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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of a characteristic aroma and health benefits, green tea is consumed worldwide as a popular beverage. The epicatechin derivatives, commonly called polyphenols, present in green tea possess antioxidant, anti-inflammatory and anti-carcinogenic properties. The major and most highly chemopreventive constituent in green tea responsible for the biochemical or pharmacological effects is (-)-epigallocatechin-3-gallate (EGCG). Epidemiological, clinical and biological studies have implicated that solar ultraviolet (UV) light is a complete carcinogen and repeated exposure can lead to the development of various skin disorders including melanoma and nonmelanoma skin cancers. We and others have shown that topical treatment or oral consumption of green tea polyphenols (GTP) inhibit chemical carcinogen- or UV radiation-induced skin carcinogenesis in different laboratory animal models. Topical treatment of GTP and EGCG or oral consumption of GTP resulted in prevention of UVB-induced inflammatory responses, immunosuppression and oxidative stress, which are the biomarkers of several skin disease states. Topical application of GTP and EGCG prior to exposure of UVB protects against UVB-induced local as well as systemic immune suppression in laboratory animals, which was associated with the inhibition of UVB-induced infiltration of inflammatory leukocytes. Prevention of UVB-induced suppression of immune responses by EGCG was also associated with the reduction in immunosuppressive cytokine interleukin (IL)-10 production at UV irradiated skin and draining lymph nodes, whereas IL-12 production was significantly enhanced in draining lymph nodes. Antioxidant and anti-inflammatory effects of green tea were also observed in human skin. Treatment of EGCG to human skin resulted in the inhibition of UVB-induced erythema, oxidative stress and infiltration of inflammatory leukocytes. We also showed that treatment of GTP to human skin prevents UVB-induced cyclobutane pyrimidine dimers formation, which are considered to be mediators of UVB-induced immune suppression and skin cancer induction. The in vitro and in vivo animal and human studies suggest that green tea polyphenols are photoprotective in nature, and can be used as pharmacological agents for the prevention of solar UVB light-induced skin disorders including photoaging, melanoma and nonmelanoma skin cancers after more clinical trials in humans.
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PMID:Skin photoprotection by green tea: antioxidant and immunomodulatory effects. 1287 Oct 30

These three stories exemplify the uniqueness of fish models in their abilities to answer important biological questions. The first one identifies the major UV-induced damage (pyrimidine dimers) that is responsible for tumor induction. Thyroid cells from isogenic fish ( Poecilia formosa) were exposed to UV in vitro, then either exposed or not to photoreactivating light that monomerizes dimers, and the cells were injected into isogenic recipients. In the absence of photoreactivating light, the recipients developed tumors; in its presence, there were very few tumors. The second story describes our use of backcross hybrids of Xiphophorus as a model for melanoma induction by several UV and visible wavelengths. All the wavelengths were effective. (Squamous cell carcinomas in mice are induced preferentially by wavelengths <320 nm.) The data strongly suggest that light absorbed by the black pigment melanin damages DNA. The third story is designed to determine the mutagenic effects on sperm of the high atomic number, high-energy (HZE) nuclei present in cosmic rays by measuring mutations in progeny of exposed male medaka.
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PMID:Three unique experimental fish stories: Poecilia (the Past), Xiphophorus (the Present), and Medaka (the Future). 1496 Dec 96

