UMLS:C0025202 - FACTA Search

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

Recent advances in melanogenesis have focused on the role of dihydroxyindole-2-carboxylic acid[(HO)2IndCOOH]. For example, it has been shown that formation of (HO)2IndCOOH from dopachrome is catalyzed by dopachrome tautomerase, that the melanogenic protein tyrosinase-related protein (TRP)-1 can oxidize (HO)2IndCOOH to its indole quinone, that (HO)2IndCOOH-melanins can be synthesized chemically, that mammalian melanins are naturally rich in (HO)2IndCOOH subunits, and that (HO)2IndCOOH is incorporated into melanins of melanomas in mice. The question thus emerges as to the mechanism(s) by which (HO)2IndCOOH and other precursors become incorporated into melanins in vivo. Accordingly, an activity was partially purified that catalyzed melanin formation with (HO)2IndCOOH as a substrate. Analyses of the (HO)2IndCOOH polymerization factor from Cloudman melanoma cells revealed the following: it was proteinaceous in that it was heat labile and destroyed by proteinase K; it was a glycoprotein in that it adhered to wheat germ agglutinin and was eluted with N-acetyl glucosamine; it was located predominantly in the melanosomal fraction of cell homogenates; the activity was reduced by exposure to the metal chelators EDTA and EGTA, but not by phenylthiourea, a tyrosinase inhibitor; the (HO)2IndCOOH polymerization reaction was inhibited by superoxide dismutase. In addition, the activity was found with the mouse pmel 17/silver locus protein immunopurified from human melanoma cells, and was significantly reduced in extracts of mouse melanocytes cultured from silver (si/si) mice compared to extracts from Si/Si melanocytes. In summary, an activity has been identified in human and mouse melanoma cells that catalyzes the superoxide-dependent polymerization of (HO)2IndCOOH to melanin in vitro, and appears to be a function of the pmel 17/silver protein of the human pmel 17 gene and the mouse silver locus.
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PMID:Polymerization of 5,6-dihydroxyindole-2-carboxylic acid to melanin by the pmel 17/silver locus protein. 861 63

The proliferation of human melanoma cell line A375-6 is inhibited by interleukin l (IL-l). However, the cells acquired resistance to IL-l after a long period of culture. We have reported that 2 resistant subclones, A375-R8 and -R19, produced IL-l alpha constitutively and that IL-l induced IL-6 production in an autocrine manner. Therefore, we supposed that IL-l alpha production renders the cells resistant to IL-l. To investigate the relationship between IL-l alpha production and IL-l resistance, we transfected the IL-l alpha expression plasmid to the IL-l-sensitive clone, A375-6, and the anti-sense mRNA expression plasmid to IL-l-resistant cells, A375-R8 and -R19. A375-6MS, a transfectant of mature IL-l alpha expression plasmid, expressed IL-l alpha mRNA and produced IL-l activity at a level comparable to the resistant cells. The transfectant also produced IL-6 and exhibited augmented expression of Mn-SOD mRNA. However, IL-l sensitivity of this transfectant was not affected. With respect to sensitivity to anti-proliferative effects of other cytokines, such as IL-6 and TNF alpha, there was no difference between the transfectant and parent cells. Although A375-R8PH10 and -R19PH10, transfectants of IL-l alpha anti-sense mRNA expression plasmid, exhibited a decrease in the level of IL-l production, their IL-l sensitivity did not differ from parent cells. These results, therefore, suggest that IL-l alpha production is not essential or sufficient for the acquisition of resistance to the anti-proliferative effect of IL-l.
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PMID:Interleukin 1 (IL-1) production is not essential for acquired resistance of human A375 melanoma cells to anti-proliferative effect of IL-1. 863 96

In order to evaluate the free radical defense systems of melanocytes and their possible correlation with melanoma, we have studied in cultured normal human melanocytes (20), normal melanocytes from melanoma patients (15), and melanoma cells (40) the fatty acid pattern of membrane phospholipids as a target of peroxidative damage and the superoxide dismutase and catalase activities, vitamin E, and ubiquinone levels as intracellular antioxidants. Cells were cultured in the same medium and analyzed at III or IV passage. Compared to the values obtained in normal human melanocytes, melanoma cells showed on average: a) higher levels of polyunsaturated fatty acids, b) increased superoxide dismutase and decreased catalase activities, higher vitamin E, and lower ubiquinone levels. Among the normal melanocytes from melanoma patients studied, two groups were differentiated: a) cultures (7) with enzymatic and non-enzymatic antioxidants level similar to those of normal human melanocytes; b) cultures (8) with antioxidant patterns similar to those observed in melanoma cells. Polyunsaturated fatty acids were also increased in the latter group. The results indicate that in melanoma cells and in a percentage of normal melanocytes from melanoma patients, an imbalance in the antioxidant system can be detected that can lead to endogenous generation of reactive oxygen species and to cellular incapability of coping with exogenous peroxidative attacks. These alterations could be correlated with the malignant transformation of cells and with the progression of the disease.
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PMID:Imbalance in the antioxidant pool in melanoma cells and normal melanocytes from patients with melanoma. 875 64

