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)

Exposure to ultraviolet-B radiation (UVB: 280-315 nm) can result in a decreased immune response. This immune suppression can be restricted to the exposed skin site (local immune suppression) but may also be systemic. To investigate whether ultraviolet-A radiation (UVA: 315-400 nm) could also exert such a systemic effect, we performed the present investigation. The study consisted of two parts. Experiment I: 24 albino hairless mice (SKH:HRI) were ventrally exposed to UVA radiation for 300 days (glass-filtered Philips TLK09 fluorescent tubes, daily dose: 350 kJ/m2), while 24 control mice were left unexposed. After this period the control animals were still tumour free, but 60% of the exposed animals had developed abdominal tumours. Subsequently ventral exposures were stopped and both groups were dorsally exposed to identical UVB regimens (Westinghouse FS40, daily dose: 900 J/m2). Experiment II: this was virtually the same as experiment I, but here the mice were dorsally exposed to UVA radiation (glass-filtered Philips TLK09, daily dose: 290 kJ/m2) instead of UVB radiation. If we look at all tumours induced dorsally, we find no significant influence of pre-exposures to UVA radiation. This holds for dorsal UVB as well as for dorsal UVA exposures. In contrast to UVB, however, the UVA radiation induced many papillomas. Excluding the papillomas from the analysis we find that the induction of non-papillomas (mainly squamous cell carcinomas) under dorsal UVA exposure, is slightly enhanced in the ventrally pre-exposed group (difference significant at the P < 0.05 level). This suggests that UVA radiation induced only a weak systemic effect. Ventral UVA pre-exposure did not appear to affect dorsal skin irritation as expressed by scratch marks. The induction period for hyperkeratosis, however, was significantly shortened by the ventral UVA pre-exposure; this applied to dorsal UVB as well as dorsal UVA exposures.
Carcinogenesis 1992 Nov
PMID:The influence of ventral UVA exposure on subsequent tumorigenesis in mice by UVA or UVB irradiation. 142 89

The tumor-producing and skin-irritating activity of the antipsoriatic drug dithranol and its 10-acyl analogues butantrone (10-butyryl dithranol), 10-isobutyryl dithranol and 10-valeryl dithranol were studied in 650 SENCAR mice using a two-stage skin carcinogenesis assay. An initiation with 20 micrograms of 7,12-dimethylbenz(alpha)anthracene (DMBA) was followed 2 weeks later by three applications per week of the test compounds in 50 microliter of acetone for 21 weeks. In addition the compounds were studied without DMBA pre-treatment using application periods of 21 and 36 weeks. The concentration of dithranol was the maximum tolerated, 3.5 mM. For the less irritating 10-acyl analogues 30 mM solutions were used. The first signs of skin irritation were observed after an application period of 1-2 weeks and the irritation continued to the end of the experiment in all groups except the acetone controls. Dithranol caused the most severe irritation although the differences between the groups were not pronounced. On histopathology, the majority of animals had hyperplasia and other inflammatory changes of the skin. The first papillomas appeared 8-11 weeks after initiation and the incidences of papillomas at the end of the experiment were 85% (dithranol 3.5 mM), 16% (butantrone 30 mM), 36% (10-isobutyryl dithranol 30 mM) and 50% (10-valeryl dithranol 30 mM). Without initiation the incidences were 6 and 2% (dithranol), 2 and 2% (butantrone) and 2 and 0% (10-valeryl dithranol) in the 21- and 36-week studies, respectively. Histologically, the papillomas were mostly squamous papillomas and only a few keratoacanthomas were found. It is concluded that the tumor-producing and skin-irritating activity of dithranol is clearly greater than that of butantrone, 10-isobutyryl dithranol and 10-valeryl dithranol.
Carcinogenesis 1986 Oct
PMID:Tumor-producing and skin-irritating activity of dithranol (anthralin) and its 10-acyl analogues in SENCAR mice. 375 76

