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

Glioblastoma multiforme is one of the most resistant of human tumors to radiation whether used alone or in combination with surgery and/or chemotherapy. This resistance may be caused by one or more of several different factors. These include inherent cellular radiation sensitivity, an efficient repair of radiation damage, an increased number of clonogens per unit of volume, a high hypoxic fraction, high [GSH] concentration, and rapid proliferation between fractions. In the present study, we evaluate the intrinsic radiation sensitivity (surviving fraction at 2 Gy or mean inactivation dose) of malignant human glioma cells in vitro. The in vitro radiation sensitivity of 21 malignant glioma cell lines (early and long term passages) has been measured using colony formation as the end-point of cell viability. The survival curve parameters (SF2 measured and calculated, alpha, beta, D0, n and MID) have been determined for single dose irradiations of exponential phase cells (18-24 hr after plating) under aerobic conditions and growing on plastic. The mean SF2 of the 21 cell lines is 0.51 +/- 0.14 (with a range of 0.19 to 0.76). This value may be compared to the mean SF2 of 0.43-0.47 for SCC, 0.43 for melanoma, and 0.52 for glioblastoma as reported from other authors when using colony formation of cells in exponential phase on plastic. Although glioblastoma is almost invariably fatal, our data demonstrate a very wide range of intrinsic radiosensitivities. These broadly overlap the radiation sensitivities of cell lines from tumors that are often treated successfully. We conclude that standard in vitro measurements of cellular radiation sensitivity (SF2) do not yield values that track in a simple manner with local control probability at the clinical level and that, for at least some of the tumors, other parameters and/or physiological factors are more important.
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PMID:In vitro intrinsic radiation sensitivity of glioblastoma multiforme. 131 13

Resistance to alkylating agents has been correlated with cellular levels of reduced glutathione (GSH) and glutathione-S-transferase (GST). GSH is also involved in regulation of melanin synthesis. Therefore, we examined sensitivity to melphalan as a function of differentiation and GSH/GST levels in three human melanoma cell lines. The Me8 cell line, classified as undifferentiated on the basis of cell shape, absence of pigment, insignificant dopa oxidase activity and presence of inhibitors of dopa-melanin formation, showed the lowest GST activity among the cell lines investigated. GLL19 cells exhibited normal differentiation as indicated by the presence of dendrites, typical eumelanosomes, melanin granules and dopa oxidase activity. These cells showed the highest GSH content and the highest GST activity. The JUSO cell line showed incomplete differentiation, and its dopa oxidase and GST activities were intermediate between the Me8 and GLL19 cell lines. The sensitivity of melanoma cell lines to melphalan increased with their degree of differentiation; it was lowest for Me8, intermediate for JUSO and highest for GLL19. Dibutyryl cyclic AMP (dbcAMP) enhanced melphalan toxicity against Me8 cells. Depletion of intracellular GSH with buthionine sulphoximine (BSO) resulted in a three-fold increase in melphalan sensitivity in all three cell lines. Our results indicate that melphalan toxicity is related to cell differentiation and GSH status of melanoma cells. Based on the observed relationship between dopa oxidase, GSH/GST levels and drug toxicity, it is proposed that competition for the GSH pool between quinonoid melanin intermediates and melphalan could diminish drug conjugation and increase cytotoxicity.
Melanoma Res 1992 Dec
PMID:Relationship between melanogenesis, glutathione levels and melphalan toxicity in human melanoma cells. 133 97

Levels of glutathione peroxidase (GSH-PX), glutathione-S-transferase (GST), gamma-glutamyl transpeptidase (gamma GTP) and glutathione reductase (GR) activities in the B16-F10 metastatic melanoma cell line are higher than those in non-metastatic B-16 murine melanoma cells. An inverse relationship was observed between the level of reduced glutathione (GSH) and metastatic capacity. Interferon (IFN), an antitumour and antimetastic agent, reduced the experimental metastatic capacity of B16-F10 cells while increasing the intracellular GSH content. This was associated with a fall in activity of GSH-metabolizing enzymes. These results suggest a correlation of intracellular GSH and its metabolizing enzymes with malignant transformation.
Melanoma Res 1992 Dec
PMID:Intracellular glutathione and its metabolizing enzyme activities in a metastatic variant melanoma cell line. 136 79

