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    Afternoon sun exposure carries greater risk of skin cancer in humans

    National report — The risk of developing skin cancer from sun exposure in the afternoon is significantly greater than from exposure in the morning, a new study shows.

    What makes the difference? It's not the exposure, per se, but the cellular repair mechanism for UV damage to DNA, which is circadian in nature and at its peak efficiency early in the day.

    Dr. Sancar
    The discovery was made in mice — nocturnal animals whose circadian cycle is the opposite of that in humans — by Aziz Sancar, M.D., Ph.D., and published in the journal Proceedings of the National Academy of Sciences. Dr. Sancar, a professor of biochemistry at the University of North Carolina School of Medicine, Chapel Hill, has made many important discoveries concerning circadian rhythms.

    UV radiation causes DNA damage either in the form of cyclobutane pyrimidine dimer (CPD) or the (6-4) photoproduct. Both changes are mutagenic and carcinogenic in the animal model. Mice and humans share the same, sole molecular mechanism to excise and repair sun-damaged nucleotides. Part of that mechanism is xeroderma pigmentosum group A (XPA) protein, whose deficiency causes the disease for which the protein is named, Dr. Sancar tells Dermatology Times.

    Dr. Sancar's earlier work determined that the core molecular circadian clock regulates XPA gene expression and the level of production of the XPA protein in the livers and brains of mice. He reasoned that it ought to apply to the skin as well. Dr. Sancar first determined that this indeed was the case, and then exposed one group of animals to UVB when the repair mechanism was at its functional nadir (4 a.m.) and another group when the cycle was it its peak (4 p.m.).

    Both groups of animals developed tumors, but the time to first tumor in the morning group was shorter (median 19 vs. 21 weeks); they developed twice as many tumors (24 vs. 12 tumors) in the 25-week observation period; the average tumor diameter was nearly twice as large as was seen in the afternoon group; and there were five times as many invasive tumors in the morning group compared to the afternoon group.

    "The main point is that we found that the same UVB dose is five times more carcinogenic in the morning than in the afternoon" in the mouse model, Dr. Sancar says. At either time point, photoproduct damage was repaired "about 10-fold faster than CPD because PP (photoproduct) distorts the DNA more severely."

    Relating to human cycles

    Repair correlated with the level of XPA; there was substantial repair during the phase of the cycle when the level of XPA was high, but little or no repair when that level was low. Repair speeded up when the level of XPA cycled back to high.

    As mice are nocturnal and humans are diurnal, their circadian cycle is reversed. "We know that in humans the repair mechanism that prevents cancer is the opposite of what we see in mice. From that we extrapolated that in humans it would be the opposite. In humans (UV exposure) is more carcinogenic in the afternoon than in the morning," he says.

    Dr. Sancar says humans can have different chronotypes, or body clocks, "but in the majority of humans, the chronotype shifts by a couple of hours; it's not a big shift. Even within the different chronotypes, one can say with relative confidence that in humans the repair will be better in the morning, whether it is at 7 o'clock, or 5 a.m. We can say with confidence that in all chronotypes, it will be better in the morning."

    Circadian impact

    This information has clinical implications. Dr. Sancar cites the example of cisplatin, one of the most commonly used cancer drugs, which damages healthy tissue as well as the tumor. He says in treating some cancers it is best to administer the drug when cellular repair mechanisms are at their highest and the healthy tissue can best repair itself.

    "In some cancer tissues the clock isn't functioning anymore," he says. "So you take this drug when repair is at the maximum in all other tissue so that you minimize the side effects while you have the same toxic effect on the cancer cells."

    Other studies have demonstrated a circadian impact on response to blood pressure medications and flu vaccination, which varied depending upon the time of day the drugs were administered. Dr. Sancar says he suspects there might be a similar response with regard to surgical trauma and healing.

    Dr. Zachary
    Christopher Zachary, M.D., chairman of the department of dermatology, University of California, Irvine, found the research intriguing and the findings robust. He says it fits with human evolution as a diurnal species that arises with first sunlight, and with other observed cyclical patterns such as those of cortisol and melatonin.

    But Dr. Zachary says he doubts that the new information will influence the advice that dermatologists give to patients regarding sun exposure. Rather than complicate the message, he says, dermatologists should stick with the simple, straightforward one of using sunscreen and minimizing sun exposure — regardless of the time of day.

    Disclosures: The research was conducted with grant support from the National Institutes of Health. Drs. Sancar and Zachary report no relevant financial interests.

    Bob Roehr
    Bob Roehr is a medical writer based in Washinton, D.C.

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