Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenases (COX)-1 and COX-2 catalyse the key steps of prostaglandin biosynthesis and are the major target for non-steroidal anti-inflammatory drugs. In general, COX-1 but not COX-2 is expressed in healthy tissues of adults. After incision or acute irritant dermatitis, COX-2 is induced transiently. The development of UV-induced erythema and edema as well as of skin tumours is significantly governed by COX-2 activity. Squamous cell carcinomas and actinic keratoses are prominent examples of epithelial tumours with COX-2 overexpression in the tumour parenchyma, inflammatory infiltrate and associated vessels. According to multi-stage carcinogenesis studies in mouse skin and experiments with transgenic mice, there is a causal relationship between aberrant COX-2 expression and activity in the epithelium and tumour promotion and tumour progression. The transgenic overexpression of COX-2 causes an "autopromoted" skin phenotype, i.e. it dramatically sensitizes the tissue for the development of squamous cell carcinomas. Vice versa, the genetic ablation of COX-2, as well as of COX-1, results in a reduced tumour burden in murine skin. A major mechanism by which COX-2 contributes to epidermal tumour formation seems to be the disturbance of terminal keratinocyte differentiation. Because of these data, selective COX-2 inhibitors are ranked among the most promising agents for skin cancer prevention and therapy.
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PMID:[Cyclooxygenases in the skin]. 1627 29

It is well known that ultraviolet (UV) radiation induces erythema, immunosuppression and carcinogenesis. We hypothesized that chronic exposure to solar UV radiation induces adaptation that eventually prevents the suppression of acquired immunity. We studied adaptation for UV-induced immunosuppression after chronic exposure of mice to a suberythemal dose of solar simulated radiation (SSR) with Cleo Natural lamps, and subsequent exposure to an immunosuppressive dose of solar or UVB radiation (TL12). After UV dosing, the mice were sensitized and challenged with either diphenylcyclopropenone (DPCP) or picryl chloride (PCl). To assess the adaptation induced by solar simulated radiation, we measured the proliferative response and cytokine production of skin-draining lymph node cells after immunization to DPCP, the contact hypersensitivity (CHS) response to PCl, and thymine-thymine (T-T) cyclobutane dimers in the skin of mice. After induction of immunosuppression by SSR or by TL12 lamps, the proliferative response of draining lymph node cells after challenge with DPCP, or the CHS after challenge with PCl, showed significant suppression of the immune response. Chronic irradiation from SSR preceding the immunosuppressive dose of UV failed to restore the suppressed immune response. Reduced lipopolysaccharide-triggered cytokine production (of IL-12p40, IFN-gamma, IL-6 and TNF-alpha) by draining lymph node cells of mice sensitized and challenged with DPCP indicated that no adaptation is induced. In addition, the mice were not protected from T-T dimer DNA damage after chronic solar irradiation. Our studies reveal no evidence that chronic exposure to low doses of SSR induces adaptation to UV-induced suppression of acquired immunity.
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PMID:No adaptation to UV-induced immunosuppression and DNA damage following exposure of mice to chronic UV-exposure. 1650 33

This study examines whether intense pulsed light (IPL) treatment has a carcinogenic potential itself or may influence ultraviolet (UV)-induced carcinogenesis. Secondly, it evaluates whether UV exposure may influence IPL-induced side effects. Hairless, lightly pigmented mice (n=144) received three IPL treatments at 2-week intervals. Simulated solar radiation was administered preoperatively [six standard erythema doses (SED) four times weekly for 11 weeks] as well as pre- and postoperatively (six SED four times weekly up to 26 weeks). Skin tumors were assessed weekly during a 12-month observation period. Side effects were evaluated clinically. No tumors appeared in untreated control mice or in just IPL-treated mice. Skin tumors developed in UV-exposed mice independently of IPL treatments. The time it took for 50% of the mice to first develop skin tumor ranged from 47 to 49 weeks in preoperative UV-exposed mice (p=0.94) and from 22 to 23 weeks in pre- and postoperative UV-exposed mice (p=0.11). IPL rejuvenation of lightly pigmented skin did not induce pigmentary changes (p=1.00). IPL rejuvenation of UV-pigmented skin resulted in an immediate increased skin pigmentation and a subsequent short-term reduced skin pigmentation (p<0.002). Postoperative UV radiation resulted in re-pigmentation of IPL-induced pigment reduction (p=0.12). No texture changes were observed. Postoperative edema and erythema were increased by preoperative UV exposure (p<0.002). IPL rejuvenation has no carcinogenic potential itself and does not influence UV-induced carcinogenesis. UV exposure influences the occurrence of side effects after IPL rejuvenation in an animal model.
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PMID:Carcinogenesis related to intense pulsed light and UV exposure: an experimental animal study. 1696 39