Prostaglandin E2 (PGE2) is associated with phorbol ester-induced skin irritation and tumour promotion, but the mechanism of action is not fully understood and the role of keratinocyte-derived PGE2 is unclear. PGE2 was recently reported to modulate keratinocyte differentiation and phorbol-12-myristate-13-acetate (PMA), the most extensively studied phorbol ester tumour promoter in mouse skin, was shown to stimulate PGE2 release in human keratinocytes. Preliminary data on PGE2 release induced by PMA, mezerein, anthralin, sodium dodecyl sulphate and acetic acid in human keratinocyte cultures is compared to their response in rat keratinocytes. Our data confirms a previously published report on stimulation of PGE2 release by PMA in human keratinocytes and also demonstrates a difference in the magnitude of the PMA- and mezerein-induced response between human and rat keratinocyte cultures at non-cytotoxic concentrations. Cytotoxicity was evaluated by the Neutral Red uptake assay and a concentration that reduced cell viability to 50% of control was selected as a maximum concentration for subsequent measurement of PGE2 release. In contrast, anthralin, sodium dodecyl sulphate and acetic acid induced a similar degree of PGE2 release in human and rat keratinocyte cultures, but release was specifically associated with a cytotoxic response. Non-cytotoxic concentrations of these three chemicals did not stimulate release of PGE2. This study illustrates that PGE2 dose-response curves may reflect different mechanisms of action that may be intimately associated with skin irritant and tumour promoting activity. The data indicates a possible species difference in keratinocyte response to PMA and mezerein. The important value of keratinocyte cultures for mechanistic studies of tumour promotion and skin irritation is highlighted and further research is warranted into the potential role of intracellular pathways, which modulate keratinocyte differentiation and proliferation, in these processes.
Carcinogenesis 1995 May
PMID:Comparison of tumour promoter-induced prostaglandin E2 release in human and rat keratinocytes. 776 93

The dermal response of three strains of mice (ICR, C3H and B6C3F1) exposed to repeated doses of 0, 1 or 4% acrylic acid was examined over 13 wk. Microscopic and gross changes to the skin were classified as being indicative of exceeding the maximum tolerated dose (MTD), reaching the MTD, or tolerating the dose based on proposed MTD guidelines established in US Environmental Protection Agency (EPA) Workshops on dermal carcinogenesis bioassays. A significant number of animals in all three strains with repeated exposure to 4% acrylic acid experienced skin irritation that was classified as having reached or exceeded the MTD compared with animals exposed to either 1% acrylic acid or the 0% acrylic acid acetone control. These results were observed within the first 3 wk of exposure, but there was some accommodation to irritation by 8 wk of exposure. Microscopic findings provided a more sensitive index for exceeding MTD than gross observations taken only at autopsy, but generally correlated well for MTD if gross observations were taken at regular intervals during treatment. That is, to set MTD, gross observations could be used if taken over the entire course of the exposure, but using microscopic findings was generally a more reliable or sensitive measure. EPA guidelines suggest that it is inappropriate to conduct a dermal bioassay at concentrations that exceed the MTD. Acrylic acid at 4% in acetone clearly exceeded the MTD based on microscopic or gross observation criteria. At 4%, strain differences were evident by gross observation only, with the ICR strain being less susceptible to irritation than C3H or B6C3F1 strains. These strain differences were not apparent with microscopic examination. Acrylic acid at 1% in acetone, although demonstrating signs of minimal irritation, was fairly well tolerated by all mice in all strains. Thus, acrylic acid at 1% in acetone, one-quarter of the concentration that was in clear excess of the MTD, would be the appropriate dose concentration for lifetime skin studies based on MTD criteria.
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PMID:Comparison of the maximum tolerated dose (MTD) dermal response in three strains of mice following repeated exposure to acrylic acid. 779 78

Cancer results from disturbances of cellular signal transduction and data processing at the genetic and epigenetic level. In the early phase of the disease these disturbances are mainly caused by environmental toxic agents, i.e. genotoxic and non-genotoxic carcinogens, whereas endogenous agents derived from dys-regulated metabolic reactions may take over this role at later stages, thereby leading to a state of 'genetic instability' and 'growth autonomy'. Among these metabolic reactions becoming dys-regulated in the course of tumorigenesis, eicosanoid biosynthesis from arachidonic acid seems to play a particular role. A steadily increasing body of evidence indicates a causal relationship between cancer development and an abnormal overexpression of eicosanoid-forming enzymes, i.e. cyclooxygenases and lipoxygenases, in a wide variety of human and animal tumors. This overexpression seems to result from disturbances of cellular signaling cascades such as the Ras-Raf-MAPkinase cascade due to oncogenic gene mutations. Presently, research is focussed on the proinflammatory enzyme cyclooxygenase-2 (COX-2) the pathological overexpression of which has been found to be related to key events of tumor promotion such as cellular hyperproliferation, inhibition of programmed cell death, and tumor angiogenesis. In the mouse skin model of multistage carcinogenesis COX-2-derived prostaglandin F(2alpha) has been indentified as an endogenous tumor promoter. Moreover, genotoxic byproducts of both cylooxygenase and lipoxygenase-catalyzed arachidonic acid metabolism (such as active oxygen species, free radicals etc.) are suspected to contribute to 'genetic instability' and thus to malignant progression of tumor cells. The enzymes of eicosanoid biosynthesis rank therefore among the most attractive targets for cancer chernoprevention. In fact, both nonsteroidal antiinflammatory drugs, i.e. non-specific COX inhibitors, and isozyme-specific COX-2 inhibitors have been shown to inhibit experimental and human cancer development, in the latter case in particular in the large bowel. Beside their role as indicators of neoplastic development eicosanoids may be also used as reporters of skin irritation. Based to this concept an in vitro test system for skin toxicity has been developed in which the release of arachidonic acid and interleukin-1alpha, i.e. two key mediators of acute inflammation, from a human keratinocyte cell line is measured. The excellent correlation found between this mediator release and the effects of various chemical irritants on human skin in vivo indicates that, in the near future, this and related methods may help to do without animal experiments in toxicological testing.
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PMID:A causal relationship between unscheduled eicosanoid signaling and tumor development: cancer chemoprevention by inhibitors of arachidonic acid metabolism. 1109 Sep 44

