583 research outputs found
UVA1 genotoxicity is mediated not by oxidative damage but by cyclobutane pyrimidine dimers in normal mouse skin
UVA1 induces the formation of 8-hydroxy-2′-deoxyguanosines (8-OH-dGs) and cyclobutane pyrimidine dimers (CPDs) in the cellular genome. However, the relative contribution of each type of damage to the in vivo genotoxicity of UVA1 has not been clarified. We irradiated living mouse skin with 364-nm UVA1 laser light and analyzed the DNA damage formation and mutation induction in the epidermis and dermis. Although dose-dependent increases were observed for both 8-OH-dG and CPD, the mutation induction in the skin was found to result specifically from the CPD formation, based on the induced mutation spectra in the skin genome: the dominance of C → T transition at a dipyrimidine site. Moreover, these UV-specific mutations occurred preferentially at the 5′-TCG-3′ sequence, suggesting that CpG methylation and photosensitization-mediated triplet energy transfer to thymine contribute to the CPD-mediated UVA1 genotoxicity. Thus, it is the CPD formation, not the oxidative stress, that effectively brings about the genotoxicity in normal skin after UVA1 exposure. We also found differences in the responses to the UVA1 genotoxicity between the epidermis and the dermis: the mutation induction after UVA1 irradiation was suppressed in the dermis at all levels of irradiance examined, whereas it leveled off from a certain high irradiance in the epidermis
Sunscreens - Which and what for?
It is well established that sun exposure is the main cause for the development of skin cancer. Chronic continuous UV radiation is believed to induce malignant melanoma, whereas intermittent high-dose UV exposure contributes to the occurrence of actinic keratosis as precursor lesions of squamous cell carcinoma as well as basal cell carcinoma. Not only photocarcinogenesis but also the mechanisms of photoaging have recently become apparent. In this respect the use of sunscreens seemed to prove to be more and more important and popular within the last decades. However, there is still inconsistency about the usefulness of sunscreens. Several studies show that inadequate use and incomplete UV spectrum efficacy may compromise protection more than previously expected. The sunscreen market is crowded by numerous products. Inorganic sunscreens such as zinc oxide and titanium oxide have a wide spectral range of activity compared to most of the organic sunscreen products. It is not uncommon for organic sunscreens to cause photocontact allergy, but their cosmetic acceptability is still superior to the one given by inorganic sunscreens. Recently, modern galenic approaches such as micronization and encapsulation allow the development of high-quality inorganic sunscreens. The potential systemic toxicity of organic sunscreens has lately primarily been discussed controversially in public, and several studies show contradictory results. Although a matter of debate, at present the sun protection factor (SPF) is the most reliable information for the consumer as a measure of sunscreen filter efficacy. In this context additional tests have been introduced for the evaluation of not only the protective effect against erythema but also protection against UV-induced immunological and mutational effects. Recently, combinations of UV filters with agents active in DNA repair have been introduced in order to improve photoprotection. This article reviews the efficacy of sunscreens in the prevention of epithelial and nonepithelial skin cancer, the effect on immunosuppression and the value of the SPF as well as new developments on the sunscreen market. Copyright (C) 2005 S. Karger AG, Basel
Mechanistic considerations on the wavelength-dependent variations of UVR genotoxicity and mutagenesis in skin: the discrimination of UVA-signature from UV-signature mutation
Langerhans Cell Contributions To Ultraviolet Light-Induced Cutaneous Carcinogenesis
Epidermal dendritic cells, called Langerhans cells (LC), were recently shown to facilitate DMBA/TPA-induced chemical carcinogenesis. LC contribution to UV-induced carcinogenesis, however, remains to be elucidated. We used the Langerin-DTA transgenic mouse model that lacks LC to characterize early and late effects of DNA damage in epidermis following exposure to UVB light. We found that LC density in LC-intact mice remains unchanged at 1hr and 24hr post 100 J/m2 UVB, suggesting that LC are poised to affect the surrounding epidermal cells following acute low-dose UVB exposure. During this time interval, LC-deficient mice had significantly fewer γH2Ax-positive cells within the epidermis, indicative of decreased UV- induced DNA damage in the absence of LC. However, when the pathognomonic direct and indirect UV-induced DNA lesions were measured (cyclobutane pyrimidine dimers and 8- oxoguanine, respectively), we found no differences in the absence or presence of LC, suggesting that LC may contribute to acute UV-induced DNA damage by a different, unidentified mechanism. Since mutant p53, a tumor suppressor protein highly associated with squamous cell carcinoma, arises from unrepaired DNA damage, we measured islands of clonally expanded keratinocytes harboring mutant following chronic UVB exposure. LC-deficient mice had significantly fewer p53 islands and a two-fold decrease in the total area occupied by p53 islands after 9 weeks of UVB irradiation, thus LC also contribute to the survival and proliferation of transformed keratinocytes during chronic UVB exposure. Collectively, these results suggest that LC influence DNA damage and clonal expansion in the surrounding epidermal cells in both acute and chronic UVB exposure. It provides new insight into the previously unknown role of LC in photocarcinogenesis with the objective to develop novel preventive and therapeutic targets against skin cancer
The Risk of Cancer Associated with Immunosuppressive Therapy for Skin Diseases
The possible carcinogenic risk of immunosuppressive therapies is an important issue in everyday clinical practise. Carcinogenesis is a slow multi step procedure, thus a long latency period is needed before cancer develops. PUVA therapy is used for many skin diseases including psoriasis, early stage cutaneous T cell lymphoma, atopic dermatitis, palmoplantar pustulosis and chronic eczema. There has been concern about the increased melanoma risk associated to PUVA therapy, which has previously been associated with an increased risk on non-melanoma skin cancer, especially squamous cell carcinoma. The increased risk of basal cell carcinoma (BCC) is also documented but it is modest compared to squamous cell carcinoma (SCC).