In contrast to sunlight-induced squamous cell carcinoma the etiology of cutaneous malignant melanoma (CMM) is not well understood. In particular, the role that sunlight exposure and DNA damage play in the initiation of this deadly form of cancer is an open question. Early UV carcinogenesis studies in the Xiphophorus backcross hybrid fish model by Richard Setlow indicated that direct DNA damage caused by exposure to the UVB component of sunlight is necessary and sufficient for melanoma formation. Subsequent studies by Setlow suggested that monochromatic UVA radiation that is not directly absorbed by DNA was also sufficient for melanoma induction in Xiphophorus and was, indeed, primarily responsible for initiating human melanoma. These results had significant public health consequences, suggesting that although sunscreens may inhibit UVB-induced erythema they may actually increase exposure to the UVA wavelengths that cause cancer. An intensive worldwide public debate on sunscreen use and "abuse" ensued. Our data do not support a major role of free radical chemistry in melanoma induction. We find evidence that the direct damage caused by the absorption of UVB wavelengths by DNA (e.g., the cyclobutane pyrimidine dimer or CPD) is required for CMM formation and that the ability to repair these lesions plays a significant role in tumor susceptibility. Using the Xiphophorus backcross hybrid fish we are currently in the process of re-evaluating the wavelength- and DNA damage-dependence of UV-induced melanoma and the role nucleotide excision repair and the genes controlling DNA repair and the UV response play in melanoma resistance. From these studies we hope to define the effective solar wavelength boundaries of melanoma, identify the class of critical DNA damage and elucidate the role of DNA repair in tumor suppression.
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PMID:The etiology of sunlight-induced melanoma in Xiphophorus hybrid fish. 1747 77

Numerous studies have demonstrated the utility of topical tacrolimus ointment in atopic dermatitis. However, there is a concern that local immunosuppression by calcineurin inhibitors may enhance dermal photocarcinogenesis and carcinogenesis. Therefore, we investigated the influence of topical tacrolimus ointment on squamous cell carcinoma formation in hairless female C3.Cg/TifBomTac immunocompetent mice exposed to solar simulated radiation (SSR). In a first experiment, mice (n = 200) had tacrolimus applied on their dorsal skin three times weekly followed by SSR (2, 4 or 6 standard erythema doses, SED) 3-4 h later. Tacrolimus did not reduce the time to tumor development and in the group receiving 4 SED it even had a protective effect (156 days vs 170 days, P = 0.008). In a second experiment, mice (n = 50) were irradiated with 6 SED three times weekly for 3 months and subsequently treated five times weekly with topical tacrolimus to mimic the use of tacrolimus on sun-damaged skin. The median time to the first skin tumor was 234 days in SSR + tacrolimus group compared with 227 days in the only SSR-irradiated group (P = 0.160). In a third experiment, mice (n = 25) had tacrolimus applied on their dorsal skin every day for 1 month, thereafter the group was irradiated with 4 SED three times weekly. The median time to the first skin tumor was 142 days in tacrolimus + SSR group compared with 156 days in the only SSR-irradiated group from experiment 1 (P = 0.363). We conclude that tacrolimus ointment does not accelerate photocarcinogenesis or induce any dermal carcinogenicity in hairless mice.
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PMID:Topical tacrolimus in combination with simulated solar radiation does not enhance photocarcinogenesis in hairless mice. 1809 46

Solar UV radiation is known to cause immune suppression, believed to be a critical factor in cutaneous carcinogenesis. Although the mechanism is not entirely understood, DNA damage is clearly involved. Sunscreens function by attenuating the UV radiation that reaches the epidermis. However, once DNA damage ensues, repair mechanisms become essential for prevention of malignant transformation. DNA repair enzymes have shown efficacy in reducing cutaneous neoplasms among xeroderma pigmentosum patients. In vitro studies suggest that RNA fragments increase the resistance of human keratinocytes to UVB damage and enhance DNA repair but in vivo data are lacking. This study aimed to determine the effect of topical formulations containing either DNA repair enzymes (Micrococcus luteus) or RNA fragments (UVC-irradiated rabbit globin mRNA) on UV-induced local contact hypersensitivity (CHS) suppression in humans as measured in vivo using the contact allergen dinitrochlorobenzene. Immunohistochemistry was also employed in skin biopsies to evaluate the level of thymine dimers after UV. Eighty volunteers completed the CHS portion. A single 0.75 minimum erythema dose (MED) simulated solar radiation exposure resulted in 64% CHS suppression in unprotected subjects compared with unirradiated sensitized controls. In contrast, UV-induced CHS suppression was reduced to 19% with DNA repair enzymes, and 7% with RNA fragments. Sun protection factor (SPF) testing revealed an SPF of 1 for both formulations, indicating that the observed immune protection cannot be attributed to sunscreen effects. Biopsies from an additional nine volunteers showed an 18% decrease in thymine dimers by both DNA repair enzymes and RNA fragments, relative to unprotected UV-irradiated skin. These results suggest that RNA fragments may be useful as a photoprotective agent with in vivo effects comparable to DNA repair enzymes.
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PMID:UV protective effects of DNA repair enzymes and RNA lotion. 1817 18