Photodynamic-induced cytotoxicity by hypericin (HYP) was studied on three human melanoma cell lines: one pigmented cell line (G361) and two amelanotic cell lines (M18 and M6). No significant variation in the rate of uptake and in the maximum level of HYP incorporation for the different cells was observed. In the dark, no cytotoxicity was observed in the range 0-10-6 M HYP for the three cell lines. Amelanotic cells were found to be more sensitive than pigmented cells to irradiation of HYP with visible light (lambda > 590 nm). In addition, for the three cell lines HYP-induced photocytotoxicity was found to be drug-dose and light-dose dependent. Under the conditions used, thiobarbituric acid-reacting substances (TBARs) were significantly increased in amelanotic cells after irradiation (P < 0.0001). By contrast, the amount of TBARS remained unchanged in pigmented cells. Antioxidant defenses including enzymes and glutathione (GSH) were assayed before and after HYP photosensitization. Significantly increased total SOD activity was observed after photosensitizaton for amelanotic cells (P < 0.05), while glutathione peroxidase (GSHPx) and catalase (Cat) activities but also GSH levels were significantly decreased (P < 0.01). In pigmented cells a significantly increased Cat activity was found (P < 0.05), whereas GSHPx was unaffected after irradiation. It can be inferred that (a) HYP may be an effective PDT agent for melanoma and (b) there is a relationship between melanin content and sensitivity to HYP phototoxicity in human melanoma cells.
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PMID:Photodynamic effects of hypericin on lipid peroxidation and antioxidant status in melanoma cells. 876 May 77

Tyrosinase isolated from cultured human melanoma cells was studied for tyrosine oxygenation activity. L-Tyrosine and D-tyrosine were used as substrates and dopa was measured with HPLC and electrochemical detection as the product of oxygenation. Incubations were performed in the presence or absence of dopamine as co-substrate. Oxygenation of L-tyrosine occurred only in the presence of dopamine as co-substrate. No oxygenation of D-tyrosine was found, and we conclude that human tyrosinase is characterised by exclusive specificity for the L-isomer of tyrosine in its oxygenase function. It has recently been suggested that superoxide anion is a preferential oxygen substrate for human tyrosinase. Incubations were therefore performed with L- and D-tyrosine, human tyrosine, and xanthine/xanthine oxidase in the system, generating superoxide anion and hydrogen peroxide. Considerable formation of dopa was observed, but the quantity was the same irrespective of whether D-tyrosine or L-tyrosine was used as the substrate. Furthermore, formation of dopa occurred in a xanthine/xanthine oxidase system when bovine serum albumin (BSA) was substituted for tyrosinase. Our results provide no evidence that superoxide anion is an oxygen substrate for human tyrosinase. In the incubate containing xanthine/xanthine oxidase, catalase completely inhibited dopa formation, and superoxide dismutase and mannitol each strongly inhibited dopa formation. The results are compatible with hydroxyl radicals being responsible for the formation of dopa, since such radicals may be secondarily formed in the presence of superoxide anion and hydrogen peroxide.
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PMID:Enzymatic and non-enzymatic oxygenation of tyrosine. 885 72

Damage to vascular endothelium may play an important role during metastasis. We used a three-dimensional model of tumour cell extravasation to test the hypothesis that certain types of tumour cells are able to induce vascular endothelial cell injury. Multicellular tumour spheroids (MCTS) of 14 human cancer cell lines and spheroids from two benign cell lines were transferred onto confluent monolayers of human endothelial cells (EC). MCTS from 4 of 7 melanoma cell lines induced damage of the endothelium which was closely associated with tumour cell attachment. Endothelial cell injury became evident morphologically by loss of cell membrane integrity and sensitivity to shear stress. Similar results were obtained with EC derived from human umbilical veins, umbilical arteries and saphenous veins. Addition of the oxygen radical scavenger catalase showed a dose- and time-dependent inhibition (up to 48 h) of EC damage in the case of the melanoma cell lines ST-ML-11, ST-ML-14 and SK-MEL-28. The scavenging enzyme superoxide dismutase proved to be protective (up to 12 h) in ST-ML-12 MCTS. In contrast, allopurinol, deferoxamine mesylate, ibuprofen, nor-dihydroguaretic acid, soybean trypsin inhibitor or aprotinin had no protective effect. None of the non-melanoma cancer cell lines or benign cells induced endothelial cell damage. Endothelial injury has been shown to enhance the process of metastasis. Our results suggest that free-radical-mediated endothelial cell damage may be one of the mechanisms contributing to the devastating metastatic potential of melanoma.
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PMID:Tumour-cell-endothelial interactions: free radicals are mediators of melanoma-induced endothelial cell damage. 892 31