This thesis evaluated melanoma and noncutaneous cancer risk associated to PUVA, and the persistence of nonmelanoma cancer risk after the cessation of PUVA treatment. Also, the influence of photochemotherapy to the development of secondary cancers in cutaneous T cell lymphoma and the role of short term cyclosporine in later cancer development in inflammatory skin diseases were evaluated.
The first three studies were performed on psoriasis patients. The risk of melanoma started to increase 15 years after the first treatment with PUVA. The risk was highest among persons who had received over 250 treatments compared to those under 250 treatments. In noncutaneous cancer, the overall risk was not increased (RR=1.08,95% CI=0.93-1.24), but significant increases in risk were found in thyroid cancer, breast cancer and in central nervous system neoplasms. These cancers were not associated to PUVA. The increased risk of SCC was associated to high cumulative UVA exposure in the PUVA regimen. The patients with high risk had no substantial exposure to other carcinogens. In BCC there was a similar but more modest tendency.
In the two other studies, the risk of all secondary cancers (SIR) in CTCL patients was 1.4 (95% CI=1.0-1.9). In separate sites, the risk of lung cancer, Hodgkin and non-Hodgkin lymphomas were increased. PUVA seemed not to contribute to any extent to the appearance of these cancers. The carcinogenity of short-term cyclosporine was evaluated in inflammatory skin diseases. No increased risk for any type of cancer including the skin cancers was detected.
To conclude, our studies confirm the increased skin cancer risk related to PUVA treatment in psoriasis patients. In clinical practice, this has led to a close and permanent follow-up of patients treated with PUVA. In CTCL patients, PUVA treatment did not contribute to the development of secondary cancers. We could not detect any increase in the risk of cancer in patients treated with short term cyclosporine, unlike in organ transplant patients under such long-term therapy.Vaikeiden tulehduksellisten ihosairauksien hoidossa joudutaan käyttämään elimistön puolustusjärjestelmään vaikuttavia hoitoja ja lääkkeitä. Näitä hoitomuotoja ovat mm. PUVA-hoito sekä siklosporiinilääkitys. Edellämainitut hoidot ovat tehokkaita, mutta puolustusjärjestelmään vaikuttavina hoitoina niihin voi pitkällä aikavälillä liittyä lisääntynyt syöpäriski. Syövän kehittyminen on monimutkainen, useita vuosia kestävä tapahtumasarja. Hoitojen mahdolliset pitkäaikaissivuvaikutukset eivät ole olleet tiedossa niitä aloitettaessa, ja epidemiologiset pitkäaikaistutkimukset ovat ainoa tapa saada uutta tietoa eri hoitomuotojen mahdollisesta syöpäriskistä.
PUVA-hoito toteutetaan herkistämällä iho ensin psoraleenilla ja sen jälkeen valottamalla UVA-säteillä. Yleisiä PUVA:lla hoidettavia ihosairauksia ovat mm. psoriaasi, lichen planus, palmoplantaarinen pustuloosi, prurigo nodularis, ihon T-solulymfooma ja erilaiset ekseemat. Immuunivastetta hillitsevällä siklo-sporiinilla hoidetaan nykyisin esim. atooppista ekseemaa, psoriaasia, palmoplantaarista pustuloosia ja hankalaa käsiekseemaa. Molempiin edellä mainittuihin hoitoihin tiedetään liittyvän lisääntynyt syöpäriski. PUVA-hoito lisää erityisesti ihon okasolusyöpien riskiä, ja myös siklosporiinia saavilla elinsiirtopotilailla näiden syöpien riski on lisääntynyt.
Väitöskirjatyössä tutkittiin sisäisen PUVA-hoidon yhteyttä melanooman ja sisäelinsyöpien kehittymiseen sekä sisäisen PUVA-hoidon yhteyttä ihosyöpien ilmaantumiseen PUVA-hoidon päättymisen jälkeen. Lisäksi tutkittiin ihon T-solulymfoomaa sairastavien potilaiden muiden syöpien riskiä ja niiden mahdollista yhteyttä PUVA-hoitoon. Tutkimme myös lyhytaikaisen, ihotauteihin käytetyn siklosporiinihoidon vaikutusta myöhemmin ilmaantuviin syöpiin.
