Chronopharmacological strategies: Intra- and inter-individual variability of molecular clock

Advanced Drug Delivery Reviews 62 (2010) 885–897

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Advanced Drug Delivery Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Chronopharmacological strategies: Intra- and inter-individual variability of molecular clock☆ Shigehiro Ohdo ⁎, Satoru Koyanagi, Naoya Matsunaga Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

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Article history: Received 7 January 2010 Accepted 7 April 2010 Available online 2 June 2010 Keywords: Chronopharmacology Clock gene Intra-individual variability Inter-individual variability Gene delivery

a b s t r a c t In all living organisms, one of the most indispensable biological functions is the circadian clock (suprachiasmatic nuclei; SCN), which acts like a multifunction timer to regulate homeostatic systems such as sleep and activity, hormone levels, appetite, and other bodily functions with 24 h cycles. Circadian rhythms regulate diverse physiologic processes, including homeostatic functions of steroid hormones and their receptors. Perturbations of these rhythms are associated with pathogenic conditions such as depression, diabetes and cancer. Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior. Clock gene regulates several diseases such as cancer, metabolic syndrome and sleep etc. CLOCK mutation affects the expression of rhythmic genes in wild-type (WT) tissue, but also affects that of non-rhythmic genes. On the other hand, the change of the drug pharmacodynamic and pharmacokinetic (PK/PD) parameters are influenced by not only inter-individual variability but also intra-individual variabilities of medications. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. The mechanisms underlying chronopharmacological findings should be clarified from viewpoint of clock genes. On the other hand, several drugs have an effect on molecular clock. Thus, the knowledge of intra- and inter-individual variability of molecular clock should be applied for the clinical practice. Therefore, we introduce the regulatory system of biological rhythm from viewpoints of clock genes and the possibility of pharmacotherapy based on the intra- and inter-individual variability of clock genes. © 2010 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . Biological clock . . . . . . . . . . . . . . . . . . . Intra- and inter-individual variability of clock genes and Chronobiology of physiological function and diseases. . 4.1. Cardiovascular disease . . . . . . . . . . . . . 4.2. Metabolic syndrome . . . . . . . . . . . . . . 4.3. Sleep disorder . . . . . . . . . . . . . . . . . 5. Chronopharmacodynamics . . . . . . . . . . . . . . 6. Chronopharmacokinetics . . . . . . . . . . . . . . . 7. The disruption and maintenance of biological rhythms . 8. The adjustment and manipulation of biological rhythms 9. Necessary of clock gene delivery on cancer therapy . . 10. Conclusions . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . chronopharmacological strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Chrono-Drug-Delivery Focused on Biological Clock: Intra- and Inter-Individual Variability of Molecular Clock”. ⁎ Corresponding author. Tel.: + 81 92 642 6610; fax: + 81 92 642 6614. E-mail address: [email protected] (S. Ohdo). 0169-409X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2010.04.005

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1. Introduction The study on the individualization of pharmacotherapy has been carried out aiming at further improvement of pharmacotherapy. The study of correlations between genome variation and phenotype diversity is a key theme in modern biosciences. Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity [1]. By doing so, pharmacogenomics aims at developing rational means to optimize drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of “personalized medicine”; in which drugs and drug combinations are optimized for each individual's unique genetic makeup [2]. The conventional method of classifying the pharmaceutical variations stated that there are two major classes of variabilities such as inter-individual and intra-individual variabilities. Basic pharmacotherapeutic researches have focused only on the interindividual variability of drug pharmacodynamic and pharmacokinetic (PK/PD). The pharmacogenomic/pharmacogenetic studies have disclosed the molecular mechanism of the inter-individual variability taking different levels ranging from the different heritable chromosomes to the protein polymorphism due to point mutations among species of the same gene at the translation and post-translation stages [3–5]. This traditional way of thinking stated that diseases are emerged due to either increased or decreased genetic expression of certain molecular targets. This hypothesis did not take the intraindividual variability in its consideration. It was before the discovery of the clock and clock-controlled genes in mammal in 1997 that enables practitioners to use medications more effectively and safely [6]. The intra-individual variability as well as inter-individual variability should be considered to aim at further improvement of rational pharmacotherapy. Because many drugs vary in potency and/or toxicity associated with the rhythmicity of biochemical, physiological and behavioral processes [7–13]. Theoretically, it has been argued that drug administration at certain times of the day should improve the outcome of pharmacotherapy. This has been accepted by the medical community and/or described in an interview form for the treatment of nocturnal asthma, allergic rhinitis, arthritis, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. However, several drugs are still given without regard to the time-of-day. The chronopharmacological findings should be systematically summarized in an applicable format for clinical practice. In all living organisms, one of the most indispensable biological functions is the circadian clock (suprachiasmatic nuclei; SCN), which acts like a multifunction timer to regulate homeostatic systems such as sleep and activity, hormone levels, appetite, and other bodily functions with 24 h cycles [14,15]. Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior [16]. Circadian rhythms regulate diverse physiologic processes, including homeostatic functions of steroid hormones and their receptors. Perturbations of these rhythms are associated with pathogenic conditions such as depression, diabetes, and cancer. Clock gene regulates several diseases such as cancer, metabolic syndrome and sleep etc. CLOCK mutation affects the expression of rhythmic genes in wild-type (WT) tissue, but also affects that of non-rhythmic genes. The knowledge of intra- and interindividual variability of molecular clock should be applied for the clinical practice. The monitoring of rhythm, overcome of rhythm disruption and manipulation of rhythm from viewpoints of molecular clock are essential to improved progress and diffusion of chronopharmacotherapy. Such approach should be achieved by the new challenges in drug delivery system that match the circadian rhythm (Chrono-DDS) [11,12]. Recent strategy on pharmacotherapy has been focused on gene delivery and antibody delivery targeting specific

molecular for some diseases. Clock genes should be also one of important candidates. Therefore, the aim of this review is to provide an overview of the regulatory system of biological rhythm from viewpoints of clock genes and the possibility of pharmacotherapy based on the intra- and inter-individual variability of clock genes. 2. Biological clock The SCN of the anterior hypothalamus are the site of the circadian pacemaker in mammals [14]. Like any timing system, the circadian clock is made up of three components [15–17]: an input pathway adjusting the time, a central oscillator generating the circadian signal, and an output pathway manifesting itself in circadian physiology and behavior. The daily changes in light intensities are thought to be the major environmental cue involved in circadian entrainment. Light-signals are perceived by photoreceptor cells in the retina and transmitted to neurons of the SCN via the retinohypothalamic tract [15]. A great deal of research shows that the inherited period of the human pacemaker clock is not precisely 24 h. In fact, in most people, it is somewhat longer, closer to 25 h. Environmental time cues, termed synchronizers or zeitgebers, the strongest one being the daily light–dark cycle occurring in conjunction with the wake–sleep routine, set the inherited pacemaker circadian timekeeping systems to 24 h each day. Clock genes are the genes that control the circadian rhythms in physiology and behavior [6]. Three mammalian clock genes (Per1, Per2 and Per3) are rhythmically expressed in the SCN. Per1 and Per2 are induced in response to light [18]. In particular, Per1 induction is considered to be an initial event in light-induced resetting and entrainment of the circadian biological clock [15]. The transcriptional machinery of the core clockwork regulates a clock-controlled rhythm as shown in Fig. 1 [16–20]. Namely, CLOCK-BMAL1 heterodimers act through an E-box enhancer to activate the transcription of Pers, vasopressin and Dbp mRNA showing a specific output function [16,17,19]. This activation can be inhibited by the PER and CRY proteins [20]. A circadian rhythm of Pers mRNA expression is discovered not only in the SCN but also in other tissues [21]. The circadian rhythm in the periphery is governed by that in the SCN, since the circadian rhythm in physiological function and Pers mRNA expression are abolished in SCNlesioned rats [21] and Clock mutant mice [16]. Such a cascade of clock

Fig. 1. Simplified model of the dual regulation of a core feedback loop [16–20]. Heterodimers of CLOCK and BMAL1 activate transcription of clock genes and clockcontrolled genes. The PER and CRY proteins shut down CLOCK–BMAL1 transcription in the nucleus, forming a negative feedback loop. The phosphorylation of PER1 (period) and PER2 by CKIε(casein kinase I epsilon) may regulate their cellular location and stability. Clockcontrolled genes products, which include DBP (D-element binding protein), and AVP (arginine vasopressin), transduce the core oscillation to downstream output systems. The monitoring of rhythm, overcome of rhythm disruption and manipulation of rhythm from viewpoints of molecular clock are essential to improved progress and diffusion of chronopharmacotherapy. Chrono-DDS may benefit the development of new therapeutic strategies for several diseases associated with the delivery of clock gene.

