Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The melanoma cell adhesion molecule is a membrane glycoprotein whose expression is associated with tumor progression and the development of metastatic potential. The mechanisms for upregulation of the melanoma cell adhesion molecule during melanoma progression are still poorly understood. In this study, we show further evidence that melanoma cell adhesion molecule expression is tightly regulated at the transcriptional level. Using a combination of chloramphenicol acetyl transferase reporter assays and DNA mobility shift experiments, we investigated the role played by three putative melanoma cell adhesion molecule regulatory elements, namely the initiator sequence, the SCA element, and the ASp element. The SCA and the ASp boxes can potentially interact with the transcription factors Sp1 and AP-2. Sp1 binding to both sites was confirmed, but only the SCA sequence could form a complex with AP-2. AP-2-driven downregulation of the melanoma cell adhesion molecule promoter, however, did not depend only on a functional SCA element. The pyrimidine-rich CTCACTTG initiator, which overlaps the RNA start site, was essential for promoter function and was shown to interact with proteins related to basic helix-loop-helix transcription factors. Binding in nonmetastatic melanoma cells was induced by cAMP. In metastatic cells, however, binding was constitutive, but could be markedly decreased upon treatment with phorbol esters. As melanoma cell adhesion molecule expression is modulated by cAMP and phorbol ester signaling, these results suggest that the initiator is the central element that mediates cAMP and phorbol ester sensitivity and initiates melanoma cell adhesion molecule overexpression in melanomas.
 ...
PMID:Role of the initiator element in the regulation of the melanoma cell adhesion molecule gene. 1099 41

A number of nucleoside analogues have been either used clinically as anticancer drugs or evaluated in clinical studies, while new nucleoside analogues continue to show promise. In this article, we report synthesis and cytotoxicity of a series of new pyrido[2, 3-d]pyrimidine nucleosides. 2-Amino-3-cyano-4-methoxypyridine was converted, in two steps, to 4-amino-5-oxopyrido[2,3-d]pyrimidine. A variety of 1-O-acetylated pentose sugar derivatives were condensed with silylated 4-amino-5-oxopyrido[2,3-d]pyrimidine, followed by protection, to afford a series of 4-amino-5-oxopyrido[2, 3-d]pyrimidine nucleosides. Further derivatizations provided an additional group of pyrido[2,3-d]pyrimidine nucleosides. These nucleosides were evaluated for in vitro cytotoxicity to human prostate cancer (HTB-81) and mouse melanoma (B16) cells as well as normal human fibroblasts (NHF). A number of compounds (1a,b, 2a-c,f, 3f+4d) showed significant cytotoxicity to cancer cells, with 4-amino-5-oxo-8-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (1b) being the most potent proliferation inhibitor (EC(50): 0.06-0.08 microM) to all types of cells tested. However, a selective inhibition to the cancer cells was observed for 4-amino-5-oxo-8-(beta-D-xylofuranosyl)pyrido[2,3-d]pyrimidine (2b), which is a potent inhibitor of HTB-81 (EC(50): 0.73 microM) and has a favorable in vitro selectivity index (28).
 ...
PMID:Synthesis and cytotoxicity of 4-amino-5-oxopyrido[2,3-d]pyrimidine nucleosides. 1102 Feb 85

Cloudman S91 mouse melanoma cells vary in constitutive and inducible melanin levels. Survival, mutation induction and DNA damage were quantitated after exposure to UVB, UVA and FS20 lamps. Assuming that the observed differences are related to melanin, induced pigment is photo-protective for survival and mutation after UVB and FS20 exposure, and is photosensitizing for survival after UVA exposure. No changes in pyrimidine dimers could be measured. DNA damage in pigmented mouse melanocytes (melan-a and melan-b) was greater than that in albino melanocytes (melan-c) after UVB and FS20, and the pigmented cells were more sensitive to killing. Pigment appears to be protective for killing by UVA in these melanocytes. Human melanocytes from different skin types vary in both melanin amount and composition (eu- and pheomelanin). Effects of pigmentation on UVB responses are unclear. In UVA, heavily pigmented cells have more DNA damage than lightly pigmented cells, but are resistant to killing. Increased pheomelanin photosensitizes DNA damage in lightly pigmented cells. Since eumelanin predominates in the mouse melanoma cells and melanocytes, they are less likely than human cells to provide a satisfactory model for human solar melanomagenesis. In order to understand the mechanism of photocarcinogenesis of melanoma, melanins in human melanocytes from different pigment types should be carefully quantitated and characterized. Mutations induced in them by solar wavelength-emitting lamps with well-characterized spectra should be measured, and mutant DNA should be sequenced to determine the nature of the solar-induced lesions. Research should focus on UVA and pheomelanin.
 ...
PMID:UVA, pheomelanin and the carcinogenesis of melanoma. 1104 72