Tuloksissa pitkäaikaiseen sisäiseen PUVA-hoitoon liittyi lisääntynyt melanoomariski, joka oli suurimmillaan yli 250 PUVA-hoitokertaa saaneilla ja/tai yli 15 vuoden kuluttua hoidon aloittamisesta. Sisäelinsyöpien kokonaisriski ei ollut kohonnut, mutta kilpirauhas-, rinta- ja keskushermostosyöpien osuus oli lisääntynyt. Nämä potilaat eivät kuitenkaan olleet saaneet suuria PUVA-hoitoannoksia (yli 300 kertaa). PUVA-hoidon ihosyöpiä (oka- ja tyvisolusyöpiä) lisäävä vaikutus on pysyvä, vaikka hoito lopetetaan. Ihon T-solulymfoomaa sairastavilla potilailla keuhkosyöpä- ja lymfoomariski olivat kohonneet, mutta PUVA-hoidolla ei ollut vaikutusta tähän. Potilailla, jotka olivat saaneet lyhytaikaisesti siklosporiinihoitoa, ei voitu todeta lisääntynyttä syöpäriskiä eikä ihosyöpien määrä ollut merkittävästi lisääntynyt.
Yhteenvetona väitöskirjatyö osoitti, että PUVA-hoidon syöpää aiheuttava vaikutus rajoittuu pelkästään iholle. Pitkäaikainen PUVA-hoito lisää melanoomariskiä ja myös muiden ihosyöpien riskiä, vaikka hoito olisi jo lopetettu. Iholymfoomapotilailla todetut syövät eivät olleet yhteydessä PUVA-hoitoihin, ja lyhyt-aikaisen siklosporiinihoidon ei voitu osoittaa aiheuttavan syöpiä. PUVA-hoidon osalta löydös on merkittävä ja on johtanut runsaasti PUVA-hoitoja saaneiden potilaiden tarkkaan seurantaan
UVB Induced Mutation of p53 in Non Melanoma Skin Cancer
There is a clear correlation between excessive sun exposure and the development of skin cancer. UVB radiation from the sun is potent, and as the ozone layer gets depleted, more UVB can reach Earth and cause cell damage. UV radiation causes DNA lesions, such as 6-4 photoproducts and cyclobutane pyrimidine dimers. Cyclobutane pyrimidine dimers are more abundant and take longer to be repaired and therefore are responsible for most of the mutation and DNA damage. These DNA lesions lead to mutation of the p53 gene. The signature mutation on p53 from UV radiation is a CC to TT mutation, which generally occurs at the binding site of p53. As a result, of the mutation, p53 is inactivated and can no longer perform its tumor suppressive functions. As a result, cancerous or damaged cells in the skin can proliferate and form tumors. P53 is an early step in skin carcinogenesis, and p53 mutation is found in abundance in actinic keratosis, a precancerous lesion of Squamous Cell Carcinoma. Experiments conducted on mice prove the effectiveness of sunscreen. Mice treated with UVB blocking sunscreen had significantly decreased percentage of mutation, compared to mice without the sunscreen
Development of a high-throughput screening system for identification of novel reagents regulating DNA damage in human dermal fibroblasts
Ultraviolet (UV) radiation is a major inducer of skin aging and accumulated exposure to UV radiation increases DNA damage in skin cells, including dermal fibroblasts. In the present study, we developed novel DNA repair regulating material discovery (DREAM) system for the high-throughput screening and identification of putative materials regulating DNA repair in skin cells. First, we established a modified lentivirus expressing the luciferase and hypoxanthine phosphoribosyl transferase (HPRT) genes. Then, human dermal fibroblast WS-1 cells were infected with the modified lentivirus, and selected with puromycin to establish cells that stably expressed luciferase and HPRT (DREAM-F cells). The first step in the DREAM protocol was a 96-well-based screening procedure, involving the analysis of cell viability and luciferase activity after pretreatment of DREAM-F cells with reagents of interest and post-treatment with UVB radiation, and vice versa. In the second step, we validated certain effective reagents identified in the first step by analyzing the cell cycle, evaluating cell death, and performing HPRT-DNA sequencing in DREAM-F cells treated with these reagents and UVB. This DREAM system is scalable and forms a time-saving high-throughput screening system for identifying novel anti-photoaging reagents regulating DNA damage in dermal fibroblasts
Occupational Skin Diseases Caused by UV Radiation
This overview highlights the risk of skin diseases arising
in workers exposed to ultraviolet radiation (UVR) at their workplace.
There is a plethora of skin manifestations in outdoor workers such
as seamen, fishermen, farmers after acute intense or long-term
exposure to solar UVR, but some cutaneous diseases may also
develop in indoor workers exposed to artificial sources. In recent
years, investigations of the biological effects and damage caused
by UVB and UVA on the skin have improved our understanding of
the cellular and molecular mechanisms of photoaging, skin cancer
and other skin diseases caused by UVR exposure. The necessity of
primary prevention in workers exposed to UVR is emphasize
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