Colon cancer: prognosis for different latitudes, age groups and seasons in Norway

The survival of colon cancer patients in Norway, as determined three years after diagnosis, is dependent on the season of diagnosis. This has been attributed to seasonal variations of the vitamin D status. Since solar radiation and food are the human sources of vitamin D, we divided Norway in three regions: The southeast region with a high annual dose of ultraviolet (UV) to the population, as evidenced by a high incidence rate of squamous cell carcinoma of the skin (SCC), the midwest region and the north region with low annual UV doses. The latter region is characterized by a high consumption of vitamin D, mainly through fish intake. Vacations to southern latitudes were equally frequent for all the three geographical regions. Two age groups were analyzed separately (< or =65 years and >65 years), since the photosynthesis of vitamin D(3) in skin decreases with age. In all three regions, and in both age groups, the survival was highest for summer and autumn diagnosis. The seasonal effect was slightly, but not significantly, better for the younger than for the older age group. The effect was similar for all three geographical regions, irrespective of SCC incidence.     

OZONE DEPLETION AND INCREASE IN ANNUAL CARCINOGENIC ULTRAVIOLET DOSE

An increase in skin cancer incidence due to an increase of solar ultraviolet (UV) radiation is one of the best quantitated effects of stratospheric ozone depletion. Until now, estimates of effective UV dosages could not be based on spectral data on carcinogenicity. Instead the spectral dependence of sunburn or mutations was used. These data contained little information on longwave ultraviolet radiation (UVA: 315-380 nm). Recently, in hairless mice, experimental data have become available on the carcinogenic effectiveness of the ultraviolet, including UVA. From these new data we can estimate the effect of ozone depletion on the ambient annual carcinogenic UV dose. We find that a 1% decrease in ozone yields a 1.56% increase in annual carcinogenic UV; this value is not strongly dependent on geographical latitude. From this result, combined with the dose-response relationship for UV carcinogenesis, we conclude that for a 1% decrease in total column atmospheric ozone an increase of 2.7% in non-melanoma skin cancer is to be expected.     

Phytochemicals for the Prevention of Photocarcinogenesis

Ultraviolet (UV) exposure has an array of damaging effects and is the main cause of skin cancer in humans. Nonmelanoma skin cancer (NMSC), including basal cell carcinoma and squamous cell carcinoma, is the most common type of cancer. Incidence of NMSC has increased due to greater UV radiation, increased life expectancy and other changes in lifestyle; the annual cost of skin cancer treatment in the United States has increased concurrently to around eight billion dollars. Because of these trends, novel approaches to skin cancer prevention have become an important area of research to decrease skin cancer morbidity and defray the costs associated with treatment. Chemoprevention aims to prevent or delay the development of skin cancer through the use of phytochemicals. Use of phytochemicals as chemopreventive agents has gained attention due to their low toxicity and anticarcinogenic properties. Phytochemicals also exhibit antioxidant, anti‐inflammatory and antiproliferative effects which support their use as chemopreventive agents, particularly for skin cancer. Preclinical and human studies have shown that phytochemicals decrease UV‐induced skin damage and photocarcinogenesis. In this review article, we discuss the selected phytochemicals that may prevent or delay UV‐induced carcinogenesis and highlight their potential use for skin protection.     

UV doses worldwide

UV radiation affects human health. Human exposure to UV radiation causes a few beneficial health effects like vitamin D3 formation but it causes many detrimental health effects: sunburn, ocular damage, photoaging, immune suppression, DNA damage and skin cancer. In countries with fair-skinned populations, skin cancer is the most diagnosed of all cancers. In the United States in 2002, there were over one million new skin cancer cases. That means one out of every 285 people got skin cancer. Skin cancer of fair-skinned individuals is increasing at an alarming rate (4-6% per year) around the world and has now reached so-called "pandemic" proportions. Thus, it is important to know what UV doses people around the world get throughout their lives. This review covers how the outdoor UV doses are weighted for different biological effects, the most commonly used measuring devices for terrestrial and personal UV doses, the natural and other effects on terrestrial and personal UV doses, the time people spend outside, their ambient exposures and the terrestrial and personal UV doses of adult outdoor and indoor workers as well as children and adolescents around the world. Overall, outdoor-working adults get about 10%, while indoor-working adults and children get about 3% (2-4%) of the total available annual UV (on a horizontal plane). People's UV doses increase with increasing altitude and decreasing latitude; most indoor-working adult Europeans get 10,000-20,000 J/m2 per year, Americans get 20,000-30,000 J/m2 per year and Australians are estimated to get 20,000-50,000 J/m2 per year (excluding vacation, which can increase the dose by 30% or more).     

