22 January 2018Accepted
Volume: 35
Number: 5
Page Range: pp. 705-718
DOI: 10.1080/07420528.2018.1432632
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access

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