Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1522102 (Melanoma)
 7,698 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of our study was to evaluate systematically the anti-proliferative effects of eight chemotherapeutic drugs as well as of four recombinant interferons (IFNs) (alpha-2a, alpha-2b, beta, gamma). All drugs and IFNs were tested separately and in combination at several concentrations on four human melanoma cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5,-diphenyltetrazolium (MTT) test. In all cases, drug inhibitory concentrations of chemotherapeutic agents required to kill 25% of melanoma cells (IC25) in vitro were in the range of the maximal achievable plasma peak level in vivo. Sensitivity to the anti-proliferative action of bleomycin, DTIC, doxorubicin, cisplatin and carboplatin was similar for all melanoma cell lines, whereas cell lines exposed to 5-fluorouracil (5-FU), vindesine and fotemustine differed up to 26-fold in their sensitivity. Studies with IFN showed that IFN-beta and IFN-gamma proved to be more antiproliferative than IFN-alpha in a dose-dependent fashion in all cell lines. However, the ability of IFNs to improve cytotoxicity of chemotherapeutic agents was limited. Pre-incubation of melanoma cells with IFN as well as exposure to IFN after incubation with the drugs showed mainly additive effects (231/256). These results confirm the high chemoresistance of human melanoma cells, independently of the drug chosen. Combinations of chemotherapeutic agents with IFN will provide additional therapeutic benefit, but are unlikely to change the overall high chemoresistance of human melanoma cells.
Melanoma Res 1994 Aug
PMID:In vitro sensitivity of human melanoma cells to chemotherapeutic agents and interferons. 752 35

Natural interferon alpha (nIFN-alpha) isotretinoin and their combination were tested for their capacity to modulate the proliferation of different human melanoma cell lines. Modulation of cell growth was measured using the MTT-assay. Isotretinoin and nIFN-alpha as single agents inhibited the proliferation in a dose dependent manner in the three cell lines: SK-Mel-30, SK-Mel-28 and MaRi. The combination of isotretinoin and nIFN-alpha led to a marked enhancement of the antiproliferative effect compared with either nIFN-alpha or isotretinoin alone in SK-Mel-30 cells. In contrast, there were no additive effects on growth inhibition of melanoma cell lines SK-Mel-28 and MaRi when nIFN-alpha and isotretinoin was combined. In one melanoma cell line (MaRi) proliferation was actually enhanced by isotretinoin in combination with nIFN-alpha. These results demonstrate the heterogeneous response of human melanoma cell lines to noncytotoxic concentrations of isotretinoin and nIFN-alpha alone and in combination.
Melanoma Res 1994 Oct
PMID:Anti-proliferative activity of natural interferon-alpha, isotretinoin and their combination varies in different human melanoma cell lines. 785 17

Human malignant melanoma is characterised by unresponsiveness to conventional chemotherapy. Melanoma-derived cell lines are often markedly chemoresistant, suggesting that cellular mechanisms mediate the multidrug resistance (MDR) phenotype. The multidrug resistance-associated protein (MRP) is a drug transporter protein associated with resistance to a broad spectrum of lipophilic drugs. To investigate whether MRP is involved in intrinsic drug resistance of human melanoma, we analysed expression and functional activity of MRP as well as its impact on chemoresistance in 40 melanoma cell lines (35 established by us from primary and metastatic lesions and 5 obtained from international sources), as well as in one dysplastic naevus-derived cell line and in normal melanocytes. By reverse transcriptase-polymerase chain reaction various levels of MRP mRNA were detected in all melanoma cell lines, and by immunoblot the corresponding protein in a high percentage of them. Functional activity of MRP was assayed by analysing cellular accumulation of 3H-daunomycin (3H-DM) and calcein in response to MRP-modulators by beta-spectrometric and fluorescence-activated cell sorter analysis, respectively. Probenecid (PRO), N-ethylmaleimide (NEM) and benzbromarone (BB) moderately (< or = 1.43-fold) but significantly enhanced intracellular accumulation of MRP substrate probes corresponding to MRP expression. Moreover, the sensitivity of melanoma cell lines to daunomycin (DM) and doxorubicin (DOX), but not to vinblastine (VBL), etoposide (VP-16) and cisplatin (CDDP), analysed by an MTT-based survival assay, were inversely correlated with MRP-gene expression. Our results imply that MRP may be a component of the intrinsic chemoresistance phenotype characteristic of human malignant melanoma.
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PMID:Possible role of the multidrug resistance-associated protein (MRP) in chemoresistance of human melanoma cells. 909 73

The cytotoxicity of the (-)- and (+)-isomers and the quinone metabolite gossypolone prepared from the naturally occurring polyphenolic dialdehyde gossypol were compared using two human melanoma cell lines (SK-mel-19 and SK-mel-28) with a similar growth rate, one melanotic (melanin content of 69 pg/cell) and one amelanotic (melanin content of 10 pg/cell). Results from two viability assays (MTT and flow cytometry) showed that the cytotoxicity of racemic gossypol was identical for both cell lines (50% inhibition of cell growth IC50 = 22 microM). Gossypolone at equimolar concentrations was inactive in the amelanotic cell line and as potent as racemic gossypol in the melanotic cell line. (-)-Gossypol was significantly more active in both cell lines compared with the (+)-isomer. The cytotoxic effect of (-)-gossypol was both concentration and time dependent. Under serum-free conditions, the cytotoxicity of both enantiomers was increased, suggesting that serum protein binding may play a role in the differential toxicity of these isomers in vitro. Morphological changes after exposure to (-)-gossypol included shrinkage and loss of adherence. Cell sensitivity to the (-)-isomer was five-fold greater (IC50 = 4 microM) using a clonogenic assay. At equimolar concentrations, (-)-gossypol was more cytotoxic to both cell lines than the clinically used drugs cisplatin, dacarbazine and melphalan. The results of this study suggest that (-)-gossypol may be of potential therapeutic benefit in melanoma patients.
Melanoma Res 1997 Oct
PMID:Cytotoxicity of gossypol enantiomers and its quinone metabolite gossypolone in melanoma cell lines. 942 19