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genes may contribute to the organization of biological rhythms in the whole body. However, the mechanisms employed by circadian output pathways are poorly understood but are likely to involve both nervous and humoral signals [22,23]. Plasma glucocorticoid levels show a circadian rhythm via the HPA axis under the control of the SCN. Glucocorticoids regulate various physiological responses and developmental processes by binding to and modulating the transcriptional activity of their cognate nuclear receptor (GR) [24,25]. A transit induction of Per1 and Dbp mRNA levels is observed by a single administration of dexamethasone [25]. Glucocorticoid hormones are particularly attractive candidates, since they are endogenous substances and play an important role in the entrainment of peripheral oscillators but not SCN [25]. The regulatory system of biological rhythm should be clarified in detail from viewpoints of clock genes. 3. Intra- and inter-individual variability of clock genes and chronopharmacological strategy Clock genes “the intra-individual variables” are subjected to genetic variations “the inter-individual variability”. Clock gene in Clock mutant mice has a point mutation causing the deletion of exon 19 (51 amino acids) of the clock gene, thus synthesizing mutant CLOCK protein (CLOCKΔ19) deficient in transcriptional activity [26]. CLOCK mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase–response curve amplitude [27]. Comparing between these two genotypes, clear interindividual variabilities are demonstrated between them. Some clockcontrolled genes showed altered rhythmicity and some others showed either increased or damped rhythmicity. For example, Dbp showed overall down-regulated damped rhythmicity, Tmlhe showed upregulated damped rhythmicity and Casp6 showed peak-shifted rhythmicity (Fig. 2) [28,29]. The complete cohort of genes that are transcriptionally regulated by CLOCK are identified using regular DNA array interrogating assay interrogating the mouse protein-encoding transcriptome measuring the gene expression in different tissues of WT and Clock mutant type and/or circadian rhythms [29]. CLOCK mutation affects the expression of many genes that are rhythmic in WT tissue, but also profoundly affects many non-rhythmic genes. So, clock-controlled genes can show either rhythmic or constant levels of expression. Some researchers did not consider non-rhythmic type of clock-controlled genes and only studied the rhythmically clock-controlled genes. As an example of the rhythmic clock-controlled genes, plasminogen activator inhibitor 1 (Pai-1) mRNA shows a peak at the early dark phase with robust rhythmic expression (Fig. 3) [30]. In the Clock mutant phenotype, this rhythmic expression is damped to the trough mRNA levels. On the other hand, N-methylpurine-DNA glycosylase (MPG) is an example of non-rhythmically clockcontrolled gene (Fig. 3) [31]. It shows statistically non-rhythmic mRNA level throughout the 24 h. Clock mutant phenotype shows statistically non-rhythmic damped mRNA level. The Clock mutant phenotype is hyperphagic, obese, hypersensitive to chemotherapeutic agent, decreased time of sleep time, and suffered from mania [32]. The treatment of hyperphagic syndrome should be by chrono- or intelligent drug delivery system due to the dependence on the 24 h of administration. To the contrary, the treatment of hypersensitivity to the chemotherapeutic agents may not be affected by the 24 h time by the administration of the MPG gene which shows no 24 h rhythmicity [31]. Most chronobiologists concentrate in their research on the circadian rhythmically oscillated clock-controlled genes. They do not pay attention to some non-rhythmically clock-controlled genes. This may be due to chromatin remodeling of the promoter region, stability of the mRNA, etc. This observation has a great therapeutic importance. To treat such condition, it does not require taking in to consideration the time of the drug administration. This model may expand the field of chronopharmacotherapy from time-dependent

Fig. 2. The influence of CLOCK mutation on circadian rhythm of several genes in WT mice [29]. The fluorescence intensity (y-axis) versus hours in dark–dark cycle (x-axis) showed the effect of CLOCK mutation on the wild-type clock-controlled genes in mouse liver cells. (A) Overall down regulation e.g. Dbp, (B) overall upregulation e.g. Tmlhe and (C) peakshifted e.g. Casp6. Solid line and closed circle represent the genetic expression in wild-type cells. Dashed line and open circle represent the genetic expression in Clock mutant cells. Proc. Natl. Acad. Sci. U. S. A. 104 (9) (2007 Feb 27) 3342–3347. Copyright (2007) National Academy of Science, USA.

therapy to non-time-dependent therapy, may open new era of discovery of modern molecular targets and new drugs and may decrease the distance between the inter- and intra-individual variabilities in considering the best dosing schedule to achieve the maximum therapeutic efficacy and/or the minimum side effects. By taking the intra- and inter-individual variability of molecular clock into consideration, the identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. To monitor the rhythmic marker such as clock genes it may be useful to choose the most appropriate time-ofday for administration of drugs that may increase their therapeutic effects and/or reduce their side effects. Furthermore, to produce new rhythmicity by manipulating the conditions of living organs by using rhythmic administration of altered feeding schedules or several drugs appears to lead to the new concept of chronopharmacotherapy. Attention should be paid to the alteration of clock genes expression and consider it an adverse effect, when it leads to altered regulation of the circadian system which is a serious problem affecting basic functioning of living organisms. One approach to increasing the

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and/or intensity of the symptoms of disease vary predicably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. The regulatory mechanisms underlying 24 h rhythm of physiological function and diseases should be clarified from viewpoints of clock genes.

4.1. Cardiovascular disease The onset of myocardial infarction occurs frequently in the early morning, and it may partly result from circadian rhythm of fibrinolytic activity. PAI-1 activity shows a circadian rhythm [35]. Basic helix-loophelix (bHLH)/PAS domain transcription factors play a crucial role in controlling the biological clock that controls circadian rhythm. A novel bHLH/PAS protein, cycle-like factor (CLIF) is isolated from human umbilical vein endothelial cells. CLIF shares high homology with Drosophila CYCLE, one of the essential transcriptional regulators of circadian rhythm. CLIF is expressed in endothelial cells and neurons in the brain, including the SCN. In endothelial cells, CLIF forms a heterodimer with CLOCK and up-regulates the Pai-1 gene through E-box sites. Furthermore, PER2 and CRY1 inhibit the Pai-1 promoter activation by the CLOCK:CLIF heterodimer. Namely, CLIF regulates the circadian rhythm of Pai-1 gene in endothelial cells. In addition, the results potentially provide a molecular basis for the morning onset of myocardial infarction.

