Abraham, Kristin (2018) In vitro and in vivo chronopharmacology of a new generation of an organometallic anticancer drug complex. PhD thesis, University of Warwick.

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Abstract

The research presented in this thesis has highlighted the complementary and consistent links between in vitro and in vivo chronopharmacology findings, as shown for the anticancer drug candidate FY26. The use of 24-hour temperature schedules as an effective synchroniser of circadian clocks in vitro and that of core body temperature rhythm as a circadian biomarker in vivo has enabled the precise determination of the endogenous circadian times of best tolerability. This was achieved, as physiological rhythm had been introduced into cell culture conditions. Should these results be applicable to humans, least FY26 toxicity could occur at night, shortly after the physiological nadir in core body temperature. More generally, the synchronisation of healthy and cancer cells with 24-h periodic temperature schedules mimicking physiological cycles could have a high potential to identify optimal drug timing options and underlying chronopharmacokinetics and chronopharmacodymics mechanisms, whilst reducing and replacing animal experiments, as illustrated here. This could indeed encourage the integration of chronotherapy concepts into drug development strategies. In such context, the objectives of animal chronotherapy studies might hence become mostly confirmatory. Thus, the use of core body temperature circadian cycle appears not only as crucial for the determination of the circadian timing resulting in best drug tolerability, antitumour efficacy, and quality of life, but it is also in agreement with the principles of the 3 R’s (reduction, refinement and replacement) and the public ethical opinion on animal experiments.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Library of Congress Subject Headings (LCSH):	Chronopharmacology, Circadian rhythms, Cancer -- Research, Cancer -- Treatment
Official Date:	August 2018
Dates:	Date Event August 2018 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Lévi, Francis A. ; Dallmann, Robert
Format of File:	pdf
Extent:	308 leaves : illustrations, charts
Language:	eng

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