Stearamide DIBA-Stearate is a substituted dihydroxyisobutylamine (DIBA) that functions in cosmetic formulations as an opacifying agent, a surfactant-foam booster, and a viscosity increasing agent. Stearamide DIBA-Stearate was reportedly used in four cosmetic formulations, at concentrations of 1% to 3%. Few data on this ingredient were available. Data on related ingredients, including Dibutyl Adipate, Diisopropyl Adipate, Stearamide DEA, and Stearamide MEA, were considered in the assessment of safety. A formulation containing 1.3% Stearamide DIBA-Stearate (further diluted to 4% of the formulation) was mildly irritating but nonsensitizing in an repeated-insult patch test (RIPT). The same dilution was noncomedogenic. At a concentration of 20%, Dibutyl Adipate had an oral LD50 of 2 g/kg. Subchronic dermal exposure of rabbits (1.0 ml/kg/day) caused a reduction in weight gain that was not observed at a dose of 0.5 ml/kg/day. In studies using rabbits, undiluted Dibutyl Adipate caused mild to moderate skin irritation and minimal ocular irritation. When pregnant rats were treated intraperitoneally with approximately 1.75 ml/kg Dibutyl Adipate during gestation, the incidence of fetal gross abnormalities was increased. No effect was observed at smaller doses. Diisopropyl Adipate had low acute oral and percutaneous toxicity, and was only a very mild ocular irritant. In skin irritation studies using rabbits, 5.0% to 100% Diisopropyl Adipate caused minimal to mild irritation; these results were also seen in clinical testing with only moderate cumulative irritation, and no sensitization or photosensitization. A formulation containing 5.27% Stearamide MEA was not toxic to rats when applied topically daily for 13 weeks. In studies using rabbits, Stearamide DEA (35% to 40%) was not a skin or ocular irritant, and Stearamide MEA (5.27%) was not an ocular irritant. At 17%, Stearamide MEA was not irritating to the skin, but caused minimal to moderate irritation to the eyes of rabbits. Stearamide MEA (5.27%) did not cause sensitization during a clinical study. It was not possible, however, to determine the relevance of these data on related ingredients. Therefore, it was concluded that the available data are insufficient. Additional data needs are (1) method of manufacture; (2) chemical characterization, including impurities; (3) dermal absorption; if significantly absorbed, then a 28-day dermal toxicity study and a reproductive and developmental toxicity study may be needed; (4) two genotoxicity assays, at least one in a mammalian system; if positive, then a 2-year dermal carcinogenesis study using National Toxicology Program (NTP) methods may be needed; (5) ultraviolet (UV) absorption data; if significant absorption occurs in the UVA or UVB range, photosensitization data are needed. Absent these data, it was concluded that the available data are insufficient to support the safety of Stearamide DIBA-Stearate as used in cosmetic products.
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PMID:Final report on the safety assessment of Stearamide DIBA-Stearate. 1176 36

Specialty acrylates and methacrylates (SAM) comprise a large family of industrial monomers. In the late 1980s, the United States EPA and the industry SAM Panel collaborated to evaluate the potential effects, particularly carcinogenesis, of this family of chemicals. As part of this arrangement, the SAM Panel, with EPA input and approval, conducted four studies with a representative acrylate, triethyleneglycol diacrylate (TREGDA), and methacrylate, triethyleneglycol dimethacrylate (TREGDMA). All studies used unoccluded skin application to male mice as follows: Study 1, evaluation of skin irritation compared to cell proliferation in the basal epithelium (BE) following 7 or 14 days of treatment; Study 2, 14-day dose range-finding study; Study 3, 90-day subchronic toxicity study; and Study 4, chronic bioassays employing the EPAs draft guidelines for dermal chronic bioassays. BE cell proliferation was determined in subchronic and carcinogenicity studies (Studies 1, 3, and 4). Organ weight changes (Studies 3 and 4) and increased mortality (Study 4) were observed for the highest dose of TREGDMA. However, there was no related histopathology. Both chemicals induced cell proliferation (7 days through 78 weeks) that correlated with acute and chronic inflammation of the skin. No skin tumors were observed in this study. TREGDA resulted in skin lesions at doses approximately 20-fold lower than TREGDMA. Most of the skin lesions showed similar patterns of microscopic cutaneous alteration suggestive of nonspecific irritation for both chemicals. However, the high concentration TREGDA group in the 78-week study also had evidence of epidermal cell necrosis. In contrast to earlier studies with acrylates, dose selection was based on careful examination of skin irritation and cell proliferation to avoid excessive skin damage. Under these conditions, TREGDA and TREGDMA were not carcinogenic.
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PMID:Skin irritation, basal epithelial cell proliferation, and carcinogenicity evaluations of a representative specialty acrylate and methacrylate. 1266 9

