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Circadian Clock May Influence Response to Some Chemotherapy



Nick Mulcahy
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January 16, 2009 — The circadian time of delivery of chemotherapeutic drugs, such as cisplatin, might be a significant contributing factor to the efficacy of the drug and the severity of its side effects, according to a report published online January 13 in the Proceedings of the National Academy of Sciences.
The study suggests that chemotherapy is most effective at certain times of day, because that is when a particular enzyme system, which can reverse the actions of chemotherapeutic drugs, is at its lowest levels in the body.
The enzyme system, known as nucleotide excision repair, fixes many types of DNA alterations that come from chemotherapy and other influences, such as sunlight.
"Timing is everything, and here we have molecular data showing why this is especially true with regard to cancer," said senior study author Aziz Sancar, MD, PhD, the Sarah Graham Kenan professor of biochemistry and biophysics in the University of North Carolina School of Medicine, in Chapel Hill, in a statement.
"By hitting cancer cells with chemo at a time when their ability to repair themselves is minimal, you should be able to maximize effectiveness and minimize side effects of treatment," he said, summarizing the potential practical applications of the new research.
Other Studies Have Lacked Mechanism of Action
Circadian rhythm or time is the daily oscillation in the biochemical, behavioral, and physiological functions of organisms. Circadian-clock disruption by environmental factors and behavioral patterns has been implicated as a contributing factor in carcinogenesis, according to the study authors.
Previous studies have indicated that the efficacy and adverse effects of chemotherapy and radiotherapy of cancer are influenced by the circadian time of administration of these therapies. Efforts have been made to put these findings into practice in preventive and clinical medicine, but the lack of mechanistic explanations for the findings has been one of the "serious obstacles" to making practical use of these findings, especially in oncology, write the authors.
In the new study, Dr. Sancar and his colleagues investigated the effect of the circadian clock on nucleotide excision repair in mice. "Excision repair is a multicomponent system that removes virtually all DNA base lesions, and is the sole system in mice and humans for the repair of bulky lesions," such as those produced by cisplatin, write the authors.
Using an "excision assay," the researchers harvested organs from mice and tested them for nucleotide excision repair. They discovered that tissue from the cerebrum or brain was best for analysis of the molecular activity. They found that excision repair activity exhibits a "bona fide circadian rhythm," and that maximum activity was about 5- to 10-fold greater than minimum activity. Furthermore, they found that that the ability to repair damage was at a minimum in the early morning and reached a maximum in the evening hours.
They then looked at various proteins that can affect repair activity. One of them, enzyme XPA, exhibited a circadian-time-dependent change in expression. To determine if the reduced excision repair in the cerebrum was indeed caused by a circadian-influenced low level of XPA, the researchers used recombinant XPA and retested for activity. Their results were verified and the researchers concluded that "the main cause of circadian oscillation of excision repair activity in mouse cerebrum is the circadian oscillation of the XPA protein level."
The findings of the mouse-model study provide a "plausible molecular explanation" for the empirical observation that the time of delivery of chemotherapies, such as cisplatin, might be a "significant contributing factor to the efficacy of the drug and the severity of its side effects," note the authors.
What's Next?
Dr. Sancar wants to extend their research to determine whether the same cyclical changes in repair activity seen in mouse brains can also be observed in mouse testes. According to a statement from the University of North Carolina, this investigation is "particularly relevant" because cisplatin is a chemotherapeutic agent commonly used to treat testicular cancer and kills cancer cells by damaging DNA.
The research was supported by the National Institutes of Health. The researchers have disclosed no relevant financial relationships.
Proc Natl Acad Sci. Published online before print January 13, 2009.

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Nick Mulcahy is a senior journalist for Medscape Oncology. Before joining Medscape, Nick was a freelance medical news writer for 15 years, working for companies such as the International Medical News Group, MedPage Today, HealthDay, McMahon Publishing, and Advanstar. He is also the former managing editor of breastcancer.org. He can be contacted at nmulcahy@medscape.net.

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