Toyocamycin and some analogues have shown potent antitumor activities; however, none of them could be used clinically primarily owing to their cytotoxicity to normal human cells. In order to overcome the weakness of these nucleoside analogues, substitution of a variety of modified sugars for the ribofuranose was explored in our laboratories with expectation that certain sugar-modified toyocamycin analogues may be selectively cytotoxic to cancer cells. In this article, we report synthesis and cytotoxicity of 4'-C- and 5'-C-substituted toyocamycins, which were prepared via the condensations of 4-C- and 5-C-substituted ribofuranose derivatives 11, 12, 13, 20, 21, and 26 with the silylated form of 4-amino-6-bromo-5-cyanopyrrolo[2,3-]pyrimidine (27) and subsequent debromination and debenzoylation. When compared to the parent toyocamycin, all these analogues showed much lower cytotoxicity to human prostate cancer cells (HTB-81), mouse melanoma cancer cells (B16) as well as normal human fibroblasts. Compound 1e showed a significant cytotoxicity to the prostate cancer cells and a moderate selectivity. The results suggested that sugar modifications, especially those that may affect phosphorylation of nucleosides, could alter cytotoxicity profile significantly.
 ...
PMID:Synthesis and cytotoxicity of 4'-C- and 5'-C-substituted toyocamycins. 1119 36

Sunlight-induced skin cancer is the most frequent cancer. Ultraviolet-B (UVB) (290-315 mm) and UVA (320-400 mm) radiation can induce DNA damage with resulting epithelial squamous cell carcinoma and melanoma by causing mutations and immunosuppressive effects that presumably contribute to photocarcinogenesis. The efficacy of photo- and photochemotherapeutic modalities is thought to result, at least in part, from the induction of immunomodulatory effects. In particular, UV radiation has been shown to affect (i) the production of soluble mediators, (ii) the expression of cell-surface receptors and (iii) to induce apoptosis in pathogenetically relevant cells. UVB radiation-induced immunomodulatory effects are limited to the epidermis, whereas UVA radiation-affects both epidermal and dermal cell populations. UVB and UVA radiation can exert essentially identical immunomodulatory effects, which result, however, from different photobiological mechanisms. UVB radiation-induced cyclobutane pyrimidine dimers within the DNA of epidermal cells are detrimental to human health. Photolyase-induced dimer repair completely prevented these UVB radiation-induced immunosuppressive effects as well as erythema and sunburn-cell formation. The Xeroderma pigmentosum (XP) is a rare syndrome of sensitivity to UV due to an inherited defect in nucleotide excision repair or daughter strand repair. Ionising radiation sensitivity is not part of the recognised syndrome. Extreme caution is advised before treating XP patients with radiotherapy. Determining the complementation group and radiosensitivity prior to treatment is recommended.
 ...
PMID:[Photocarcinogenesis]. 1125 31

The goal of this investigation was to correlate the melanin content in human pigmentary cells with the generation of UVB-induced photoproducts and to examine the relationship between the melanin content and the removal of the photoproducts. Cultured melanocytes from light-skinned individuals synthesized less melanin and produced more cyclobutane pyrimidine dimers and 6-4 photoproducts upon UVB exposure than did melanocytes from black skin. Tyrosine-stimulated melanogenesis provided protection against DNA damage in both cell types. In another set of pigmented cell lines a ratio between eumelanin and pheomelanin was determined. The assessment of association between DNA damage induction and the quantity and quality of melanin revealed that eumelanin concentration correlated better with DNA protection than pheomelanin. Skin type-I and skin type-VI melanocytes, congenital nevus (CN)-derived cells and skin type-II melanocytes from a multiple-melanoma patient were grown in media with low or high L-tyrosine concentration. The cells were irradiated with 200 J/m2 UVB, and the levels of the photoproducts were determined immediately and after 6 and 24 h. Once again the induction of the photoproducts was mitigated by increased melanogenesis, and it was inversely correlated with the skin type. No significant differences were found for the removal of photoproducts in the cultures of skin types I and VI and CN cells. No indications of a delay in the removal of photoproducts in the melanocytes from the multiple-melanoma patient were found either.
 ...
PMID:Melanin offers protection against induction of cyclobutane pyrimidine dimers and 6-4 photoproducts by UVB in cultured human melanocytes. 1159 56