Ferulic acid (FA) can be used as an antioxidant to prevent damage from ultraviolet (UV) radiation and skin carcinogenesis. To this end, the feasibility of the skin absorption of FA and its derivatives was evaluated in the present study. The percutaneous absorption of five compounds into/across porcine skin was measured and compared using Franz diffusion cells. The skin delivery from pH 6 and 9.9 buffers was the highest for ferulic acid ethyl ether (FAEE), followed by coniferyl aldehyde (CD), coniferyl alcohol (CA), FA, and 3-hydroxy-4-methoxycinnamic acid (HMA). The skin deposition and flux of FAEE with a pH 6 buffer were 136 nmol/g and 26 nmol/cm(2)/h, respectively. No significant difference in permeation profiles was observed between the two pH buffers. According to permeation via the skin with different treatments (delipidization, ethanol, and oleic acid treatments), it was determined that the lipid bilayers in the stratum corneum (SC) comprised the predominant barrier for FA permeation. On the other hand, FAEE could easily partition into and penetrate across the skin through intercellular pathways. Nude mouse was used as an in vivo animal model to examine the amount of permeants remaining in the skin. The in vivo skin deposition was generally correlated with the in vitro results. The in vivo skin deposition of FAEE (145 nmol/g) was comparable to that of CD (150 nmol/g). The safety study which examined transepidermal water loss (TEWL), erythema, and the skin pH value demonstrated that the topical application of FA and related compounds for up to 24h did not cause skin irritation. It can be concluded that topical delivery may serve as an efficient and safe route for FA and its derivatives against photodamage.
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PMID:A comparison of skin delivery of ferulic acid and its derivatives: evaluation of their efficacy and safety. 2069 28

Chrysin (5,7-dihydroxyflavone), a natural flavonoid occurring in various plants and foods such as propolis and honey, reportedly opposes inflammation and carcinogenesis, but has rarely been applied in skin care. This study, therefore, aimed to explore the roles of chrysin in protection against UV-induced damage in HaCaT keratinocytes. Results showed that chrysin can attenuate apoptosis, reactive oxygen species (ROS) production, and cyclooxygenase 2 (COX-2) expression induced by UVB and UVA. Chrysin predominantly reversed the down-regulation of aquaporin 3 (AQP-3) by UVB. It predominantly reversed JNK activation and also mildly inhibited p38 activation triggered by UVA and UVB. Animal studies revealed that chrysin's topical application demonstrated efficient percutaneous absorption and no skin irritation. Overall, results demonstrated significant benefits of chrysin on the protection of keratinocytes against UVA- and UVB-induced injuries and suggested its potential use in skin photoprotection.
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PMID:Chrysin protects epidermal keratinocytes from UVA- and UVB-induced damage. 2169 66

The positive effects of sunlight have been known for many years, and the negative ones, too. Sunscreens are physical and chemical UV absorbers. Nanotechnology has developed nanoparticles of physical blockers: titanium dioxide (TiO2) and zinc oxide (ZnO). Their smaller diameter and increased bioreactivity are the focus of many toxicological studies. The usage of sunscreens has increased around the world, so all toxicological aspects should be carefully considered. There are in vitro and in vivo studies: studies on animal and human skin; investigations of potential genotoxicity and cytotoxicity; generation of reactive oxygen species; penetration; skin irritation; acute, subchronic, and chronic toxicity; and carcinogenesis. The experimental conditions of these studies differ from study to study, but most authors agree that there is no penetration of nanoparticles into viable skin layers. Risk-benefit analysis of TiO2 and ZnO nanoparticles (NPs) usage in sunscreens strongly indicates that potential risks are vastly outweighed over the benefits. Because of the results of some authors indicating possible penetration through damaged skin, further studies should be conducted, primarily addressed on skin penetration mechanisms.
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PMID:Titanium Dioxide and Zinc Oxide Nanoparticles in Sunscreens: A Review of Toxicological Data. 3159 27


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