Circadian schedules

Fig. 7. A schematic representation of treatment of 5-FU and external irradiation. The stippled rectangles represent weekly irradiation (9 Gy total/wk, given in five doses of 1.8 Gy). Concurrent 5-FU is represented by the solid bars beneath the irradiation, and the height of the bars represents the peak level of radiosensitizing chemotherapy. By using protracted infusional schedules of 5-FU, radiosensitizing chemotherapy can be given with each daily dose of irradiation (from 5 to 3 5 d). Newer schedules using continuous intermittent and circadian schedules have achieved high tumor activity with acceptable toxicity in recent trials.

To investigate the effect of the peak time of circadian delivery of 5-FU, we compare in Fig. 10.4a four circadian schedules with peak delivery at 4 a.m., 10 a.m., 4 p.m., and 10 p.m., for a cell cycle variability of 15%. The data on cumulated cell kill by 5-FU indicate a sharp difference between the circadian schedule with a peak at 4 a.m., which is the least toxic, and the other schedules. This difference is even more striking when cells are better synchronized, for smaller values of variability V (data not shown). The most toxic circadian schedules are those with a peak delivery at 4 p.m. or 10 a.m. We compare in Fig. 10.4b the least and most toxic circadian patterns of 5-FU delivery with the continuous infusion of 5-FU. Continuous delivery of 5-FU appears to be slightly more toxic than the circadian pattern with a peak at 4 p.m. 

To clarify the reason why different circadian schedules of 5-FU delivery have distinct cytotoxic effects, we used the cell cycle automaton model to determine the time evolution of the fraction of cells in S phase in response to different patterns of circadian drug administration, for a cell cycle variability of 15%. The results, shown in Fig. 10.5, correspond to the case considered in Fig. 10.4, namely, entrainment of a 22-h cell cycle by the circadian clock. The data for Fig. 10.5a clearly indicate why the circadian schedule with a peak at 4 a.m. is the least toxic. The reason is that the fraction of cells in S phase is then precisely in antiphase with the circadian profile of 5-FU. Since 5-FU only affects cells in the S phase, the circadian delivery of the anticancer drug in this case kills but a negligible amount of cells. 

Fig. 10.5 Explanation of the cytotoxic effect of various circadian schedules of5-FU delivery with peak at 4 a.m. (a), 10 a.m. (b), 4 p.m. (c), or 10 p.m. (d), and of continuous 5-FU delivery (e). Data are obtained for variability V = 15% and for a cell cycle duration of 22 h, in the presence of entrainment by the circadian clock. The hatched area shows the fraction of cells in S phase exposed to 5-FU and thus likely marked to exit the cell cycle at the next G2/M transition. The curves in Fig. 10.4 showing the cumulated number of cells killed indicate that the schedule with peak delivery at 4 a.m. is the one that causes minimal damage to the cells because the peak...

The case of the continuous infusion of 5-FU is considered in Fig. 10.5e. Because the total amount of 5-FU administered over 24 h is the same as for the circadian semi-sinusoidal patterns, the level of 5-FU - and hence the cytotoxic effect of the drug - is sometimes below and sometimes above that reached with the circadian schedule. The numerical simulations of the automaton model indicate that the cytoxicity is comparable to that observed for the most toxic circadian pattern, with peak delivery of 5-FU at 4 p.m. 

We have already alluded to the effect of synchronization governed by variability V. To further address this point, Fig. 10.6 shows, as a function of V, the cytotoxic effect of the 5-FU profile considered in Fig. 10.2b, with the peak at 4 a.m., in the presence of entrainment of the 22-h cycle by the circadian clock. The results indicate that the cumulated cell kill increases when V rises from 0% to 20%. For this circadian schedule of 5-FU, which is the least toxic to the cells (see above), we see that the better the synchronization, the smaller the number of cells killed. Here, in the presence of entrainment, a larger increase occurs between V 10% and... 

The effect of variability on drug cytotoxicity markedly depends on the temporal pattern of 5-FU delivery. When the peak in the circadian delivery of 5-FU occurs at 4 p.m., i.e. when the circadian schedule of 5-FU administration is most toxic to the cells, whether in the absence or presence of entrainment by the circadian clock, cytotoxicity increases as the degree of variability decreases. The effect is more marked in the conditions of entrainment a threshold in cytotoxicity then exists between... 

Numerical simulations therefore indicate that the least damage to the cells occurs when the peak of 5-FU circadian delivery is at 4 a.m., and when cells are well synchronized, i.e., when cell cycle variability V is lowest. In contrast, when the peak of 5-FU circadian delivery is at 4 p.m., cytotoxicity is enhanced when cells are well synchronized. The cytotoxic effect of the drug, therefore, can be enhanced or diminished by increased cell cycle synchronization, depending on the relative phases of the circadian schedule of drug delivery and the cell cycle entrained by the circadian clock. Continuous infusion of 5-FU is nearly as toxic as the most cytotoxic circadian pattern of anticancer drug delivery. 