The influence of alpha-lipoic acid (CAS 62-46-4) on the amount of intracellular glutathione (GSH) was investigated in vitro and in vivo. Using murine neuroblastoma as well as melanoma cell lines in vitro, a dose-dependent increase of GSH content was observed. Dependent on the source of tumor cells the increase was 30-70% compared to untreated controls. Normal lung tissue of mice also revealed about 50% increase in glutathione upon treatment with lipoic acid. This corresponds with protection from irradiation damage in these in vitro studies. Survival rate of irradiated murine neuroblastoma was increased at doses of 100 micrograms lipoic acid/d from 2% to about 10%. In agreement with the in vitro studies, in vivo experiments with whole body irradiation (5 and 8 Gy) in mice revealed that the number of surviving animals was doubled at a dose of 16 mg lipoic acid/kg. Improvement of cell viability and irradiation protection by the physiological compound lipoic acid runs parallel with an increase of intracellular GSH/GSSG ratio.
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PMID:Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. 141 40

We measured the glutathione content of a panel of human malignant melanoma cell lines by flow cytometry after staining with mercury orange, using visible light (488 nm) excitation, and compared the values obtained with those measured biochemically using a modified Tietze assay. Glutathione levels were depleted by culturing cells with various concentrations of buthionine sulphoximine to provide a suitable spread of glutathione concentrations. The two assays showed good correlation (r = 0.93). We found a number of technical factors to be critically important. In particular, the conditions of staining, cell number, and method of mixing media, cells and stain were responsible for wide variations in fluorescence intensity. We applied the flow cytometric technique to cell suspensions obtained by fine needle aspiration biopsy of human malignant melanoma deposits, and observed a proportion of cells with high glutathione levels in many samples. The results confirm the feasibility of measuring glutathione content by visible light flow cytometry, and raise the possibility of monitoring glutathione content as an indicator of drug resistance in clinical therapy of human malignant melanoma.
Melanoma Res
PMID:Glutathione content of human malignant melanoma cell lines: correlation of flow cytometric and biochemical assays, and application to human tumour aspirates. 142 88

Murine neuroblastoma (C-1300 NMB) and malignant melanoma (B16) cells were radiated in presence of radiopharmaceutics. Sensibilization was carried out with BSO and protection with TMX. Changes in fluidity of the plasma membrane, in cellular GSH contents and cell cycle were observed. After radiation fluidity of the plasma membrane is increased, whereas intracellular GSH decreased. These changes were intensified by BSO and reduced by TMX. Fluidity of the plasma membrane correlates with intracellular GSH and also with cell cycle. It is suggested that changes in plasma membrane fluidity can be used as an additional parameter for the determination of sensitivity towards radiation.
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PMID:[Plasma-membrane fluidity studies of murine neuroblastoma and malignant melanoma cells under irradiation]. 149 53

The effect of DOPA and glutathione (GSH) on enzyme systems for 5-S-cysteinyl-DOPA (5SCD) genesis in murine melanoma cells cultured in tyrosine- and cystine-free medium were studied. DOPA at its optimum concentration (10(-5) M) when added alone did not alter tyrosinase, glutathione-S-transferase or gamma-glutamyl transpeptidase activities. In the presence of GSH at its optimum concentration (10(-5) M), DOPA loading did not cause any significant changes in tyrosinase or glutathione-S-transferase (GST) activities. This indicates that the higher 5SCD levels observed in the medium because of DOPA loading in the GSH dependent system results from increased substrate availability rather than the increased enzyme activity. An acute drop in 5SCD at DOPA concentrations above 10(-5) M observed in the GSH dependent system may be due to the inhibition of tyrosinase at high substrate concentrations (10(-4) M). Conversely, in the presence of DOPA, when GSH was increased, the resultant higher production of 5SCD could be explained by the increased activity of GST. When added alone, GSH (10(-5) M) caused a significant increase in GST (approximately 125%) and gamma-GTP (approximately 50%) activities. A drop in 5SCD in the medium when GSH was added beyond its optimum concentration (10(-5) M) in the DOPA-dependent system could be due to competitive inhibition of gamma-GTP by GSH. The data demonstrate that 5SCD genesis may be enhanced due to the accumulation of cytotoxic melanin precursors such as DOPA/DOPA quinone. The relative quantities of GSH at the sites of DOPA quinone formation and the levels of its metabolising enzymes can influence the type of product formed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of dopa-loading on glutathione metabolising enzymes and tyrosinase in relation to 5-S-cysteinyl-dopa genesis in cultured B-16 melanoma cells. 168 90