4.2. Metabolic syndrome

Fig. 3. The effect of CLOCK mutation on both rhythmic and non-rhythmic clock-controlled genes [30,31]. (A) Temporal expression profile of plasma Pai-1 mRNA levels both in wildtype and Clock mutant mice tissues. Reproduction with permission from [Ohkura N. et al. J. Thromb Haemost. 4, 2478-2485, 2006. Wiley-Blackwell]. (B) Temporal expression profiles of MPG mRNA in liver of wild-type and Clock mutant mice. Solid line and closed circle represent the genetic expression in wild-type cells. Dashed line and open circle represent the genetic expression in clock mutant cells. Each value represents the mean±S.E. (n= 3). *P b 0.05 when compared with wild-type mice. Reproduced with permission from [31].

efficiency of pharmacotherapy is administering drugs at times during which they are best tolerated. The monitoring of rhythm, overcome of rhythm disruption and manipulation of rhythm from viewpoints of molecular clock as shown in Fig. 1 are essential to improved progress and diffusion of chronopharmacotherapy. Thus, elucidating the connections between clock genes and PK or PD could benefit the development of new therapeutic strategies for several diseases associated with delivery of clock gene.

4. Chronobiology of physiological function and diseases Chronotherapeutic approach is based on the presence of 24 h rhythms in physiological functions and diseases. The knowledge of 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy (chronotherapy) [33,34]. Chronotherapy is especially relevant in the following cases. The risk

BMAL1 is a transcription factor controlling circadian rhythm and contributes to the control of adipogenesis and lipid metabolism activity in mature adipocytes [36]. The level of Bmal1 mRNA increases during adipose differentiation in 3T3-L1 cells. In white adipose tissues isolated from mice, BMAL1 is more highly expressed in the adipocytes fraction than the stromal-vascular fraction. Bmal1 knockout mice embryonic fibroblast cells fail to be differentiated into adipocytes. Adding BMAL1 back by adenovirus gene transfer restores the ability of Bmal1 knockout mice embryonic fibroblast cells to differentiate. Knock-down of Bmal11 expression in 3T3-L1 cells allows the cells to accumulate only minimum amounts of lipid droplets in the cells. Adenovirus-mediated expression of Bmal1 in 3T3-L1 adipocytes results in induction of several factors involved in lipogenesis. The promoter activity of these genes is stimulated in a BMAL1-dependent manner. These factors show a circadian rhythm in mice adipose tissue. Furthermore, overexpression of BMAL1 in adipocytes increases lipid synthesis activity. Thus, BMAL1 plays important roles in the regulation of adipose differentiation and lipogenesis in mature adipocytes.

4.3. Sleep disorder A sleep disorder in humans is associated with a genetic mutation affecting circadian clock function. Familial advanced sleep-phase syndrome (FASPS) is documented in three families [37]. Affected individuals experience early evening sleepiness (around 19:30) and early morning awakening (around 04:30). Individuals with FASPS have a circadian period about an hour shorter than normal. Taking one of the FASPS families, Toh uses multiple sets of dense genomic markers to map the mutation and clarifies that the mutant gene is hPer2, the human homolog of mPer2 [38]. The hPer2 mutation changes serine 662 to a glycine (S662G). This occurs in a region of hPER2 homologous to the casein kinase I epsilon (CKIε) binding region of mPER1 and mPER2. Serine 662 is in fact part of a consensus CKIε phosphorylation site, and the S662G substitution renders the mutant protein less readily phosphorylated by CKIε than the wild-type hPER2 in vitro. Thus, a variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period.

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5. Chronopharmacodynamics Biological rhythms not only impact the pathophysiology of diseases, but the pharmacokinetics and pharmacodynamics of medications. Chronopharmacology is the investigative science that elucidates the biological rhythm dependencies of medications. Biological rhythms at the cellular and subcellular level can give rise to significant dosing time differences in the pharmacodynamics of medications that are unrelated to their pharmacokinetics. This phenomenon is termed chronesthesy. Rhythms in receptor number or conformation, second messengers, metabolic pathways, and/or free-to-bound fraction of medications help explain this phenomenon. For example, the antitumor effect of IFN-β and the antiviral effect and lymphocyte stimulating effect of IFN-αin mice are more efficient during the early rest phase than during the early active phase [39,40]. The dosing schedule-dependent effect of IFN-β or IFN-α is also closely related to that of IFNs receptors and ISGF expression in tumor cells or lymphocytes. Imatinib mesylate, known as Gleevec or STI-571, is a molecule that inhibits the function of various receptors with tyrosine kinase activity, such as Abl, the bcr-abl chimeric product, KIT, and plateletderived growth factor (PDGF) receptors. The influence of dosing time on the ability of imatinib to inhibit tumor growth in mice is investigated [41]. The antitumor efficacy of imatinib is enhanced by administering the drug when PDGF receptor activity is increased. The term chronotoxicity refers specifically to predictable-in-time variation in patient vulnerability to the side effects of medications due to biological rhythm determinants. Chronotoxicities are known especially for antitumor agents. For example, the body weight loss of irinotecan hydrochloride (CPT-11) in nocturnally active mice is more serious in the late active phase and the early rest phase and milder in the late rest phase and the early active phase [42]. The CPT-11-induced leukopenia is more serious in the late active phase and milder in the late rest phase. The lower toxicity of CPT-11 is observed when DNA synthesis and type I DNA topoisomerase activity in bone marrow cells decrease and the higher toxicity is observed when these activities begin to increase. Cell division in many mammalian tissues is associated with specific times of day. In the regenerating liver of mice, the circadian clock controls the expression of cell cycle-related genes that in turn modulate the expression of active Cyclin B1-Cdc2 kinase, a key regulator of mitosis [43]. Among these genes, expression of Wee1 is directly regulated by the molecular components of the circadian clockwork. On the other hand, the circadian clockwork oscillates independently of the cell cycle in single cells. The intracellular circadian clockwork can control the celldivision cycle directly and unidirectionally in proliferating cells. The

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finding indicates that the choice of dosing time associated with the 24 h rhythm of DNA synthesis may help to achieve a rational chronotherapeutic strategy, reducing the toxic effects of antitumor drugs and/or increasing its therapeutic effects. Thus, the regulatory mechanisms underlying 24 h rhythm of pharmacodynamics should be also clarified from viewpoints of clock genes. Angiogenesis is essential for tumor growth and metastasis. The inhibition of angiogenesis has emerged as a new therapy to treat cancers. Hypoxia-induced expression of vascular endothelial growth factor (VEGF) plays a key role in tumor-induced angiogenesis. The levels of VEGF mRNA in tumor cells implanted in mice rise substantially in response to hypoxia, but the levels show a circadian rhythm as schematically described in Fig. 4 [44]. Luciferase reporter gene analysis reveals that PER2 and CRY1, whose expression in the implanted tumor cells shows a circadian rhythm, inhibit the hypoxiainduced VEGF promoter activity. Namely, the negative limbs of the molecular loop periodically inhibit the hypoxic induction of VEGF transcription, resulting in the circadian fluctuation of its mRNA expression. Furthermore, the antitumor efficacy of antiangiogenic agents is enhanced by administering the drugs at the time when VEGF production increases. Methionine aminopeptidase2 (MetAP2) plays an important role in the growth of endothelial cells during the tumor angiogenesis stage. MetAPs show a circadian rhythm in implanted tumor masses [45]. The mechanism underlying the circadian rhythm of MetAP2 activity is investigated in tumor-bearing mice. The 5′ flanking region of MetAP2 includes eight E-boxes. The transcription of the MetAP2 promoter is enhanced by the CLOCK:BMAL1 heterodimer, and its activation is inhibited by PER2 or CRY1. Namely, the circadian rhythm of MetAP2 activity is regulated by the transcription of clock genes within the clock feedback loops. Furthermore, the antitumor efficacy of MetAP2 inhibitor is enhanced by administering the drugs at the time when MetAP2 activity increases. Activating transcription factor 4 (ATF4) is upregulated in cisplatinresistant cells and plays a role in cisplatin resistance. ATF4 is a direct target of Clock, and Clock is overexpressed in cisplatin-resistant cells [46]. Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The genes for glutathione metabolism are generally down-regulated by the knock-down of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also

