The best of times...the worst of times.

Times are good for the study of biological pacemakers. With the sequencing of the human genome has come a rapid increase in understanding of the complex function and control of ‘clock genes’. In mammals, the master oscillator appears to be located in the suprachiasmatic nuclei (SCN) of the hypothalamus and to be entrained by light through neural pathways connecting the retina to the SCN, in part via a p42/44 mitogen activated protein kinase mechanism [1]. Semi-autonomous circadian pacemakers also exist in peripheral tissues. Approximately 2% of all genes in rat fibroblasts have been shown to have robust circadian rhythmicity in their expression [2,3]. Disruption of these rhythms may predispose to a number of diseases, including cancer. For example, it has been reported that mice deficient in the mPer2 gene show a marked increase in tumour development, and that destruction of the SCN in mice is associated with accelerated growth of tumour xenografts [4,5]. Popular attention has been caught by reports that graveyard shift work is associated with an increased risk of breast cancer in women, and that an increased number of longdistance flights may be associated with an increased risk of prostate cancer in male pilots [6,7]. Interest in the importance of diurnal variation for human function is, however, far from new. Aside from the classic rhythms of secretion for cortisol and other hormones, it has been recognised for years that there are cycles both in biological parameters, such as blood pressure (which drops at night and peaks during midmorning for normal subjects), and in the occurrence of pathological events, such as heart attacks (which are most frequent within the first few hours of awakening [8]). Many of these cycles have a potential role on drug effects. These include variability in target tissue sensitivity (e.g. variation in cell proliferation kinetics), drug absorption and distribution (e.g. variation in gastric acid production), drug metabolism (e.g. variation in hepatic blood flow or enzyme activity [9-11]), and drug excretion (e.g. nocturnal increase in urine acidity [12]). Many anticancer agents with a variety of intracellular targets show clear periodic variations in both toxicity and efficacy based on the time of day (or, more correctly, time of light/dark cycle) of administration in animal models. These include celecoxib [13], doxorubicin, cisplatin, docetaxel [14], and 5-fluoro-20-deoxyuridine (FUDR) [15]. Given the narrow therapeutic index of most antineoplastic drugs, the promise of being able to improve results by accounting for diurnal rhythms is tantalising to cancer clinicians, but attempts to implement the available information have been frustrating. Studies in mice that strictly control conditions including light cycle, feeding schedule, and food and drug intake do not necessarily clarify what parameters are most responsible for the diurnal variability in toxicity and/or efficacy observed. For example, fasting has been shown to alter circadian rhythms of acetaminophen lethality and glutathione levels in mice, even when the light/dark schedule remains fixed [16]. For no anticancer drug class has there been more effort directed to untangling the potentially circadianrelated variation in toxicity and efficacy than for the fluoropyrimidines. 5-Fluorouracil (5-FU) is a widely used anticancer drug with a short half-life; over 80% of the drug is catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD). In rats, the hepatic extraction rate of 5-FU peaks in the mid-light period (rest period for a rat), which corresponds to their time of peak liver DPD activity [17]. Porsin and colleagues [18] and others [19] confirm that liver DPD activity in mice peaks during the light period. However, results in humans have been exceedingly variable. Harris and