Malignant melanoma tumors are inherently resistant to anticancer drugs, yet the mechanism of this resistance is not understood. B16 melanoma, a spontaneous tumor which arose in the C57BL/6 mouse; BL6 melanoma, a highly invasive variant; and Mel-ab melanocytes, isolated from C57BL/6 mouse skin, were examined for intracellular glutathione (GSH) content. GSH was higher in BL6 and B16 cells than in Mel-ab cells, with the highest concentration in BL6 cells. Since GSH is thought to be involved in the resistance of many cells, including melanoma, to cytotoxic drugs, we determined whether intracellular GSH content was altered during transformation of Mel-ab cells. After transfection with pHO6T1 plasmid DNA, containing an activated c-H-ras oncogene flanked by transcriptional enhancers, 1.3% of successfully transfected Mel-ab melanocytes formed distinct colonies in soft agar, compared to 0.2% of cells transfected with control pHO6 plasmid without H-ras. Approximately 53% of the pHO6T1-transfected colonies isolated from soft agar grew in 5% CO2 in the absence of phorbol-12-myristate-13-acetate, a requirement for the extended growth of Mel-ab cells. Cells transfected with control pHO6 plasmid and non-transfected Mel-ab cells did not survive under these conditions. All of the isolated pHO6T1 transfected cells formed tumors when inoculated into C57BL/6 mice. Transformed cells had higher GSH content than non-transfected Mel-ab cells, whether expressed on a cellular or cell volume basis. Although the amount of oxidized glutathione was greater in the tumorigenic cells, this could not account for the overall increase in GSH. Neither glutathione S-transferase nor gamma-glutamyl transpeptidase activities were increased in the H-ras-transfected cells. Northern blot analysis confirmed H-ras-specific RNA in pHO6T1-transformed cells.
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PMID:Induction of glutathione content in murine melanocytes after transformation with c-H-ras oncogene. 171 78

The cytotoxic and growth-inhibitory effect of levodopa methylester (LDME) in murine B16BL6 (BL6) melanoma cells after glutathione (GSH) depletion was studied in vitro. Pretreatment of BL6 cells with 50 microM buthionine sulfoximine (BSO) depleted GSH content by nearly 90% and enhanced the growth-inhibitory effect of even a minimally cytotoxic concentration of LDME. Radiothymidine incorporation into BL6 cells significantly increased compared to untreated controls during the first 4 h of exposure to 0.2 mM LDME. However, pretreatment with BSO prevented this LDME-induced increase in radiothymidine incorporation. Because the percentage of cells in S-phase of the cell cycle was not altered, these results suggest that BSO exposure may be inhibiting unscheduled DNA synthesis, which could contribute to the cytotoxic effects of LDME. In addition, spectrophotometric studies indicated that in a cell-free system, GSH scavenged dopaquinone produced by the tyrosinase-mediated oxidation of LDME, presumably by formation of glutathionyldopa. Thus, enhancement of LDME cytotoxicity by BSO may also involve depleting the amount of GSH available for the nucleophilic addition to the quinone.
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PMID:Effect of L-dopa methylester and glutathione depletion on murine B16BL6 melanoma growth in vitro. 174 17

A high-performance liquid chromatographic method with fluorometric detection is described which is suitable for determination of glutathione in small samples. Reduced glutathione (GSH) and total glutathione obtained as GSH after reduction with glutathione reductase is derivatized with N-(7-dimethylamino-4-methyl-3-coumarinyl) maleimide (DACM) and subjected to chromatography. The detection limit for the GSH-DACM derivative was 5-10 fmol/injection, and analytical recovery was quantitative. The method is suitable for determination of both reduced and total glutathione in samples from microdialysis of melanoma tumours, and cysteine can be quantified in the same chromatogram. Application is shown also for glutathione determinations in cultured melanoma cells, melanoma homogenates and plasma.
Melanoma Res
PMID:A high-sensitivity fluorometric high-performance liquid chromatographic method for determination of glutathione and other thiols in cultured melanoma cells, microdialysis samples from melanoma tissue, and blood plasma. 182 68


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