Fig. 4. Simplified model for the molecular clock mechanisms of vascular endothelial growth factor (VEGF) and the dosing time-dependent antitumor efficacy of antiangiogenic agents in mice [44]. Angiogenesis is essential for tumor growth and metastasis. The inhibition of angiogenesis has emerged as a therapy to treat cancers. Hypoxia-induced expression of VEGF plays a key role in tumor-induced angiogenesis. The levels of VEGF mRNA in tumor cells implanted in mice rise substantially in response to hypoxia, but the levels show a circadian rhythm. Luciferase reporter gene analysis reveals that PER2 and CRY1, whose expression in the implanted tumor cells shows a circadian rhythm, inhibit the hypoxia-induced VEGF promoter activity. Namely, the negative limbs of the molecular loop periodically inhibit the hypoxic induction of VEGF transcription, resulting in the circadian fluctuation of its mRNA expression. Furthermore, the antitumor efficacy of antiangiogenic agents is enhanced by administering the drugs at the time when VEGF production increases.

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indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy. On the other hand, DNA repair is intimately linked to circadian rhythm. Since the repair of DNA lesions contributes to the resistance of chemotherapy with DNA damaging agents such as cisplatin, understanding the fundamental molecular mechanism regulating DNA repair pathways is important for cancer therapy [47]. The significance of the connection linking the circadian clock with nucleotide excision repair and the potential implications for chemotherapy are being considered. Circadian clocks are molecular timekeeping systems that underlie daily fluctuations in multiple physiological and biochemical processes. The dysfunctions of the circadian system are associated with the development of various pathological conditions. The application of high throughput screening approach is performed to search for small molecules capable of pharmacological modulation of the molecular clock [48]. The evidence for the feasibility and value of this approach is being accumulated for both scientific and therapeutic purposes. 6. Chronopharmacokinetics Chronopharmacokinetic studies have been reported for many drugs in an attempt to explain chronopharmacological phenomena and demonstrate that the time of administration is a possible factor of variation in the pharmacokinetics of a drug. Time-dependent changes in pharmacokinetics may proceed from 24 h rhythms at each process, e.g. absorption, distribution, metabolism and elimination. Thus, 24 h rhythms in gastric acid secretion and pH, motility, gastric emptying time, gastrointestinal blood flow, drug protein binding, liver enzyme activity and/or hepatic blood flow, glomerular filtration, renal blood flow, urinary pH and tubular resorption may play a role in such pharmacokinetic variations [10,11]. The clock genes are expressed not only in the SCN, but also in other brain regions and various peripheral tissues. A microarray analysis experiment has revealed that there are many genes expressing a circadian rhythm in the liver [49]. The liver is a biological clock capable of generating its own circadian rhythms [50]. Since the liver is a major organ of metabolism and detoxification, knowledge of circadian effects on transcriptional activities that govern daily biochemical and physiological processes in the liver may play a key role in toxicology. Analysis of relative levels of gene expression in the liver of rats is investigated as a function of time-of-day [49]. Expression levels are determined for 3906 genes using high-density oligonucleotide microarrays. Of them 30% are clearly expressed while 70% are not expressed or the expression is too low to distinguish from background levels. The maximum estimated changes observed for most genes (90%) of rhythmic genes are less than 1.5-fold. There are 67 genes whose expression is significantly altered as a function of time-of-day. These altered genes include DNA binding and regulation of transcription, drug metabolism, ion transport, signal transduction and immune response. A circadian rhythm is demonstrated for six genes involved in regulation of gene transcription [49]. The retinoic acid receptor-alpha and the retinoid X receptors, nuclear receptor, play a key role in regulation of gene expression by forming transcriptionally active complexes on DNA. Aryl hydrocarbon receptor nuclear translocator (Arnt) works as a transcription factor in diverse signaling events including response to xenobiotics. A circadian expression is also demonstrated for Pitx2 and Pitx3 genes. These genes encode paired-like homeodomain transcription factors 2 and 3, the members of homeobox gene family involved in the regulation of other genes and gene products. Drug metabolism is the main function of the liver. There is a significant circadian rhythm in cytochrome P-450 4a3 (Cyp4a3) and putative N-acetyltransferase camello 4 (Clm4) of phase I and phase II of drug metabolism [49]. Liver cytochrome P450 4a isoforms play a major role in regulation of renal function by catalyzing the formation of 20-hydroxyeicosatetraenoic acid, which has a potent effect on the renal vasculature and tubular ion transport. This may partly explain

circadian rhythm of renal function and blood pressure. In the mouse liver, circadian regulation of transcripts are demonstrated for the cytochrome P450 such as Cyp17, Cyp2a4, Cyp2e1, Cyp2c22 and so on. Clm4 encodes a protein catalyzing acetylation of aromatic amines and hydrazines. The rhythmic pattern corresponds to the pattern of Cml2 in the mouse liver. Circadian rhythm is demonstrated for other members of the phase II of drug metabolism such as glutathione-S-transferases (GST) and carboxylesterase. The liver is the major organ of metabolism and endures a flux of metabolites across membranes. A significant circadian rhythm is demonstrated for genes involved in ion transport [49]. Among the genes are those encoding proteins of the solute carrier transporter such as solute carrier family 34 (Slc34a1), an insulin-regulated facilitative glucose transporter, and solute carrier family 2 (Slc2a8), a phosphate ion transporter. A rhythmic gene expression is demonstrated for solute carrier such as Slc12a2, Slc16a1, Slc19a1, and Slc25a11. In addition to the anion and solute transporters Abcc2 and Aqp9, expression of Slc10a1, Slc22a1, Slc27a1, Slc2a2, and Slc7a2 show circadian rhythm. Furthermore, there is a significant circadian expression of genes Hcn4, Trpc4, Scn2b, Scn4a, Chrnb2, Atp9a, Atp7b, Timm10, and Nritp that are involved in ion transport activity. Since one of the important defense mechanisms includes the active extrusion of xenobiotics by commonly shared transport proteins mainly located in the liver, kidney, and intestine, genes involved in ion or solute transport activity may have significant implications in toxicology studies. Coordinated rhythmic oscillations in phase I and phase II components of drug metabolism during the day may account for differential responses to drugs in toxicology. DBP is able to activate the promoter of a putative clock oscillating gene, Per1, by directly binding to the Per1 promoter [19,51,52]. The Per1 promoter is cooperatively activated by DBP and CLOCK-BMAL1. On the other hand, Dbp transcription is activated by CLOCK-BMAL1 through Eboxes and inhibited by the PER and CRY proteins, as is case for Per1. Thus, Dbp, a clock-controlled gene whose expression oscillates with a very high circadian amplitude, may play an important role in central clock oscillation. Dbp participates in the regulation of several clock outputs, including locomotor activity, sleep distribution, and liver gene expression. Also, DBP is a major factor controlling circadian expression of the steroid 15 α-hydroxylase (Cyp2a4) and coumarin 7-hydroxylase (Cyp2a5) genes in mouse liver [53]. Thus, the mechanisms underlying 24 h rhythm of drug metabolism have been gradually clarified. A significant portion of the transcriptome in mammals, including the PAR-domain basic leucine zipper (PAR bZip) transcription factors DBP, HLF, and TEF, is under circadian clock control. Triple mutant mice are born at expected Mendelian ratios, but are epilepsy prone, age at an accelerated rate, and die prematurely [54]. The PAR bZip transcription factors DBP, TEF, and HLF accumulate in a highly circadian manner in several peripheral tissues, including liver and kidney. To identify PAR bZip target genes whose altered expression might contribute to the high morbidity and mortality of PAR bZip triple knockout mice, the liver and kidney transcriptomes of these animals are compared with those of wild-type or heterozygous mutant mice. The disruption of these three genes in mice alters gene expression patterns of many proteins involved in drug metabolism and in liver and kidney responses to xenobiotic agents. The various levels at which PAR bZip transcription factors might intervene in the coordination of xenobiotic detoxification are schematically described [54]. The PAR bZip proteins control the expression of many enzymes and regulators involved in detoxification and drug metabolism, such as cytochrome P450 enzymes, carboxylesterases, aminolevulinic acid synthase (ALAS1), P450-oxidoreductase(POR), sulfotransferases, glutathione-S-transferase (GST), aldehyde dehydrogenases, UDP-glucuronosyltransferases, members of drug transporter families, and constitutive androstane receptor (CAR). Some genes encoding detoxification enzymes (e.g. CYP2A5, CYP2C50, CES3) may be direct PAR bZip target genes. The expression of other detoxification enzymes (e.g. CYP2B10), is mostly controlled by CAR, whose circadian transcription is governed by PAR bZip proteins. Yet other enzymes in the xenobiotic defense (e.g. ALAS1 and POR) appear to be under the control