I was trained as a physicist in graduate school. Hence, when I decided to go into the field of biophysics, it was natural that I concentrated on the effects of light on relatively simple biological systems, such as proteins. The wavelengths absorbed by the amino acid subunits of proteins are in the ultraviolet (UV). The wavelengths that affect the biological activities, the action spectra, also are in the UV, but are not necessarily parallel to the absorption spectra. Understanding these differences led me to investigate the action spectra for affecting nucleic acids, and the effects of UV on viruses and cells. The latter studies led me to the discovery of the important molecular nature of the damages affecting DNA (cyclobutane pyrimidine dimers) and to the discovery of nucleotide excision repair. Individuals with the genetic disease xeroderma pigmentosum (XP) are extraordinarily sensitive to sunlight-induced skin cancer. The finding, by James Cleaver, that their skin cells were defective in DNA repair strongly suggested that DNA damage was a key step in carcinogenesis. Such information was important for estimating the wavelengths in sunlight responsible for human skin cancer and for predicting the effects of ozone depletion on the incidence of non-melanoma skin cancer. It took experiments with backcross hybrid fish to call attention to the probable role of the longer UV wavelengths not absorbed by DNA in the induction of melanoma. These reflections trace the biophysicist's path from molecules to melanoma.
 ...
PMID:Shedding light on proteins, nucleic acids, cells, humans and fish. 1190 39

The development of cutaneous malignant melanoma (CMM) and its precursor lesions, melanocytic nevi, has been linked to sun exposure. Cyclobutane pyrimidine dimers (CPDs) are the majority of DNA lesions induced by sun exposure. In our study, we investigated if CMM patients have impaired ability to repair CPDs in skin as well as in melanocytic nevi. The repair kinetics were followed up to 3 weeks after exposure to 40 mJ/cm(2) of solar simulating radiation. Altogether 12 CMM patients and 10 healthy controls were included in our study. Buttock skin biopsies were taken at 0 hr, 48 hr and 3 weeks after UV exposure, whereas melanocytic nevi and surrounding skin biopsies were taken only at 0 hr and 3 weeks. The CPD levels were measured by a (32)P-postlabeling method. The results showed that the repair rate of CPDs in neither the skin nor the nevi was significantly different between the CMM patients and the control group. For both groups, the repair rate of TT = C was faster than that for TT = T. The important finding is that about 10% of the initial TT = T damage remained unrepaired after 3 weeks, and was detectable in normal epidermis as well as in nevi of all subjects. We also found that the amount of TT = C and TT = T at 0 hr in nevi was significantly lower than that in surrounding skin (Wilcoxon rank sum test, p < 0.05).
 ...
PMID:In situ repair of cyclobutane pyrimidine dimers in skin and melanocytic nevi of cutaneous melanoma patients. 1192 May 82

We report here that DNA polymerase beta (pol beta), the base excision repair polymerase, is highly expressed in human melanoma tissues, known to be associated with UV radiation exposure. To investigate the potential role of pol beta in UV-induced genetic instability, we analyzed the cellular and molecular effects of excess pol beta. We firstly demonstrated that mammalian cells overexpressing pol beta are resistant and hypermutagenic after UV irradiation and that replicative extracts from these cells are able to catalyze complete translesion replication of a thymine-thymine cyclobutane pyrimidine dimer (CPD). By using in vitro primer extension reactions with purified pol beta, we showed that CPD as well as, to a lesser extent, the thymine-thymine pyrimidine-pyrimidone (6-4) photoproduct, were bypassed. pol beta mostly incorporates the correct dATP opposite the 3'-terminus of both CPD and the (6-4) photoproduct but can also misinsert dCTP at a frequency of 32 and 26%, respectively. In the case of CPD, efficient and error-prone extension of the correct dATP was found. These data support a biological role of pol beta in UV lesion bypass and suggest that deregulated pol beta may enhance UV-induced genetic instability.
 ...
PMID:A role for DNA polymerase beta in mutagenic UV lesion bypass. 1238 48

Chromosomal instability plays a pivotal role in multistep carcinogenesis by facilitating the acquisition of the multiple genetic alterations necessary for malignant transformation. In order to study the role of abnormal DNA repair in malignant melanoma, we measured the ability of cell lines from malignant melanoma and that of primary melanocytes to process 4 different kinds of DNA damage (pyrimidine dimers, oxidative DNA lesions, replication errors, and DNA double-strand breaks) using 4 different plasmid assays. Based on the number of chromosomes, the DNA index, and the rates of spontaneous micronuclei, the chromosomal stability in primary melanocytes and the melanoma line LIBR was characterized as being high, intermediate in M1, and low in MeWo. Repair of UVB photoproducts, of oxidative DNA damage, and of replication errors was not impaired in any melanoma line. Using linearized shuttle vector plasmid pZ189, LIBR cells and primary melanocytes exhibited a high efficiency of joining overlapping DNA ends, reflecting proficient repair of DNA double-strand breaks. Joining efficiency was reduced slightly in M1 and 2.9-fold in MeWo. This indicates that in the melanoma cell lines studied here, an increase in chromosomal instability is accompanied by a pronounced impairment in the ability to join DNA ends. Although a small sample was studied, this raises the possibility that defects in DNA end joining may also contribute to genetic instability and chromosome aberrations in melanoma.
 ...
PMID:Reduced joining of DNA ends correlates with chromosomal instability in three melanoma cell lines. 1285 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>