The Library
The immune system as a chronotoxicity target of the anticancer mTOR inhibitor everolimus
Tools
Tools
Tools
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
Research output not available from this repository, contact author.
Official URL: http://dx.doi.org/10.1080/07420528.2018.1432632
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: |
|
||||||
| 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 |
Request changes or add full text files to a record
Repository staff actions (login required)
 |
View Item |