The genus Xiphophorus is an important model for investigating the etiology and genetics of sunlight-induced melanoma as well as other cancers. We investigated the role DNA damage plays in tumorigenesis in Xiphophorus using a variety of immunological techniques to examine the induction, distribution, and repair of the major photoproducts in DNA after exposure to solar (ultraviolet-B) radiation. We found that cyclobutane pyrimidine dimers (CPDs) were induced at 5- to 10-fold greater frequency than the (6-4) photoproduct ((6-4)PD) in Xiphophorus signum, and the efficiency of photoproduct formation was tissue-dependent, with the scales providing considerable photoprotection against both types of damage. Both of these lesions are efficiently repaired in the presence of visible light by photoenzymatic repair with CPDs repaired at about twice the rate of (6-4)PDs. Photoenzymatic repair of cyclobutane dimers is inducible by prior exposure to low levels of visible light and can be extremely rapid, with most of the lesions removed within 30 minutes. In the absence of light, dimers are removed by nucleotide excision repair with somewhat greater efficiency for the (6-4)PD compared with the CPD in most species. The relative efficiencies of nucleotide excision repair and photoenzymatic repair are tissue-specific and species-specific. The diverse photochemical and photobiological responses observed in Xiphophorus fishes suggest that heritable traits governing the induction and repair of DNA damage may be involved in the susceptibility of Xiphophorus hybrids to melanomagenesis.
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PMID:Resolution of UV-induced DNA damage in Xiphophorus fishes. 1496 1

Selected hybridization in the fish genus Xiphophorus has been used for many years to study the genetics of malignant melanoma. Because DNA damage caused by ultraviolet radiation is implicated in the etiology of sunlight-induced melanoma, the heritability of mechanisms that mitigate DNA damage is a matter of some interest. We examined nucleotide excision repair of the two major types of DNA-damage induced by sunlight; the cyclobutane pyrimidine dimer (CPD) and the pyrimidine(6-4)pyrimidone dimer [(6-4)PD]. In most cases, removal of the (6-4)PD was more rapid than the CPD, and in many cases, the F1 hybrid showed reduced repair efficiency compared with the parental species. These data demonstrate reduced function in multienzyme hybrid systems and provide molecular support for potential reduced fitness in hybrid fish under conditions of environmental stress.
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PMID:Decreased levels of (6-4) photoproduct excision repair in hybrid fish of the genus Xiphophorus. 1519 Oct 54

Ultraviolet radiation is a well established epidemiologic risk factor for malignant melanoma. This observation has been linked to the relative resistance of normal melanocytes to ultraviolet B (UVB) radiation-induced apoptosis, which consequently leads to accumulation of UVB radiation-induced DNA lesions in melanocytes. Therefore, identification of physiologic factors regulating UVB radiation-induced apoptosis and DNA damage of melanocytes is of utmost biological importance. We show that the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) blocks UVB radiation-induced apoptosis of normal human melanocytes in vitro. The anti-apoptotic activity of alpha-MSH is not mediated by filtering or by induction of melanin synthesis in melanocytes. alpha-MSH neither leads to changes in the cell cycle distribution nor induces alterations in the expression of the apoptosis-related proteins Bcl(2), Bcl(x), Bax, p53, CD95 (Fas/APO-1), and CD95L (FasL). In contrast, alpha-MSH markedly reduces the formation of UVB radiation-induced DNA damage as demonstrated by reduced amounts of cyclobutane pyrimidine dimers, ultimately leading to reduced apoptosis. The reduction of UV radiation-induced DNA damage by alpha-MSH appears to be related to induction of nucleotide excision repair, because UV radiation-mediated apoptosis was not blocked by alpha-MSH in nucleotide excision repair-deficient fibroblasts. These data, for the first time, demonstrate regulation of UVB radiation-induced apoptosis of human melanocytes by a neuropeptide that is physiologically expressed within the epidermis. Apart from its ability to induce photoprotective melanin synthesis, alpha-MSH appears to exert the capacity to reduce UV radiation-induced DNA damage and, thus, may act as a potent protection factor against the harmful effects of UV radiation on the genomic stability of epidermal cells.
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PMID:alpha-Melanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damage. 1556 80