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of both CAR and PAR bZip proteins. Rhythmic changes in transcriptional regulators will be further analyzed in future studies. Although the pharmacokinetics of several drugs that are mainly eliminated by the CYP3A4 metabolism vary according to their dosing time, the mechanism of the variation remains poorly understood. The 24 h oscillation in the expression of CYP3A4 mRNA is investigated in hepatic cells [55]. As brief exposure of HepG2 cells to 50% serum induced the 24 h oscillation in the expression of clock genes, serum-shocked HepG2 cells are employed as an in-vitro model to study the molecular mechanism underlying the circadian clock in the human liver. Both mRNA levels and metabolic activity of CYP3A4 in serum-shocked HepG2 cells fluctuate rhythmically with a period length of about 24 h. The oscillation in the expression of the CYP3A4 gene seems to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay reveal that the circadian transcriptional factor, D-site-binding protein (DBP), activates the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP is repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock. Results from this study suggest that DBP and E4BP4 might consist of a reciprocating mechanism in which DBP activates the transcription of the CYP3A4 gene during the time-of-day when DBP is abundant, and E4BP4 suppresses the transcription at other times of day. Cytochrome P450 2E1 (CYP2E1) is clinically and toxicologically important and exhibits 24 h periodicity in its activity. Hepatic nuclear factor1alpha (HNF-1alpha) and clock genes with a striking 24 h rhythm in the mouse liver contributes to the 24 h regulation of CYP2E1 expression [56]. P-glycoprotein, the product of the multidrug resistance (mdr) gene, functions as a xenobiotic transporter contributing to the intestinal barrier. Although intestinal expression of the mdr1a gene and its efflux pump function have been shown to exhibit 24 h variation as described in Fig. 5, the mechanism of the variations remains poorly understood. It is clarified that the molecular components of the circadian clock act as regulators to control 24 h variation in the expression of the mdr1a gene [57]. Luciferase reporter assay and gel mobility shift assay are used to study the mechanism of transcriptional regulation of the mdr1a gene by clock gene products. The messenger RNA levels and protein abundances in colon 26 cells and the mouse intestine are measured by quantitative real-time polymerase chain reaction and Western blotting, respectively. Hepatic leukemia factor (HLF) and E4 promoterbinding protein-4 (E4BP4) regulate transcription of the mdr1a gene by competing with each other for the same DNA binding site. Molecular and biochemical analyses of HLF- and E4BP4-down-regulated colon 26 cells and the intestinal tract of clock mutant mice suggest that these 2 proteins consist of a reciprocating mechanism in which HLF activates the transcription of the mdr1a gene, whereas E4BP4 periodically suppresses transcription at the time-of-day when E4BP4 is abundant. The intestinal expression of the mdr1a gene is influenced by the circadian organization of molecular clockwork. A significant 24 h variation in intestinal accumulation of [3H]-digoxin is also observed in wild-type mice. The cyclic accumulation of [3H]-digoxin is nearly antiphase to the rhythmicity of P-gp expression. On the other hand, Clock mutant mice fail to show significant 24 h variation in the intestinal accumulation of [3H]-digoxin. Mean [3H]-digoxin concentrations are consistently increased throughout the day. These findings suggest that efflux pump function of mdr1a is reduced in Clock mutant mice. Also, the intestinal H(+)/peptide cotransporter 1 (PEPT1) plays important roles as a nutrient and drug transporter. The expression profiles of transcription factors under two kinds of feeding schedules have been investigated to clarify the molecular mechanism governing the diurnal rhythm of PEPT1 expression [58]. Expression of dihydropyrimidine dehydrogenase (DPD) displays a regular daily oscillation in nonmalignant cells. In colorectal cancer cells, the expression of this 5-fluorouracil-metabolizing enzyme is decreased, but the reason remains unclear. The expression of DPD and of members

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Fig. 5. 24 h rhythm in intestinal accumulation of [3H]-digoxin and multidrug resistance (mdr1a) mRNA expression in wild-type and Clock mutant mice [57]. Solid line and closed circle represent the results in wild-type cells. Dashed line and open circle represent the results in Clock mutant cells. Each point represents the mean± SD of 3–4 observations. **P b 0.01, *P b 0.05, compared with the value of wild-type mice at corresponding ZTs (Bonferroni's test). White bars indicate the light period, and grey bars indicate the dark period. P-glycoprotein, the product of mdr1a gene, functions as a xenobiotic transporter contributing to the intestinal barrier. Although intestinal expression of the mdr1a gene and its efflux pump function exhibit 24 h variation, the intestinal expression of the mdr1a gene is influenced by the circadian organization of molecular clockwork. Reproduced with permission from [57].

of the cellular oscillation machinery, Per1, Per2, and Clock, are investigated in primary colorectal tumors and normal colon mucosa derived from the same patients [59]. Analysis of tumors according to differentiation grade reveals a 0.46-fold decrease for DPD mRNA and a 0.49-fold decrease for Per1 mRNA in undifferentiated (G3) tumors compared with paired normal mucosa. In this tumor cohort, the significant correlation between DPD and Per1 levels is demonstrated. In moderately differentiated (G2) colon carcinomas, reduction of DPD and Per1 mRNA levels do not reach significance, but a significant correlation between the respective mRNA levels is detectable. The decrease and correlation of DPD and Per1 mRNA levels are even more pronounced in female (G3) patients. These results also reveal a disturbed transcription of Per1 during tumor progression, which might be the cause for disrupted daily oscillation of DPD in undifferentiated colon carcinoma