SKIN CANCER AND ULTRAVIOLET RADIATION

Abstract. A new model is presented for the calculation of the increased incidence of non-melanoma skin cancer in Caucasians resulting from ozone reduction. The model postulates that the probability of first incidence of such skin cancer is distributed log-normally as a function of total accumulated lifetime dose of harmful ultraviolet radiation. The effect on skin cancer incidence of an increase in harmful ultraviolet radiation due to ozone reduction can then be calculated directly from the extent to which each individual's lifetime accumulated dose is thereby increased. The result of such a perturbation, on average, would be to cause skin cancer to appear at a slightly earlier age. Since skin cancer is predominantly a disease of the elderly, this shift to younger ages has the effect, when integrated over the entire population, of increasing the overall total incidence of skin cancer.     

ULTRAVIOLET-RADIATION and SKIN CANCER. EFFECT OF AN OZONE LAYER DEPLETION

The effect of changes in the ozone layer on the incidence of skin cancer was explored using data for Norway. Attempts were made to arrive at a relationship between the "environmental effective UV-dose" and the skin cancer incidence. Norway is well suited for this purpose because of the large variation in the annual UV-dose from north to south. Furthermore we have a well developed cancer registry and a homogeneous population with regard to skin type. Four different regions of the country, each with a broadness of 1 degree in latitude (approximately 111 km), were selected (located around 69.5, 63.5, 60 and 58.5 degrees N). The annual effective UV-doses for these regions were calculated, assuming normal ozone conditions throughout the year and the action spectrum proposed by CIE, which extends up to 400 nm. The incidence rate (in the period 1970-1980) of malignant melanoma and non-melanoma skin cancer (mainly basal cell carcinoma) increased with the annual environmental UV-doses. For both these types of cancer a quadratic dose-effect relationship seems to be valid to a first approximation. The present data indicate that the incidence of skin cancer would increase by approximately 2% for each percent ozone reduction.     

UV doses of young adults

Since 1986, people have been informed that they get about 80% of their lifetime ultraviolet (UV) dose by the age of 18. This belief originated from the mathematical conclusion that diligent use of sunscreens (sun protection factor 15 or higher) during the first 18 years of life would reduce the lifetime incidence of nonmelanoma skin cancers by 78%. These data were misconstrued to mean that individuals also got about 80% of their lifetime dose of UV by the age of 18 (linear relationship). However, these calculations were based on the incidence of nonmelanoma skin cancers being related to the square of the UV dose. Careful analysis of UV exposure data shows that Americans actually get less than 25% of their lifetime UV dose by the age of 18. This finding also appears to be true worldwide because Australia, UK and The Netherlands report a similar UV exposure pattern. UV-initiated damage early in life can be promoted by subsequent exposures to progress into tumors later in life. For example, the nonmelanoma skin cancer, squamous cell carcinoma, is dependent on the cumulative UV dose. Thus, a better educational approach for reducing skin cancers would be to instruct fair-skinned individuals to protect themselves throughout their lives from being exposed to too much UV radiation.     

PROMOTIONAL EFFECTS OF ULTRAVIOLET RADIATION ON HUMAN BASAL AND SQUAMOUS CELL CARCINOMA

Abstract— Recent data on the incidence of basal and squamous cell skin cancer among Caucasians in eight regions of the United States have been analyzed. Principal conclusions are that (1) ultraviolet radiation is an effective promoter of non-melanoma skin tumors; (2) the probability of a skin tumor becoming observable in an individual of some given age is well described by the log-normal distribution: (3) the fluence-response relation for both basal and squamous cell tumors is linear with a positive intercept, although the parameter values are clearly different for the two types; (4) a 1% ozone layer depletion would lead to an eventual 1.7% increase in basal cell carcinoma, and a 2.3% increase in squamous cell carcinoma.     