Overexposure to short- and long-wave ultraviolet radiations (UVB, UVA) may contribute to melanoma development through combined genotoxic and mitogenic effects in melanocytes. This study compares the impact of UVA-1 versus UVB, and single versus fractionated exposures on melanocyte proliferation in hairless SKH-2 mice. A single erythemal dose was compared with an equal dose fractionated over 8 d, and dose-dependency was studied. Proliferation (Ki-67 positive-sign) in melanocytes (melanoma antigen recognized by T-cells-1 positive or micropthalmia transcription factor positive) was ascertained in double-labeled skin sections. Single erythemal UVB exposures caused a delayed, dose-dependent increase of melanocyte proliferation. The highest, 17-fold, increase (from 0.05% to 0.8% of melanocytes) occurred 4 d after UVB exposure, without any detectable effect on overall melanocyte numbers. Correspondingly, DNA repair-deficient xeroderma pigmentosum A (Xpa) mice proved exquisitely sensitive to melanocyte proliferation induction by UVB exposure. No discernable effects were measured from fractionated suberythemal UVB exposures, or from any UVA-1 exposure regimen. Hence, melanocyte proliferation appears to be most efficiently induced by a single UVB overexposure. Moreover, the ineffectiveness of UVA-1 radiation and the enhanced sensitivity of Xpa mice point at pyrimidine dimers as causative DNA lesions. Consequently, murine nevi and melanoma are expected to be most effectively induced by intermittent UVB overexposures.
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PMID:Single UVB overexposure stimulates melanocyte proliferation in murine skin, in contrast to fractionated or UVA-1 exposure. 1565 80

Solar radiation gives rise to DNA damage in mammalian cells not only directly by excitation of DNA, which generates predominantly pyrimidine dimers, but also indirectly by the excitation of endogenous photosensitizers, which causes oxidative DNA modifications. The latter mechanism has a low quantum yield, but it is the only one proceeding in the visible range of the spectrum. To investigate its relevance for the genotoxicity of sunlight, we have analysed the generation of micronuclei associated with the induction of oxidative DNA damage by visible light in melanoma cells and primary human skin fibroblasts. Similar yields of light-induced oxidative DNA base modifications sensitive to the repair glycosylase Fpg (7,8-dihydro-8-oxoguanine and other oxidative purine modifications) were observed in the normal fibroblasts and the malignant melanoma cells of the same donor. When irradiations were carried out at intervals to compensate for a photodecomposition of the endogenous chromophore, a significant generation of micronuclei was observed in both cell types. Cyclobutane pyrimidine dimers could be excluded to be responsible for the micronuclei induction at wavelengths >395 nm. Experiments with a cut-off filter indicate that the ratio of pyrimidine dimers and Fpg-sensitive oxidative modifications in irradiated cells not only reflects the relative contributions of direct and indirect mechanisms, but is also similar to the ratio by which the two mechanisms contribute to the generation of the micronuclei. The results suggest that indirectly generated oxidative DNA modifications can contribute significantly to the adverse effects of sunlight.
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PMID:Visible light (>395 nm) causes micronuclei formation in mammalian cells without generation of cyclobutane pyrimidine dimers. 1579 Apr 97

UV radiation is an important etiologic factor for skin cancer, including melanoma. Constitutive pigmentation and the ability to tan are considered the main photoprotective mechanism against sun-induced carcinogenesis. Pigmentation in the skin is conferred by epidermal melanocytes that synthesize and transfer melanin to keratinocytes. Therefore, insuring the survival and genomic stability of epidermal melanocytes is critical for inhibiting photocarcinogenesis, particularly melanoma, the most deadly form of skin cancer. The paracrine factors alpha-melanocortin and endothelin-1 are critical for the melanogenic response of cultured human melanocytes to UV radiation. We report that alpha-melanocortin and endothelin-1 rescued human melanocytes from UV radiation-induced apoptosis and reduced DNA photoproducts and oxidative stress. The survival effects of alpha-melanocortin and endothelin-1 were mediated by activation of the melanocortin 1 and endothelin receptors, respectively. Treatment of melanocytes with alpha-melanocortin and/or endothelin-1 before exposure to UV radiation activated the inositol triphosphate kinase-Akt pathway and increased the phosphorylation and expression of the microphthalmia-related transcription factor. Treatment with alpha-melanocortin and/or endothelin-1 enhanced the repair of cyclobutane pyrimidine dimers and reduced the levels of hydrogen peroxide induced by UV radiation. These effects are expected to reduce genomic instability and mutagenesis.
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PMID:alpha-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes. 1589 21