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cells. Clock genes seem to play a critical role in the molecular clockworks of SCN and peripheral tissues such as liver, kidney and intestine. Although oscillation of clock genes in peripheral tissues is controlled under the circadian clock mechanism in the SCN, the resetting signals on liver clock function has not been clarified yet. Over the past few years, use of the pseudorabies virus, a transsynaptic tract tracer, has allowed us to map neural connections between the SCN and peripheral tissues in several physiological systems. Communication between the SCN and peripheral tissues occurs through autonomic nervous systems involving the sympathetic and parasympathetic neurons. Although further study is necessary to produce the precise mechanism underlying neural control of peripheral clock systems, evolution of this mechanism will help our understanding of peripheral clock functions such as drug metabolism and energy metabolism. 7. The disruption and maintenance of biological rhythms The circadian clock system is necessary to adapt endogenous physiological functions to daily variations in environmental conditions. Abnormality in circadian rhythms, such as the sleep-wake cycle and the timing of hormonal secretions, is implicated in various physiological and psychiatrical disorders. Recent molecular studies have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of 24 h cycles of physiology and behavior. It has been noticed that patients receiving chemotherapeutic agents experience disturbances in their behavioral and physical performances, including circadian rhythms. Several drugs cause alterations in the 24 h rhythms of biochemical, physiological and behavioral processes [13,60,61]. The alteration of rhythmicity is sometimes associated with therapeutic effects, or may lead to illness and altered homeostatic regulation. Interferons (IFNs) have been widely used as antiviral and antitumor agents. However, IFNs cause adverse neuropsychiatric effects such as depression and neurosis and they are reported to sometimes lead to suicide [62,63]. When IFNs are administered during the early active phase in diurnally active humans, alterations in the 24 h rhythm are suggested by the changes in the lymphocyte counts and cortisol levels [64]. However, the mechanism has not been clarified from the viewpoint of the disruptive effect of the drug on the clock genes. Fig. 6 shows the disruptive effect of interferon-α (IFN-α) on the rhythm of Per genes mRNA expression in the SCN [60]. These findings are supported by the inhibitory effect of IFN-α on the mRNA expression of Clock and Bmal1, which are important factors in activating the transcription of Pers, vasopressin and the Dbp gene showing specific output function [16,17,19]. Also, the rhythmicity of locomotor activity and body temperature are severely blunted by the repetitive administration of IFN-α. Since IFN-αinfluenced both the SCN and periphery, it is difficult to clarify whether the IFN-α effects on clock genes are secondarily related to the IFN-α effect on locomotor activity. However, IFN-α acts on the SCN as shown in the expression of ISGF [60] and the rhythmicity that SCN controls in the periphery [16]. The rhythmicity of locomotor activity is severely altered by the continuous administration of corticosterone or a time-restricted feeding schedule while leaving the rhythmic phase of clock genes in the SCN unaffected [65,66]. Thus, the possibility that altered locomotor activity could in turn lead to changed clock gene expression in the SCN is low in the case of IFN-α. The photic induction of the Per1 gene in SCN is also completely disturbed by daily administration of IFN-α at the early active phase, which may have caused a functional disorder in the resetting and entrainment of SCN. Therefore, IFN-α effects at the SCN clock gene level may be responsible for some of the adverse behavioral and physiological effects. IFN-α sometimes causes ocular adverse effects associated with retinal or optic neuropathy [67,68], although the mechanism is not clear at present. Such ocular adverse effects caused by IFN-α may decrease the photic information from the retina to SCN and the stimulation of the light responsive element of the period gene.

Fig. 6. Influence of IFN-α dosing schedule on mRNA expression of clock genes in the SCN [60]. Each panel show RNA levels for the Per1 (A) or Bmal1 (B) in the SCN of mice after a single dose of IFN-α (2 MIU/kg, sc) at ZT0 (zeitgeber time 0) (closed square) or ZT12 (closed triangle), or saline (open circle) daily for 6 days. Each point represents the mean ± SEM of 6 observations. All mRNAs except for Bmal1 in groups injected with IFN-α at ZT12 show significant 24 h rhythms (Per1 in groups injected with IFN-α at ZT12; P b 0.05, respectively, others; P b 0.01, respectively, ANOVA). **P b 0.01, *P b 0.05, compared with the value of controls at corresponding ZTs (Bonferroni's test). White bars indicate the light period, and grey bars indicate the dark period.

Interestingly, an inhibitory effect of mRNA expression of each clock gene in the SCN is observed by the repetitive administration of IFN-α during the early active phase, but not the early rest phase (Fig. 6) [60]. Similar dosing schedule-dependent inhibition of Per1 mRNA expression is demonstrated during the repetitive administration of IFN-γ, which can be induced by IFN-α or IFN-β in combination with other cytokines [69]. The expression of IFN-γ receptor in SCN follows a 24 h rhythm with a peak at the early active phase [70]. This may be why the administration of IFN-α during the early rest phase can reduce its side effect. The observations for humans described above correspond well to the findings indicating that alteration of the clock genes is induced by IFN-α administration during the early active phase in nocturnally active rodents. Furthermore, the 24 h dependency of the disruptive effect of IFN-α on clock genes in SCN may be applicable to other drugs as shown in the case of IFN-γ. Thus, alteration of the clock function, a new concept of adverse effects, can be overcome by devising a dosing regimen that minimizes adverse drug effects on clock function. Also, the influence of 5-fluorouracil (5-FU) on the expression of clock genes is investigated to explore the underlying mechanism of chemotherapeutic agent-induced disturbance of these rhythms [61]. Continuous

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administration of 5-FU to mice attenuated the oscillation in the expressions of Per1 and Per2 mRNA in the liver and SCN. These results reveal a possible pharmacological action by 5-FU on the circadian clock mechanism, which is the underlying cause of its adverse effects on 24 h rhythms of physiology and behavior. The shift work in human is probably carcinogenic associated with circadian disruption. The chronic jet-lag (CJL) as experimental models suppresses the rhythms of behavior and physiology and accelerates growth of two transplantable tumors in mice. The role of CJL as a tumor promoter is investigated in mice exposed to the hepatic carcinogen, diethylnitrosamine (DEN) [71]. The mice received DEN are randomized to remain in a photoperiodic regimen where 12 h of light alternates with 12 h of darkness (LD 12:12) or to be submitted to CJL (8 h advance of light onset every 2 days). All the mice suffer from liver cancers caused by DEN. The diameter of the largest liver tumor is twice as large in CJL mice as compared to LD mice. LD mice have a single histologic tumor type per liver. On the other hand, CJL mice have up to four different types in the same liver. DEN disrupts the circadian rhythms of behavior and physiology in all mice. The association of circadian disruption with chronic DEN exposure suggests that circadian clocks actively control the mechanisms of liver carcinogenesis in mice. Persistent circadian coordination may further be critical for slowing down and/or reverting cancer development after carcinogen exposure. 8. The adjustment and manipulation of biological rhythms The 24 h rhythms of physiology and behavior are influenced by various environmental factors such as feeding schedules, genetic factors and social interactions as well as lighting condition and several drugs [13,15,37,65]. Since the period of the central circadian pacemaker in humans is slightly longer than 24 h described above, synchronization of the circadian system with the light–dark cycle occurs by daily phaseadvances of the circadian clock. In humans, the time-of-day-dependent phase-shifting effects of light are summarized in a phase–response curve (PRC) [13]. Morning light advances the central circadian pacemaker, late afternoon and evening light delays the pacemaker, and light during the midday is without phase-shifting effects. On the other hand, the phase-shifting agents (zeitgebers) such as melatonin, 5hydroxytryptamine (5-HT, serotonin), and behavioral arousal have a PRC distinct from light. The phase-advances occur between midday and early evening. The phase delays occur between late night and midday. As a group, phase shifts produced by nonphotic zeitgebers are similar to phase shifts produced by dark pulses presented to animals housed in constant light. Photic and nonphotic (i.e., extrinsic timekeeping) effects on intrinsic timekeeping may be important components of disordered timekeeping in depressive illness. SCN neurons receive information about the light intensity in the environment via direct synaptic connections with the retina, which adapts the phase of SCN oscillator to the photoperiod [72]. The SCN clock then synchronizes overt rhythms in physiology and behavior. Per1 and Per2 transcription is rapidly induced by light in a time-of-day-dependent manner [15]. The responsiveness of Per1 mRNA to light is closely related to behavioral phase delays induced by light. Light-induced phase delays in locomotor activity during subjective night are significantly inhibited when mice are pretreated with Per1 antisense phosphorothioate oligodeoxynucleotide (ODN) [73]. Therefore, the gated expression of Per1 may be an important step in causing photic entrainment. It is well known that not only photic but also nonphotic stimuli can entrain the SCN clock and several drugs have been investigated to modulate the circadian rhythm by causing a phase shift in the rhythm in the peripheral or central nervous system [13]. A recent study indicates that the acute and circadian time-dependent reduction of Per1 and/or Per2 mRNA in the hamster SCN by 5-HT1A/7 receptor agonists is strongly correlated with the phase resetting in response to the drug [74]. Therefore, nonphotic shifts may involve change in Per1 and/or Per2 mRNA levels in the SCN. However, with the exception of