ANNUAL EXPOSURES TO CARCINOGENIC RADIATION FROM THE SUN AT DIFFERENT LATITUDES and AMPLIFICATION FACTORS RELATED TO OZONE DEPLETION. THE USE OF DIFFERENT GEOMETRICAL REPRESENTATIONS OF THE SKIN SURFACE RECEIVING THE ULTRAVIOLET RADIATION

In most calculations of annual fluences of carcinogenic light as well as of the radiation amplification factor and of biological amplification factors associated with ozone depletions, the radiation is assumed to fall on a horizontally oriented plane surface. This is obviously a bad approximation of the surface of the human body. In order to evaluate the importance of using a realistic geometric representation of the surface of the human body we here present calculations of the flux of carcinogenically effective radiation falling on three different bodies: a vertically standing cylinder, a sphere and a horizontally oriented surface. The exposure to carcinogenic radiation depends strongly on the surface geometry. However we find that the radiation amplification factors are almost independent of the surface geometry chosen. The biological amplification factors for the three geometrical representations are also similar to within 20%. The total amplification factor for the increase in the incidence of non-melanoma skin cancer related to ozone depletion is about 17% larger when a cylindrical representation is used compared to when a plane horizontal surface is considered.     

Deciphering UV-induced DNA Damage Responses to Prevent and Treat Skin Cancer

Ultraviolet (UV) radiation is among the most prevalent environmental factors that influence human health and disease. Even 1 h of UV irradiation extensively damages the genome. To cope with resulting deleterious DNA lesions, cells activate a multitude of DNA damage response pathways, including DNA repair. Strikingly, UV-induced DNA damage formation and repair are affected by chromatin state. When cells enter S phase with these lesions, a distinct mutation signature is created via error-prone translesion synthesis. Chronic UV exposure leads to high mutation burden in skin and consequently the development of skin cancer, the most common cancer in the United States. Intriguingly, UV-induced oxidative stress has opposing effects on carcinogenesis. Elucidating the molecular mechanisms of UV-induced DNA damage responses will be useful for preventing and treating skin cancer with greater precision. Excitingly, recent studies have uncovered substantial depth of novel findings regarding the molecular and cellular consequences of UV irradiation. In this review, we will discuss updated mechanisms of UV-induced DNA damage responses including the ATR pathway, which maintains genome integrity following UV irradiation. We will also present current strategies for preventing and treating nonmelanoma skin cancer, including ATR pathway inhibition for prevention and photodynamic therapy for treatment.     

Models relating ultraviolet light and non-melanoma skin cancer incidence.

Abstract— The literature relating ultraviolet (UV) light to skin cancer (SC) has developed very rapidly recently. In this work we review and intercompare the various approaches of dose-response relationships for nonmelanoma skin cancer. After defining a number of options for specifying dose, we describe several statistical epidemiological analyses. Then we discuss a number of models obtained by the inductive method. Finally, we illustrate the application of the mathematical machinery of Reliability Theory to this problem. We note that methodologies which have been used for the UV-SC problem might also find application to broader environmental dose-response problems.     

Inflammatory doses of UV may not be necessary for skin carcinogenesis

The UV wavelengths in sunlight are the main cause of skin cancer in humans. Sunlight causes gene mutations, immunosuppression and, at higher doses, inflammation. While it is clear that immunosuppression and gene mutations are essential biologic events via which UV causes skin cancer, the requirement for UV-induced inflammation is less certain. Both the UVB (290-320 nm) and UVA (320-400 nm) wavebands within sunlight can cause skin cancer, gene mutations and immunosuppression. However, UVB, but not UVA, at realistic doses can cause inflammation, and UVB induces skin cancer, immunosuppression and gene mutations at doses much lower than those required to cause inflammation. Inflammation enhances skin carcinogenesis, but may not be UV induced, and inflammatory mediators at doses too low to cause inflammation may be required. UV-induced mutations can cause epidermal cells to make proinflammatory factors or to induce them in the surrounding stroma, creating an oxidizing environment in which additional oncogenic mutations are likely to take place, even in the absence of UV. Our hypothesis is therefore that subinflammatory doses of both UVA and UVB cause benign skin tumors. One of the effects of sunlight-induced mutations may be the production of inflammatory mediators that enhance carcinogenesis.     