The most prevalent forms of cancer in humans are the non-melanoma skin cancers, with over a million new cases diagnosed in the United States annually. The portions of the body where these cancers arise are almost exclusively on the most heavily sun-exposed tissues. It is now well established that exposure to ultraviolet light (UV) causes not only damage to DNA that subsequently generates mutations and a transformed phenotype, but also UV-induced immunosuppression. Human cells have only one mechanism to remove the UV-induced dipyrimidine DNA photoproducts: nucleotide excision repair (NER). However, simpler organisms such as bacteria, bacteriophages and some eukaryotic viruses contain up to three distinct mechanisms to initiate the repair of UV-induced dipyrimidine adducts: NER, base excision repair (BER) and photoreversal. This review will focus on the biology and the mechanisms of DNA glycosylase/AP lyases that initiate BER of cis-syn cyclobutane pyrimidine dimers. One of these enzymes, the T4 pyrimidine dimer glycosylase (T4-pdg), formerly known as T4 endonuclease V has served as a model in the study of this entire class of enzymes. It was the first DNA repair enzyme: (1) for which a biologically significant processive nicking activity was demonstrated; (2) to have its active site determined, (3) to have its crystal structure solved, (4) to be shown to carry out nucleotide flipping, and (5) to be used in human clinical trials for disease prevention.
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PMID:Investigations of pyrimidine dimer glycosylases--a paradigm for DNA base excision repair enzymology. 1592 14

Recent evidence suggests that combination therapy of cancer with receptor tyrosine kinase (RTK) inhibitors, which are usually cytostatic, with conventional chemotherapeutic agents, which are usually cytotoxic, provide an improved treatment option. We have designed, synthesized, and evaluated a series of novel 2,4-diamino-5-substituted furo[2,3-d]pyrimidines with RTK and dihydrofolate reductase (DHFR) inhibitory activity in single molecules, as potential cytostatic and cytotoxic agents with antitumor activity. These compounds were synthesized from 2,4-diamino-5-chloromethyl furo[2,3-d]pyrimidine and aryl methyl ketones using the Wittig reaction to afford the C-8-C-9 unsaturated analogs followed by catalytic reduction to the corresponding saturated compounds. The saturated and unsaturated C-8-C-9 bridged compounds were evaluated as inhibitors of vascular endothelial growth factor receptor (VEGFR-2, Flk, KDR), epidermal growth factor receptor, and platelet-derived growth factor receptor-beta (PDGFR-beta). Selected analogs were also evaluated as antiangiogenic agents in the chicken embryo chorioallantoic membrane (CAM) assay. The compounds were also evaluated as inhibitors of human (h) DHFR and Toxoplasma gondii (tg) DHFR. In each evaluation, a known standard compound was used as a comparison. Of the compounds evaluated, compound 32 was as potent as the standard compounds against VEGFR-2 and PDGFR-beta, showing dual inhibitory activity against RTK. This analog was also highly effective in the CAM assay. A second analog 18 also demonstrated dual VEGFR-2 and PDGFR-beta inhibitory activity as well as potent antiangiogenic activity in the CAM assay. Four additional analogs were also effective against PDGFR-beta and in the CAM assay. An unsaturated C-8-C-9 moiety was necessary for RTK inhibitory activity. Compound 32 also showed inhibitory activity against hDHFR and tgDHFR, illustrating the multitarget inhibitory potential of these analogs. The biological activity of these analogs also suggests the necessity of an unsaturated C-8-C-9 bridge for dual RTK and DHFR inhibitory activity. Compounds 18 and 32 were also evaluated in a B16 melanoma mouse model and were found to be more active as antitumor agents than methotrexate. In addition, both 18 and 32 were also active in decreasing lung metastases in a mouse model of B16 melanomas.
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PMID:Novel 5-substituted, 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors with antiangiogenic and antitumor activity. 1603 63


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