Melatonin involvement in cancer: methodological considerations

On the one hand, melatonin has been determined in different body fluids to seek markers of a heightened risk of cancer development. On the other hand, it has been used as an oncostatic drug in the treatment plan of cancer patients. For both applications, timing has proved to be critical, not only along the circadian scale but in relation to a number of other multifrequency rhythms as well. Like other immunomodulators, melatonin has been shown in the experimental laboratory to inhibit cancer growth when administered at one circadian stage but to enhance it when given at another. Such circadian stage-dependence of melatonin effects was observed in a mouse leukemia model, in a mouse sarcoma model, and in spontaneous mammary carcinogenesis. In the latter model, circannual and/or other secular changes were also noted. “First do no harm” is hence a particularly restrictive possibility in the clinical use of immunomodulators such as melatonin. Marker rhythmometry is a useful tool offered by chronobiology to guide treatment timing while, if specific, it can also serve for the assessment of the patienfs response to treatment. In relation to cancer chronorisk, a prominent circadian rhythm was found to characterize urinary melatonin in groups of clinically healthy women at high or low risk of developing breast cancer. The major difference between women at high vs low breast cancer risk was in the circadian amplitude, the rhythm being more prominent in the high risk women. In the presence of actual disease, however, the circadian amplitude of circulating melatonin is statistically significantly reduced in comparison with healthy women. In view of the absence of a difference in mean value, it thus becomes critical to assess the circadian variation since a difference can only be validated at some, but not all circadian stages. This is particularly true since the validated difference can be in either direction. Doing no harm, in this case and many others, gene therapy included, is a critical commandment, when harm can be avoided by scheduling according to body time. Individual differences in the timing of the acrophase of the circadian melatonin rhythm further speak against reliance on spot-checks, even if they are clock time-specified. Whether focus is placed on chronorisk assessment or on chronotherapy, the multifrequency rhythms of a broad time structure (chronome) should be kept in mind. Central to the chronomes are feedsideward mechanisms, that is interactions among multiple rhythmic entities that result in predictable sequences of attenuation, no effect, and amplification of the effect of one entity (the actor) upon another entity (the reactor) as it may be modified by a third entity (the modulator). The pineal gland, whose major product is melatonin, has been documented to be primarily involved in feedsidewards, which may account for seemingly contradictory phenomena that become predictable once the data are properly time-specified and analyzed for rhythms. Apart from circadian behavior, the pineal gland is also eminently circaseptan-periodic and is known to be sensitive to changes in magnetic field, aspects awaiting exploitation in the clinic, where circaseptan scheduling may be more practical to optimize than the circadian routine; but both these and other roles of timing can be assessed by marker rhythmometry. Variability, a terrible foe when it remains unassessed, can become a new resolving tool, particularly useful in the study of neuroimmunomodulation.