Noninvasive Assessment of UV-induced Skin Damage: Comparison of Optical Measurements to Histology and MMP Expression

Acute exposure to UV radiation (UVR) causes visible skin damage such as erythema and results in local and systemic immunosuppression while chronic exposure can result in photocarcinogenesis. These deleterious effects can be quantified by histology and by bioassays of key biological markers, including matrix metalloproteinases (MMPs), or tryptophan moieties. We now report our results in quantifying UV skin damage with noninvasive optical methods based on reflectance and fluorescence spectroscopy and compare these noninvasive measurements to histopathology and MMP-13 expression. A solar simulator with spectral output nearly identical to that of solar radiation was developed and used in our experiments. SKH1 hairless mice were exposed to solar-simulated UVR at a total dose of 21 MED delivered over 10 weeks. Changes in oxygenated and deoxygenated hemoglobin were measured by diffuse reflectance spectroscopy, and tryptophan changes were monitored via a fluorescence monitor. Our results show that there is an increase in erythema, skin fluorescence, sunburn cells and MMP-13 after a series of suberythemal doses of UV irradiation on a hairless mouse animal model. Increased skin fluorescence is observed with increasing UV exposure. The levels of MMP-13 increase as the cumulative UV dose increases but their increase does not correspond to noninvasively measured changes.     

Assessment of cutaneous photosensitivity of TOOKAD (WST09) in preclinical animal models and in patients

TOOKAD (WST09) is a new, long-wavelength palladium bacteriopheophorbide photosensitizer that targets tissue vasculature. The cutaneous phototoxicity of TOOKAD was assessed in normal rat and pig animal models and in patients in a Phase-I trial of TOOKAD-mediated photodynamic therapy (PDT) for recurrent prostate cancer. Controlled skin exposures were administered using solar-simulated light at various times after drug administration. Two different spectral ranges were used. In the first, the UV portion of the spectrum was removed (UV(-)) because UV irradiation in nondrugged control animals produced an erythema response at incident energy densities (J/cm(2)) lower than those required to induce a PDT response. In the second, the full solar spectrum (UV(+)) was used, and the potentiation by the photosensitizer of the UV-mediated minimum erythema dose was assessed. Results showed that the PDT skin response was negligible at clinical drug doses of 2 mg/kg for any period after administration at light doses of 128 J/cm(2) in the animal models. In patients, there was no observed UV(-) skin response at doses of up to 2 mg/kg, drug-light intervals of 1-3 h or greater and light exposures up to 128 J/cm(2). At higher drug doses in the rat and pig models, the duration of skin phototoxicity was found to be approximately 3 h and less than 1 h, respectively. Using the full spectrum of solar-simulated light, the presence of TOOKAD did not measurably enhance the UV(+)-induced erythema in the rats, pigs or patients.     

Objective measurement of minimal erythema and melanogenic doses using natural and solar-simulated light

Very little information exists on the amount of natural and artificial UV light required to cause sunburn and tanning in individuals with very pale skin who are at the greatest risk of developing skin cancer. We have investigated minimal erythema dose (MED) and minimal melanogenic dose (MMD) in a group of 31 volunteers with Fitzpatrick skin types I and II using an Oriel 1000 W xenon arc solar simulator and natural sunlight in Sydney, Australia. We measured the erythemal and melanogenic responses using conventional visual scoring, a chromameter and an erythema meter. We found that the average MED measured visually using the artificial UV source was 68.7 +/- 3.3 mJ/cm2 (3.4 +/- 0.2 standard erythema doses [SED]), which was significantly different from the MED of sunlight, which was 93.6 +/- 5.6 mJ/cm2 (P < 0.001) (11.7 +/- 0.7 SED). We also found significant correlations between the solar-simulated MED values, the melanin index (erythema meter) and the L* function (chromameter). The average MMD (obtained in 16 volunteers only) using solar-simulated light was 85.6 +/- 4.9 mJ/cm2, which was significantly less than that measured with natural sunlight (118.3 +/- 8.6 mJ/cm2; P < 0.05). We mathematically modeled the data for both the chromameter and the erythema meter to see if we were able to obtain a more objective measure of MED and differentiation between skin types. Using this model, we were able to detect erythemal responses using the erythema index function of the erythema meter and the a* function of the chromameter at lower UV doses than either the standard visual or COLIPA methods.     