Ultraviolet radiation in sunlight produces a range of acute and chronic adverse effects on the skin including sunburn, photosensitivity rashes, immunosuppression, photoageing and carcinogenesis. Sunscreens aim to provide protection, but standard testing procedures primarily involve assessment of ability to protect against acute erythema, as evidenced by the sun protection factor (SPF). The SPF may correlate poorly with other aspects of protection, particularly since ultraviolet A is weakly erythemogenic compared with ultraviolet B, yet may make a greater contribution to certain other skin effects of sunlight. Nevertheless, there is an increasing tendency for the sunscreen industry to make claims for their products beyond the SPF data. There is a need to develop systems for clinical testing of sunscreens against other endpoints caused by ultraviolet exposure of skin, including immunosuppression and photosensitivity rashes. In particular, there is a largely unrecognized need for testing of sunscreens against the condition known as polymorphic light eruption, a photosensitivity disorder estimated to affect a staggering 10-20% of the population in the northern hemisphere. Ultimately, protection of the skin by sunscreens can only be as effective as their adequacy of application to the skin surface in the everyday setting permits. Optimal sunscreen formulation, and public and patient education in appropriate application technique, both make vital contributions to efficacy of sunscreen protection. This article focuses on the need for extended clinical testing of sunscreens, with particular reference to the photosensitivity disorders, and for improvements in sunscreen formulation and in the adequacy of sunscreen application to the skin surface.
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PMID:Beyond sun protection factor testing. 1849 27

Ultraviolet (UV) irradiation plays a pivotal role in human skin carcinongenesis. Preclinically, systemically and topically applied green tea extract (GTE) has shown reduction of UV-induced (i) erythema, (ii) DNA damage, (iii) formation of radical oxygen species and (iv) downregulation of numerous factors related to apoptosis, inflammation, differentiation and carcinogenesis. In humans, topical GTE has so far only been tested in limited studies, with usually very high GTE concentrations and over short periods of time. Both chemical stability of GTE and staining properties of highly concentrated green tea polyphenols limit the usability of highly concentrated green tea extracts in cosmetic products. The present study tested the utility of stabilized low-dose GTE as photochemopreventive agents under everyday conditions. We irradiated with up to 100 mJ/cm(2) of UVB light skin patches which were pretreated with either OM24-containing lotion or a placebo lotion. Biopsies were taken from both irradiated and un-irradiated skin for both immunohistochemistry and DNA microarray analysis. We found that while OM24 treatment did not significantly affect UV-induced erythema and thymidine dimer formation, OM24 treatment significantly reduced UV-induced p53 expression in keratinocytes. We also found that OM24 treatment significantly reduced the number of apoptotic keratinocytes (sunburn cells and TUNEL-positive cells). Carefully controlled DNA microarray analyses showed that OM24 treatment does not induce off-target changes in gene expression, reducing the likelihood of unwanted side-effects. Topical GTE (OM24) reduces UVB-mediated epithelial damage already at low, cosmetically usable concentrations, without tachyphylaxis over 5 weeks, suggesting GTE as suitable everyday photochemopreventive agents.
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PMID:Green tea extract reduces induction of p53 and apoptosis in UVB-irradiated human skin independent of transcriptional controls. 1863 Dec 47