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chronic treatment with antidepressant drugs which are given over the course of many months, most studies report normal temporal response of the clock to an acute treatment and the response to repetitive administration is generally unknown. A variety of physiological rhythmic variables are influenced by the cyclic variation of environmental factors [75]. One of those factors is feeding schedule [66]. The change in glucocorticoid rhythmicity appears to play an important role in the physiological rhythmicity by the manipulation of the feeding schedule, because plasma corticosterone levels show anticipatory increases preceding the time of feeding, and the continuous administration of corticosterone disturbed the rhythmicity of behavior, physiological function and cyclic genes expression. Such effects are not influenced by SCN lesions [76]. Also a time-restricted feeding schedule can change the rhythmic phase of locomotor activity, physiological function including corticosterone and clock genes in periphery by up to 12 h while leaving the rhythmic phase of clock genes in the SCN unaffected [65,66]. Ventromedial hypothalamic lesions abolish food-shifted circadian adrenal rhythmicity [77]. The paraventricular nucleus (PVN) appears to be the site where the feeding-associated circadian oscillation is connected to the HPA axis [78]. On the other hand, the manipulation of the feeding schedule can modify the chronopharmacological action and chronopharmacokinetics of drugs [79]. In humans, the pattern of diet intake substantially modifies plasma cortisol levels in addition to body temperature rhythm [80]. Namely, the rhythmicity of the plasma cortisol levels can be kept normal only when the feeding pattern is diurnal, but is reversed or disturbed under a nocturnal or continuous feeding pattern. To produce new rhythmicity by manipulating the conditions of living organs by using rhythmic administration of altered feeding schedules or several drugs appears to lead to the new concept of chronopharmacotherapy. Circadian synchronization of cell proliferation is observed not only in normal healthy tissues but also in malignant solid tumors. However, the proliferation rhythm of tumor cells is often different from that of normal cells. It is clarified that the peculiar rhythm of tumor cell proliferation is modulated by inhibition of PDGF signaling (Fig. 7) [81]. DNA synthesis in tumor cells implanted in mice shows a 24 h oscillation apparently differing from that of normal bone marrow cells. Continuous administration of AG1295 (10 µg/h, s.c.), a PDGF receptor tyrosine kinase inhibitor, substantially suppresses DNA synthesis in the implanted tumor cells but not in the healthy bone marrow cells. During the administration of this drug, the rhythm of DNA synthesis in the tumor cells is synchronized with that in bone marrow cells. The results suggest that the circadian rhythm of DNA synthesis in tumor cells is modulated by PDGF receptor signaling, which is activated following tumor progression. 9. Necessary of clock gene delivery on cancer therapy The effectiveness and toxicity of many drugs vary depending on the relationship between the dosing schedule and the 24 h rhythms of biochemical, physiological and behavioral processes. In addition, several drugs can cause alterations to the 24 h rhythms leading to illness and altered homeostatic regulation. The alteration of biological rhythm is a new concept of adverse effects. The latter can be minimized by optimizing the dosing schedule [60]. A large body of literature exists demonstrating the rationale behind chronotherapy. Chronopharmaceutics should address these new challenges in Chrono-DDS [82]. The compounds have been developed as examples of Chrono-DDS on the market [83]. Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior. Clock gene regulates several diseases such as cancer, metabolic syndrome and sleep etc. Comparison between the tissues from WT and Clock mutant mice reveals that the CLOCK mutation affects the expression of many genes that are rhythmic in WT tissue, but also profoundly affects many non-rhythmic genes. The knowledge of intra- and inter-individual variability of molecular clock should be applied for

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Fig. 7. Influence of continuous administration of AG1295, a platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor, on the daily variations in DNA synthesis in implanted sarcoma 180 tumor cells (closed circle) and in healthy bone marrow cells (open circle) [81]. Tumor-bearing mice are continuously administered Saline (A) or AG1295(10 μg/h, s.c.) (B) by means of osmotic mini-pumps for 5 days. DNA synthesis of cells in tumor and bone marrow are assessed by BrdU labeling. Each point represents the mean ± S.E.M of 4–6 observations. Circadian rhythm of cell proliferation is observed not only in normal healthy tissues but also in malignant solid tumors. However, the proliferation rhythm of tumor cells is different from that of normal cells. Continuous administration of AG1295 substantially suppressed DNA synthesis in the implanted tumor cells but not in the healthy bone marrow cells. During the administration of this drug, the rhythm of DNA synthesis in the tumor cells is synchronized with that in bone marrow cells.

the clinical practice. The change of PK/PD are influenced by not only inter-individual variability but also intra-individual variabilities of medications. It is commonly thought that disruption of the circadian clock increases cancer growth rate, and clinical circadian disruption is associated with higher cancer incidence, faster cancer progression, and shorter cancer patient survival [84]. Patients with advanced lung cancer suffering greater circadian activity/sleep cycle disruption suffer greater interference with function, greater anxiety and depression, poorer nighttime sleep, greater daytime fatigue, and poorer quality of life than comparable patients who maintain good circadian integra-

tion. Thus, the disruption of circadian rhythms, daily oscillations in biological processes that are regulated by an endogenous clock, has been linked to tumorigenesis. The whole genome inspections of mutations in human colon and breast cancer have observed specific retained clock gene mutations. Single nucleotide polymorphisms within the genes of clock, clock-controlled, and melatonin pathways have been found to confer excess cancer risk or protection from cancer. The significance of clock gene on cancer is summarized in Table 1 [85–97]. Cellular proliferation and the expression of cell cycle regulators are also controlled by the circadian clock [43]. Disruption of the circadian

Table 1 The significance of clock gene on cancer. Clock gene

Cancer type

Genotype

Cancer prognosis

Suggested mechanism

Reference

Per2 (Mouse)

Lymphoma

Deficient

Increase tumor development Reduce apoptosis

[85]

Per1,2,3 (human)

Brest cancer

Increase tumor development

Per2 (human)

AML

Downregulation/methylation of the Per1 or Per2 promoter Downregulation

Per2 (Human) Per1 (Human)

Colorectal cancer Prostate cancer

Downregulation Downregulation

Cry2 (human)

Non-Hodgkin's lymphoma (NHL)

Single nucleotide polymorphisms

Increase tumorigenesis Increase tumor development Reduce apoptosis Extend the lifespan and decrease cancer onset in p53 deficient mice

Cry1,2 (mouse)

Thymic lymphoma in p53 mutant mice

Deficient

Delay in onset of cancer

Cry1 (human)

Chronic lymphocytic leukemia (CLL)

Change of CRY1:PER1 expression ratio

Outcome in chronic lymphocytic leukemia is predicted

Bmal1 (human)

B-cell lymphoma, acute lymphocytic and myeloid leukemias Neuro-degenerative disorder such as alzheimer's and parkinson's diseases, sleep disorder and cancer Non-hodgkin's lymphoma/ Breast cancer