Impact of the Circadian Clock on UV‐Induced DNA Damage Response and Photocarcinogenesis

The skin is in constant exposure to various external environmental stressors, including solar ultraviolet (UV) radiation. Various wavelengths of UV light are absorbed by the DNA and other molecules in the skin to cause DNA damage and induce oxidative stress. The exposure to excessive ultraviolet (UV) radiation and/or accumulation of damage over time can lead to photocarcinogenesis and photoaging. The nucleotide excision repair (NER) system is the sole mechanism for removing UV photoproduct damage from DNA, and genetic disruption of this repair pathway leads to the photosensitive disorder xeroderma pigmentosum (XP). Interestingly, recent work has shown that NER is controlled by the circadian clock, the body's natural time‐keeping mechanism, through regulation of the rate‐limiting repair factor xeroderma pigmentosum group A (XPA). Studies have shown reduced UV‐induced skin cancer after UV exposure in the evening compared to the morning, which corresponds with times of high and low repair capacities, respectively. However, most studies of the circadian clock–NER connection have utilized murine models, and it is therefore important to translate these findings to humans to improve skin cancer prevention and chronotherapy.     

Dietary agents in cancer prevention: an immunological perspective(†)

Skin cancer is the most common form of cancer diagnosed in the United States. Exposure to solar ultraviolet (UV) radiations is believed to be the primary cause for skin cancer. Excessive UV radiation can lead to genetic mutations and damage in the skin's cellular DNA that in turn can lead to skin cancer. Lately, chemoprevention by administering naturally occurring non-toxic dietary compounds has proven to be a potential strategy to prevent the occurrence of tumors. Attention has been drawn toward several natural dietary agents such as resveratrol, one of the major components found in grapes, red wines, berries and peanuts, proanthocyanidins from grape seeds, (-)-epigallocatechin-3-gallate from green tea, etc. However, the effect these dietary agents have on the immune system and the immunological mechanisms involved therein are still being explored. In this review, we shall focus on the role of key chemopreventive agents on various immune cells and discuss their potential as antitumor agents with an immunological perspective.     

Seasonal erythemal UV doses in Belo Horizonte, Brazil

The ultraviolet radiation (UVR) emitted by the Sun causes many effects on the biosphere. On human beings they vary from the benefit of vitamin D synthesis to the harm of skin cancer induction. The biological dose depends on the effect, the exposure time to the Sun and the amount of UVR received. In this work we show that the measured incidence of erythemal dose (ED) in Belo Horizonte (19.92 degrees S, 43.94 degrees W, 858 m a.s.l., Brazil) for a cloudless day can vary from 7503 to 2926 J m(-2) in the summer-winter seasonal variation. In addition, supposing a linear relationship between the ED and the geophysical parameters of solar zenith angle cosine (cos(SZA)), column ozone and reflectivity from the ozone monitoring instrument overpass measurements, a model for the forecast of UVR incidence on a monthly-based period is developed. From this an annual ED of 1,451,099 J m(-2) is obtained.     

POTENTIAL EFFECTS OF ALTERED SOLAR ULTRAVIOLET RADIATION ON HUMAN SKIN CANCER

There is highly significant evidence that non-melanoma skin cancers are primarily due to chronic repeated exposure to solar ultraviolet radiation, and that there is a significant, although somewhat different relationship between solar radiation and the development of cutaneous malignant melanoma. Recent experimental and epidemiologic studies show that the biologically most effective UVR wavelengths are in the segment of the solar UVR spectrum that would be significantly augmented by decreases in stratospheric ozone content. A recent report on measurements of column ozone changes in the stratosphere has shown that in the past 18 yrs, there has been an ozone decrease between 2 and 3%, greater in the winter months, and somewhat differing with latitude in the Northern Hemisphere. Calculations of the relationship of ozone decrease to increase in biologically effective UVR show great dependence on the biologic action spectrum assumed. Based on extensive epidemiologic studies of skin cancer incidence, it appears that the estimated increase in biologically effective UVR due to the measured ozone decreases in the past (almost) two decades are not likely to be the cause of the sharp increase in skin cancer incidence which have been observed. Most likely these increases in incidence are the result of increasing personal exposure, due to striking changes in personal behavior that have taken place for social reasons. However, there is every reason to believe that increases in biologically effective UVR due to stratospheric ozone decreases will have significant impact on human skin cancer incidence in the future.