The circadian clock regulates a wide range of physiological activities and, for many years, it has been suggested that the time of day at which cancer patients receive chemotherapy or radiation therapy can influence both the effectiveness and side-effects of the treatment. A lack of understanding of the complex mechanisms underlying this effect – together with logistical considerations – has, however, prevented timing from becoming a major determinant in most treatment centres. A study from scientists at the University of North Carolina at Chapel Hill has now identified a biochemical mechanism which may explain circadian sensitivity to the anti-cancer drug cisplatin.
The results, published in the 21st January Early Edition of PNAS, suggest that treatment with chemotherapy may be most effective at times of the day when levels of one the DNA repair enzymes are at their lowest. The enzyme is xeroderma pigmentosum A (XPA), the component of the nucleotide excision repair system that repairs bulky lesions in DNA such as those caused by cisplatin. The study showed that the activity of XPA in brain tissue from mice followed a circadian rhythm with peak levels some 5-10-fold higher than the lowest levels. It is not yet known whether the circadian levels of XPA in tumour cells or other cells of the body follow the same oscillations as those in the brain, but the study clearly suggests that circadian changes in levels of XPA should be taken into account when designing chemotherapy regimens. Studies on the effect of timing on treatment with cisplatin in rodents and human patients have so far focussed largely on reducing toxicity, and results are complicated by the fact that rodents are nocturnal. Cisplatin was generally found to be most toxic in both rodents and humans when administered soon after awakening.
The present study could also have implications for the prevention of cancer, for example by allowing people to use extra protection against the damaging effects of ultraviolet irradiation from the sun at those times of day when levels of DNA repair enzyme in the skin are at their lowest.