Recombinant human interleukin 1 alpha (rh IL-1 alpha) and etoposide (VP-16) synergize for direct growth inhibition of several human tumor cell lines in vitro. Our previous studies demonstrated that VP-16 increased the number of membrane-associated IL-1 receptors (IL-1Rs) and also enhanced the internalization of receptor-bound rh IL-1 alpha. The purposes of this study were to test our hypotheses that these events were critical to the synergy between rhIL-1 alpha and VP-16, to determine whether rhIL- 1 alpha and VP-16 synergize to increase superoxide (SO) anion radical production in vitro since SO anion has been implicated in the toxic effects of IL-1, and to investigate the antitumor efficacy of the combination against tumors in vivo. A375/C6 melanoma cells and OVCAR-3 ovarian carcinoma cells were tested with IL-1 receptor antagonist (IL-1 ra) before exposure to rhIL-1 alpha, VP-16 and rhIL-1 alpha plus VP-16. The synergistic or antagonistic effects were assessed by MTT assay. SO production was measured by reduction of cytochrome C. Athymic female mice bearing the A375/C6 melanoma were treated by rhIL-1 alpha, VP-16, and rhIL- 1 alpha+VP-16. The antitumor effects were evaluated by quantitating tumor growth and survival time. Pretreatment with the IL-1ra abrogated the synergistic effects of rhIL-1 alpha and VP-16. The production of SO radical by A375/C6 cells was increased 2.5 fold by the combination of rhIL-1 alpha and VP-16, and the addition of exogenous SOD blocked the synergy between rhIL-1 alpha and VP-16. However, when A375/SOD15 cells which over-expressed manganese superoxide dismutase (MnSOD) after MnSOD cDNA transfection were exposed to rhIL-1 alpha and VP-16, in vitro antagonism was observed. In vivo studies demonstrated that the combination of rhIL-1 alpha and VP-16 delayed tumor growth better than either agent alone, although long-term survival was not improved because of substantial toxicity. Our results suggest that the synergistic antitumor effects of IL-1 alpha and VP-16 may be due to IL-1R modulation and increased internalization of IL-1-IL-1R complex by VP-16 treatment, as well as to a subsequent increase in SO anion radical production from the tumor cells exposed to both drugs. Thus, the combination of IL-1 alpha and VP-16 might prove useful for the treatment of malignant disease in vivo, if the increased toxicity can be reduced or managed.
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PMID:Antitumor effects of human recombinant interleukin-1 alpha and etoposide against human tumor cells: mechanism for synergism in vitro and activity in vivo. 901 39

The hepatic sinusoidal endothelium (HSE) releases large amounts of reactive oxygen species (ROS) in response to endotoxins and interleukin-1 (IL-1). Such pro-inflammatory mediators have been shown to promote hepatic metastasis. We have investigated the involvement of ROS released by IL-1-stimulated HSE in this promoting effect. Recombinant human interleukin-1 beta (rHuIL-1 beta) (5 micrograms/kg) was intravenously injected into C57BL/6J mice, and the hepatic metastasizing ability of B16 melanoma cells following intrasplenic injection was studied in the presence of ROS scavengers. rHuIL-1 beta-promoted hepatic metastases were significantly (P < .01) reduced by catalase (1 mg/kg) and enhanced by recombinant human superoxide dismutase (rHuSOD) (5 mg/kg). rHuIL-1 beta-stimulated HSE-conditioned medium (HSE-CM) significantly (P < .01) enhanced B16 melanoma cell adhesion to HSE compared with unstimulated HSE-CM, which in turn also significantly (P < .01) increased with melanoma cell adherence compared with basal medium. The addition of catalase completely abrogated proadhesive effects induced by rHuIL-1 beta-stimulated HSE-CM with respect to unstimulated HSE-CM, but did not affect the proadhesive effects induced by unstimulated HSE-CM over basal medium. The rat monoclonal antibody to mouse vascular cell adhesion molecule-1 (VCAM-1) significantly (P < .01) inhibited the enhanced melanoma cell adherence effects of both unstimulated and rHuIL-1 beta-stimulated HSE-CM, indicating that adherence was very late antigen-4 (VLA-4)-mediated. Not surprisingly, the percentage of VLA-4 expressing B16 melanoma cells significantly (P < .05) increased in response to unstimulated (21% of controls) and rHuIL-1 beta-stimulated (32% of controls) HSE-CM. Catalase addition abrogated these effects of rHuIL-1 beta-stimulated-HSE-CM. Melanoma cell damage was observed from the second hour of adhesion to HSE and significantly (P < .01) increased when the cells adhered to rHuIL-1 beta-stimulated HSE. This increase was abrogated by catalase. Cytolysis of the HSE was not observed during melanoma cell adhesion. Neither was the enhancement of B16 melanoma hydrogen peroxide production observed in response to rHuIL-1 beta. Thus, the effects of IL-1 in the liver may consist of a balance between the prometastatic effect of enhanced adherence to the HSE and the antimetastatic effect of H2O2-mediated cytotoxicity. Our results suggest that the enhancement of H2O2 production by the rHuIL-1 beta-stimulated HSE may contribute to the hepatic metastasis progression of ROS-resistant melanoma cells. Results in vitro indicate that this progression is associated with a H2O2-mediated increase in melanoma cell adhesion to HSE.
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PMID:Sinusoidal endothelium release of hydrogen peroxide enhances very late antigen-4-mediated melanoma cell adherence and tumor cytotoxicity during interleukin-1 promotion of hepatic melanoma metastasis in mice. 909 86

