Abstract
The circadian timing system (CTS) controls various biological functions in mammals including xenobiotic metabolism and detoxification, immune functions, cell cycle events, apoptosis and angiogenesis. Although the importance of the CTS is well known in the pharmacology of drugs, it is less appreciated at the clinical level. Genome-wide studies highlighted that the majority of drug target genes are controlled by CTS. This suggests that chronotherapeutic approaches should be taken for many drugs to enhance their effectiveness. Currently chronotherapeutic approaches are successfully applied in the treatment of different types of cancers. The chronotherapy approach has improved the tolerability and antitumor efficacy of anticancer drugs both in experimental animals and in cancer patients. Thus, chronobiological studies have been of importance in determining the most appropriate time of administration of anticancer agents to minimize their side effects or toxicity and enhance treatment efficacy, so as to optimize the therapeutic ratio. This review focuses on the underlying mechanisms of the circadian pharmacology i.e., chronopharmacokinetics and chronopharmacodynamics of anticancer agents with the molecular aspects, and provides an overview of chronotherapy in cancer and some of the recent advances in the development of chronopharmaceutics.
Highlights
Circadian rhythms are oscillations in the behavior and biochemical reactions of organisms, and occur with a periodicity of approximately twenty-four hours [1,2]
Gorbacheva et al [69] indicated that mice with a Bmal1 null allele or a mutation of the Clock gene exhibited enhanced sensibility to the toxic effect of the anticancer drug cyclophosphamide, mice lacking of two Cry genes were more resistant to the toxic effect. These findings suggest that the circadian clock is directly involved in the chronotoxicity of drugs, via regulating genes involved in drug metabolism directly or through the circadian clock-regulated transcription factors [35]
Pharmaceutical industry, local drug authorities and clinicians should consider the effects of circadian rhythms on the efficacy and/or tolerability of drugs, and drug dosing time which is a critical factor should not be underestimated
Summary
Circadian rhythms are oscillations in the behavior and biochemical reactions of organisms, and occur with a periodicity of approximately twenty-four hours (cf Latin circa, or “about”, and dies, or “day”) [1,2]. Because the environmental changes that accompany the day are so predictable, nature has devised an ingenious system, the circadian clock, to anticipate these changes and regulate physiology and behavior [3,4,5]. The circadian clock regulates the timing of sleep and wakefulness, and all dependent behavioral and physiological processes. A defect in the clock gene Period (PER2) produces familial advanced sleep phase syndrome (FASPS) [10,11], and an analogous mutation causes the same phenotype in mice [12]. A human Circadian Locomotor Output Cycles Kaput (CLOCK) variant is associated with diurnal sleep preference [15]. Impairment of the CTS in cancer patients is concerned with many various systemic symptoms with the inclusion of fatigue, sleep disorders, body weight loss due to appetite loss in addition to poor therapeutic outcomes [23,26,27,28]
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