Upregulation Downregulation

Decrease cancer Increase cancer

Deregulation

Increase cancer

Decrease Bmal1 expression Derepression of c-myc Deregulation of cell cycle and tumor suppressing genes Deregulation of c-erbB2 expression Decrease of CCAAT/enhancerbinding proteins Decrease of beta-catenin Deregulation of transcriptional activity of androgen receptor Alteration of the immune response Alteration of the hepatic system development Sensitizing p53 mutant cells to apoptosis in response to genotoxic stress. Expression change of cell cyclerelated and DNA-damage response genes Growth inhibition Unable to arrest upon p53 activation Growth activation Participation in signal transduction pathways

Single nucleotide polymorphisms Downregulation

Increase cancer

Repression in expression of several cell cycle and DNA repair genes

[96] [97]

Ck1

Npas2 (human)

Initiation and/or progression

[86] [87] [88] [89] [90]

[91]

[92]

[93] [94] [95]

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895

Table 2 The therapeutic possibility of clock gene delivery in cancer. Target molecule

Approach

Cancer prognosis

Suggested mechanism

Reference

PER2

Overexpression using recombinant adenovirus vector/polyethyleniminemediated intratumoral Per2 gene delivery

Reduced cellular proliferation

Downregulation of c-MYC, Bcl-2, Bcl-X(L), Cdc2 and cyclin B1 Upregulation of p53 and Bax inhibits cell cycle Induces arrest in a circadian rhythmic manner

[98]

Increase Cyclin D and E

[101]

Interacts with the checkpoint ATM and Chk2

[102]

Suppression of expression of both Per1 and Per3 Upregulation of Bax and increase the cleavage of caspase poly-ADP-ribose-polymerase downregulation of Bcl-2 Deregulated cell proliferation Per1 and Per2 differentially regulate tumor growth rhythm.

[103]

Downregulation using siRNA

PER1

Overexpression Exposure with TNF-alpha Downregulation using siRNA

PER1, PER2

Downregulation

Induced apoptosis. Significant antitumor effect Synergic cell killing effects with the anticancer agent cisplatin Accelerate and double the amplitude of the tumor growth in a time-dependent circadian rhythmic manner Increase the sensitivity to DNAdamage-induced apoptosis Increase the tumor growth Reduced cellular proliferation in pancreatic cancer (MIA PaCa-2 and PANC-1) and hepatocellular carcinoma (HepG2) Increase tumor growth Therapeutic efficacy of antiproliferation agents depends on the time-of-day of drug delivery

clock may thereby lead to deregulated cell proliferation. The specific core clock genes (Per2 and Per1) are tumor suppressors because their genetic absence doubles tumor numbers, and decreasing their expression in cancer cells doubles cancer growth rate, whereas their overexpression decreases cancer growth rate and diminishes tumor numbers [84]. The therapeutic possibility of clock gene delivery in cancer is shown in Table 2 [98–106]. The biological clock, with its core transcriptional unit BMAL1/CLOCK, is composed of several selfsustaining feedback loops. The other mechanism impinging on the core components of the circadian clock is considered [107]. Using a forward genetic screen, the miR-192/194 cluster is identified as a potent inhibitor of the entire Period gene family. In accordance, the exogenous expression of miR-192/194 leads to an altered circadian rhythm. These results may clarify a new mechanism for the control of the circadian clock at the post-transcriptional level. Several academic laboratories are screening for small molecules targeting the circadian clock to stabilize its phase and enhance its amplitude and thereby consolidate and coordinate circadian organization, which in turn is likely to help prevent and control human cancer. These drugs and strategies can be used to make cancer patients with advanced disease feel and function more normally. Adriamycin-encapsulated liposomes modified with the Ala-Pro-Arg-Pro-Gly (APRPG) peptide (APRPG-LipADM) are prepared, after the APRPG peptide has been shown to have affinity to angiogenic sites [108]. Colon 26 NL-17 tumorbearing mice are injected three times with APRPG-LipADM at zeitgeber time (ZT) 2, 8, 14, and 20 where ZT 0 is the time lights are turned on, and tumor growth was monitored. Tumor growth suppression changed with dosing time and is significantly more potent at ZT 14 compared with ZT 20. The circadian oscillation of VEGF is related to dosing time dependency with ANET. These results indicate that tumor growth suppression is correlated to some extent with the VEGF concentration in the plasma, and that chronopharmacologic treatment of cancer with ANET may enhance the therapeutic efficacy and reduce the side effects. Such strategy may be applicable to the delivery of clock gene in cancer. Future development in chronopharmaceutics may be made at the interface of other emerging disciplines such as system biology and nanomedicine. Such novel and more biological approaches to drug delivery may lead to safer and more efficient disease therapy. 10. Conclusions Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior. Clock gene regulates several disease such as cancer, metabolic syndrome and sleep

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etc. Comparison between the tissues from WT and Clock mutant mice reveals that the CLOCK mutation affects the expression of many genes that are rhythmic in WT tissue, but also profoundly affects many nonrhythmic genes. So, clock-controlled genes can show either rhythmic or constant levels of expression. The knowledge of intra- and interindividual variability of molecular clock should be applied for the clinical practice. The change of PK/PD are influenced by not only inter-individual variability but also intra-individual variabilities of medications. One approach to increasing the efficiency of pharmacotherapy is administering drugs at times during which they are best tolerated. The monitoring of rhythm, overcome of rhythm disruption and manipulation of rhythm from viewpoints of molecular clock are essential to improved progress and diffusion of chronopharmacotherapy. Chrono-DDS may benefit the development of new therapeutic strategies for several diseases as well as provide insights into chronotherapy as a way to optimize current therapies. Recent strategy on pharmacotherapy has been focused on gene delivery and antibody delivery targeting specific molecular for some disease. Clock genes should be also one of important candidates. Further elucidating the connections between clock genes and PK or PD could benefit the development of new therapeutic strategies for several diseases as well as provide insights into chronotherapy as a way to optimize current therapies. References [1] M. Sissung, C. English, D. Venzon, W. Figg, F. Deeken, Clinical pharmacology and pharmacogenetics in a genomics era: the DMET platform, Pharmacogenomics 11 (2010) 89–103. [2] F. Zhou, M. Di, E. Chan, Y. Du, V. Chow, C. Xue, X. Lai, J. Wang, C. Li, M. Tian, W. Duan, Clinical pharmacogenetics and potential application in personalized medicine, Curr. Drug Metab. 9 (2008) 738–784. [3] S. Koster, S. Rodin, A. Raaijmakers, H. Maitland-van der Zee, Systems biology in pharmacogenomic research: the way to personalized prescribing? Pharmacogenomics 10 (2009) 971–981. [4] W. Hope, L. Drusano, Antifungal pharmacokinetics and pharmacodynamics: bridging from the bench to bedside, Clin. Microbiol. Infect. 15 (2009) 602–612. [5] H. Xu, M. Murray, J. McLachlan, Influence of genetic polymorphisms on the pharmacokinetics and pharmaco-dynamics of sulfonylurea drugs, Curr. Drug Metab. 10 (2009) 643–658. [6] H. Tei, H. Okamura, Y. Shigeyoshi, C. Fukuhara, R. Ozawa, M. Hirose, Y. Sakaki, Circadian oscillation of a mammalian homologue of the Drosophila period gene, Nature 389 (1997) 512–516. [7] F. Halberg, Chronobiology, Annu. Rev. Physiol. 31 (1969) 675–725. [8] A. Reinberg, F. Halberg, Circadian chronopharmacology, Annu. Rev. Pharmacol. 11 (1971) 455–492. [9] B. Lemmer, B. Scheidel, S. Behne, Chronopharmacokinetics and chronopharmacodynamics of cardiovascular active drugs: propranolol, organic nitrates, nifedipine, Ann. N.Y. Acad. Sci. 618 (1991) 166–181. [10] G. Labrecque, P. Belanger, Biological rhythms in the absorption, distribution, metabolism and excretion of drugs, Pharmacol. Ther. 52 (1991) 95–107.

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