Manganese superoxide dismutase (MnSOD) enzyme activity and SOD2 gene expression have often been reported to decrease during the development of cancer. SOD2 has also been implicated as a candidate tumor suppressor gene for human malignant melanoma. Genomic DNA methylation patterns are also known to change during carcinogenesis and serve as a mechanism for tumor suppressor gene inactivation. We hypothesized that decreased SOD2 gene expression in some malignant cell populations may be due, at least in part, to methylation of upstream transcriptional regulatory sequences in the SOD2 gene. To test this hypothesis we transfected methylated and unmethylated SOD/2-CAT promoter-reporter constructs in cells known to express the SOD2 gene. Our results indicate that methylation of specific cytokines in the SOD2 5' flanking region is sufficient to repress transcriptional activity of the SOD2 promoter by at least 50%. Moreover, we show that this transcriptional repression was likely mediated by inhibition of AP-2 DNA binding and transactivation from a methylated AP-2 binding site in the SOD2 promoter. DNA methylation may provide a mechanism for transcriptional inactivation of the SOD2 gene during the development of some cancers.
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PMID:Transcriptional inhibition of manganese superoxide dismutase (SOD2) gene expression by DNA methylation of the 5' CpG island. 919 94

4-S-Cysteaminylphenol (4-S-CAP) and the corresponding catechol 4-S-cysteaminylcatechol (4-S-CAC) have been evaluated for melanocytotoxicity. It was shown recently that tyrosinase oxidation of these substrates produces a violet pigment, dihydro-1,4-benzothiazine-6,7-dione (BQ). In this study we examined whether BQ is the ultimate toxic metabolite produced in melanoma cells from 4-S-CAP/4-S-CAC. Biochemical experiments showed that (1) BQ was formed by autoxidation of 4-S-CAC as well as by tyrosinase oxidation of 4-S-CAP/4-S-CAC, (2) BQ reacted rapidly with thiols such as reduced glutathione (GSH), and (3) BQ inhibited the activity of alcohol dehydrogenase, an SH enzyme. In vitro experiments showed that (1) the cytotoxicity of 4-S-CAC was mostly prevented by catalase and superoxide dismutase, (2) BQ was highly cytotoxic to B16 melanoma cells (IC50 being 3.9 microM as compared with 507 microM for 4-S-CAP), (3) BQ was metabolized rapidly to a GSH adduct in melanoma cells, and (4) the same GSH adduct was also formed upon incubation of melanoma cells with 4-S-CAP, the reaction being tyrosinase dependent. In vivo experiments showed that intratumoral administration of BQ (0.5 micromol) inhibited the subcutaneous growth of B16 melanoma nearly as effectively as 4-S-CAP/4-S-CAC (20 micromol). These results indicate that BQ is the ultimate toxic metabolite produced by tyrosinase oxidation of 4-S-CAP/4-S-CAC. BQ deprives melanoma cells of GSH and may inactivate SH enzymes essential for DNA synthesis and cell proliferation by covalent binding through their cysteine residues, thereby exerting melanocytotoxicity. Cytotoxicity of 4-S-CAC depends mostly on autoxidation producing BQ and active oxygens.
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PMID:Dihydro-1,4-benzothiazine-6,7-dione, the ultimate toxic metabolite of 4-S-cysteaminylphenol and 4-S-cysteaminylcatechol. 926 Aug 70

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