Poloxamers are polyoxyethlyene, polyoxypropylene block polymers. The impurities of commercial grade Poloxamer 188, as an example, include low-molecular-weight substances (aldehydes and both formic and acetic acids), as well as 1,4-dioxane and residual ethylene oxide and propylene oxide. Most Poloxamers function in cosmetics as surfactants, emulsifying agents, cleansing agents, and/or solubilizing agents, and are used in 141 cosmetic products at concentrations from 0.005% to 20%. Poloxamers injected intravenously in animals are rapidly excreted in the urine, with some accumulation in lung, liver, brain, and kidney tissue. In humans, the plasma concentration of Poloxamer 188 (given intravenously) reached a maximum at 1 h, then reached a steady state. Poloxamers generally were ineffective in wound healing, but were effective in reducing postsurgical adhesions in several test systems. Poloxamers can cause hypercholesterolemia and hypertriglyceridemia in animals, but overall, they are relatively nontoxic to animals, with LD(50) values reported from 5 to 34.6 g/kg. Short-term intravenous doses up to 4 g/kg of Poloxamer 108 produced no change in body weights, but did result in diffuse hepatocellular vacuolization, renal tubular dilation in kidneys, and dose-dependent vacuolization of epithelial cells in the proximal convoluted tubules. A short-term inhalation toxicity study of Poloxamer 101 at 97 mg/m(3) identified slight alveolitis after 2 weeks of exposure, which subsided in the 2-week postexposure observation period. A short-term dermal toxicity study of Poloxamer 184 in rabbits at doses up to 1000 mg/kg produced slight erythema and slight intradermal inflammatory response on histological examination, but no dose-dependent body weight, hematology, blood chemistry, or organ weight changes. A 6-month feeding study in rats and dogs of Poloxamer 188 at exposures up to 5% in the diet produced no adverse effects. Likewise, Poloxamer 331 (tested up to 0.5 g/kg day(-1)), Poloxamer 235 (tested up to 1.0 g/kg day(-1)), and Poloxamer 338 (at 0.2 or 1.0 g/kg day(-1)) produced no adverse effects in dogs. Poloxamer 338 (at 5.0 g/kg day(-1)) produced slight transient diarrhea in dogs. Poloxamer 188 at levels up to 7.5% in diet given to rats in a 2-year feeding study produced diarrhea at 5% and 7.5% levels, a small decrease in growth at the 7.5% level, but no change in survival. Doses up to 0.5 mg/kg day(-1) for 2 years using rats produced yellow discoloration of the serum, high serum alkaline phosphatase activity, and elevated serum glutamicpyruvic transaminase and glutamic-oxalacetic transaminase activities. Poloxamers are minimal ocular irritants, but are not dermal irritants or sensitizers in animals. Data on reproductive and developmental toxicity of Poloxamers were not found. An Ames test did not identify any mutagenic activity of Poloxamer 407, with or without metabolic activation. Several studies have suggested anticarcinogenic effects of Poloxamers. Poloxamers appear to increase the sensitivity to anticancer drugs of multidrug-resistant cancer cells. In clinical testing, Poloxamer 188 increased the hydration of feces when used in combination with a bulk laxative treatment. Compared to controls, one study of angioplasty patients receiving Poloxamer 188 found a reduced myocardial infarct size and a reduced incidence of reinfarction, with no evidence of toxicity, but two other studies found no effect. Poloxamer 188 given to patients suffering from sickle cell disease had decreased pain and decreased hospitilization, compared to controls. Clinical tests of dermal irritation and sensitization were uniformly negative. The Cosmetic Ingredient Review (CIR) Expert Panel stressed that the cosmetic industry should continue to use the necessary purification procedures to keep the levels below established limits for ethylene oxide, propylene oxide, and 1,4-dioxane. The Panel did note the absence of reproductive and developmental toxicity data, but, based on molecular weight and solubility, there should be little skin penetration and any penetration of the skin should be slow. Also, the available data demonstrate that Poloxamers that are introduced into the body via routes other than dermal exposure have a rapid clearance from the body, suggesting that there would be no risk of reproductive and/or developmental toxicity. Overall, the available data do not suggest any concern about carcinogenesis. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used, and at what concentration, indicates a pattern of use. Based on these safety test data and the information that the manufacturing process can be controlled to limit unwanted impurities, the Panel concluded that these Poloxamers are safe as used.
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PMID:Safety assessment of poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, poloxamer 105 benzoate, and poloxamer 182 dibenzoate as used in cosmetics. 1883 Aug 66

Cutaneous immunity, which is a key defence against the development of skin cancers, is suppressed by even small doses of ultraviolet (UV) radiation. Preventing this UV-induced immunosuppression may therefore reduce the incidence of skin cancer. Nicotinamide (vitamin B3) has immune-protective and cancer-preventive effects against UV radiation in mice, and we have shown previously that topical nicotinamide is immune protective in humans. Using the Mantoux model of skin immunity in healthy volunteers, we compared oral nicotinamide to placebo (both administered for 1 week) in a randomized, double-blinded, crossover design against the effects of solar-simulated ultraviolet (ssUV) radiation on delayed-type hypersensitivity to tuberculin purified protein derivative. Discrete areas of the back were irradiated with low doses of ssUV daily for three consecutive days. Immunosuppression, calculated as the difference in Mantoux-induced erythema of irradiated sites compared with unirradiated control sites, was determined in volunteers taking oral nicotinamide and placebo. Significant immunosuppression occurred in an UV dose-dependent manner in the presence of placebo. Oral nicotinamide, at doses of either 1500 or 500 mg daily, was well tolerated and significantly reduced UV immunosuppression with no immune effects in unirradiated skin. Oral nicotinamide is safe and inexpensive and looks promising as a chemopreventive supplement for reducing the immunosuppressive effects of sunlight.
Carcinogenesis 2009 Jan
PMID:Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. 1902 5


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