The present modeling approach to circadian cancer chronotherapy is based on an automaton model for the cell cycle. Continuous approaches to cell cycle progression have also been used to study the link between cell proliferation and circadian rhythms [44] and to determine, in conjunction with optimal control theory, the most efficient circadian schedules of anticancer drug administration [45]. Including more molecular details of the cell cycle in continuous models for cell populations represents a promising line for future research. Hybrid models incorporating molecular details into the automaton approach presented here will also likely be developed. 

Here, as in a previous publication [33], we used the cell cycle automaton model to probe the cytotoxic effect of various patterns of circadian or continuous 5-FU delivery. The results provide a framework to account for experimental and clinical observations, and to help us predict optimal modes of drug delivery in cancer chronotherapy. By explaining the differential cytotoxicity of various circadian schedules of 5-FU delivery, the model clarifies the foundations of cancer chronothera-peutics. In view of its versatility and reduced number of parameters, the automaton model could readily be applied to probe the administration schedules of other types of anticancer medications active on other phases of the cell cycle. 

The practical implications of this experiment are that when evaluating the effects of shift work due to circadian effects, the type of task being carried out by the worker must be taken into account. For example, skill-based tasks would be expected to exhibit the performance changes characteristic of low memory load tasks, whereas performance variations in knowledge-based tasks would be expected to follow the pattern of high memory load tasks. Performance on rule-based tasks may depend on the degree of frequency of use of the rules, which in turn may determine the memory load. If these results were confirmed by further process plant studies, it would have implications for when different types of operation (involving different levels of memory load) should be scheduled to reduce circadian rhythm effects and minimize errors. 

Figure 7.5 Histograms illustrating typical behavioral state changes observed following bilateral lesions of dopaminergic ventral tegmental pathways in rats receiving 6-hydroxydopamine into the nucleus accumbens (217). Notable amounts of REM sleep are evident during both the major wake (1900-0700) and major sleep (0700-1900) periods. Maintenance of the rest and activity periods to the 12 12 h light dark schedule, respectively, demonstrates the relative preservation of circadian processes.

The final category is termed the sleep-wake schedule disorders. These are seen in people who get their days and nights turned around. The most common examples are shift workers and travelers with jet lag. Additionally, in the elderly, especially those with dementia, a malfunction in the circadian biological rhythm that regulates sleep can leave them awake and alert at night but drowsy and sleeping during the day. 

Stephan FK 2002 The other circadian system. Food as a Zeitgeber. J Biol Rhythms 17 284-292 Stephan FK, Swann JM, Sisk CL 1979 Anticipation of 24-hr feeding schedules in rats with lesions of the suprachiasmatic nucleus. Behav Neural Biol 25 346—363 Stephan FK, Zucker I 1972 Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci USA 69 1583-1586 Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M 2001 Entrainment of the circadian clock in the liver by feeding. Science 291 490-493... 

This disorder occurs when there is a mismatch between the normal rest—activity schedule for a person s environment and the person s circadian sleep— wake pattern. There are four subtypes ... 

Lavie P, Zomer J. Ultrashort sleep-waking schedule. II. Relationship between ultradian rhythms in sleepability and the REM-NONREM cycles and effects of the circadian phase. Electroencephalogr and Clin Neurophysiol 1984 57 35 -2. 

Phase advances of the circadian system and sleep-wake activity have been reported in a number of studies, with daily administration of melatonin (180-183). Termination of melatonin administration resulted in a reversal of the phase advances, with subjects reverting to their preadministration phase. Therefore, continued administration of melatonin may provide a means for those with DSPS to maintain a normal phase, and avoid the associated sleep deprivation due to having to live on a normal schedule. It is important to note, however, that at present the effective dose of melatonin to be administered and the safety of long-term melatonin administration have yet to be established (184). Therefore, melatonin should be thought of as a research compound and not a clinical solution to DSPS. 

Inherent in RTC Ops is the associated sleep and circadian disruption that makes the opportunities for recovery sleep very important. Therefore, time off is an important scheduling issue to zero out any accumulated sleep debt and potentially stabilize any circadian disruption. It is critical that these recovery opportunities are both predictable and protected. Individuals working RTC Ops can plan for recovery sleep if the opportunity can be anticipated. Therefore, protecting the recovery opportunity from interruptions, whether work- or home-... 

Predictability provides an individual with the opportunity to plan, whether for work, recovery requirements, or home activities. When possible, schedule stability provides more consistent circadian cues and the opportunity to create individual patterns and habits that minimize the physiological disruptions. Modem work demands, especially 24/7 requirements, are often associated with overtime, which may be elective or on occasions required. Extending work has the potential to increase the continuous hours awake, be affected by circadian factors by working through a window of circadian low, and contribute to both acute sleep loss and a cumulative sleep debt. The timing and amount of overtime and whether it is elective or required, can all affect the level of physiological disruption. 

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