Coumarin has antitumour effects in vivo and cytostatic effects in vitro. Its half-life in humans is short (1-1.5 h) and the monohydroxylated biotransformation products have significantly longer half-lives. One or several of these products may thus be responsible for the antitumoral effects. We have assayed the in vitro cytostatic activity of five monohydroxylated coumarins (3-, 4-, 6-, 7- and 8-monohydroxycoumarin), their acetates and methyl-ethers. Murine melanoma cells (cell line B16-F10) and murine fibroblasts (B82) were exposed to the test compounds at concentrations between 10 and 160 microg/ml. The cytostatic effects were estimated by reduction of the tetrazolium dye MTT. In the melanoma cells, some of the compounds inhibited growth after exposure for 1 day. In contrast, coumarin inhibited growth to a smaller extent, and only after exposure for 3 days. The most active compounds (3-acetoxycoumarin, 4-methoxycoumarin and 6-hydroxycoumarin), as well as coumarin, were also assayed in murine fibroblasts. The cytostatic effects of 4-methoxycoumarin and 6-hydroxycoumarin were less pronounced in fibroblasts than in melanoma cells. Our observations suggest that these compounds may have a greater therapeutic margin.
Melanoma Res 1999 Jun
PMID:Cytostatic activity of coumarin metabolites and derivatives in the B16-F10 murine melanoma cell line. 1046 79

Our laboratory has synthesized two new phenolic thioether amines, N-propionyl-4-S-cysteaminylphenol (N-Pr-4-S-CAP) and N[2-[(4-propionyloxyphenyl)thio]ethyl] propionamide (N,O-diPr-4-S-CAP). These compounds, along with the previously described phenolic thioether amine N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) and its acetyl form (N,O-diAc-4-S-CAP), are tyrosine-amine derivative analogues. The cytotoxicity of these compounds is thought to be tyrosinase dependent, which may make them suitable for targeted anti-melanoma therapy since only melanocytes and their malignant counterparts contain this active enzyme. To further investigate this hypothesis, we performed MTT [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide] assays to determine the cytotoxicity of these compounds in 10 different cell lines. Specifically, we examined to what extent cytotoxicity is related to tyrosinase and tyrosine hydroxylase activity using melanoma and neuroblastoma cells, which have a common metabolic pathway using tyrosinase and tyrosine hydroxylase, respectively. The most sensitive cell line was the highly pigmented SK-MEL-23 melanoma cell line, which shows a very high tyrosinase activity with the highest melanin pigmentation. KAN and SK-NSH (two neuroblastoma cell lines), which have no tyrosinase activity but high tyrosine hydroxylase, were also sensitive. However, C32 (a non-pigmented melanoma with a lower tyrosinase activity) was also sensitive, and MeWo (a moderately pigmented melanoma with a high tyrosinase activity) was less sensitive. This in vitro study may indicate that there is a non-tyrosinase-mediated mechanism of cytotoxicity for phenolic thioether amines in addition to the tyrosinase-mediated one described previously.
Melanoma Res 2000 Feb
PMID:Comparison of in vitro cytotoxicity of N-acetyl and N-propionyl derivatives of phenolic thioether amines in melanoma and neuroblastoma cells and the relationship to tyrosinase and tyrosine hydroxylase enzyme activity. 1071 35

A selection of natural and synthetic coumarin compounds, including the hydroxylated and nitrated derivatives, were assessed for their cytotoxic potential using the microculture 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cellular viability. For the first time this study utilized both human skin malignant melanocytes (SK-MEL-31) and normal human skin fibroblastic cells (HS613.SK), allowing identification of those coumarin derivatives that are selectively toxic. Coumarin was found to exhibit comparatively low toxicity in both cell types, while 7-hydroxycoumarin (7-OHC) and coumarin had similar activity in SK-MEL-31 cells. The entire series of hydroxylated coumarins were considerably more toxic in HS613.SK than in SK-MEL-31 cells. Novel synthetic nitrated coumarins, 6-nitro-7-hydroxycoumarin (6-NO2-7-OHC) and 3,6,8-nitro-7-hydroxycoumarin (3,6,8-NO2-7-OHC), were shown to be significantly more toxic to SK-MEL-31 than HS613.SK cells. In the malignant melanocyte skin cell line (SK-MEL-31) the cytotoxic effects of these nitro-derivatives were shown to be dose and time dependent. Therefore, the cytotoxic potential of coumarins appears to be highly dependent on the nature and position of the functional group. In addition, nitration of 7-OHC produced compounds that were cytotoxic to malignant melanocytes, suggesting that these nitro-derivatives may have a chemotherapeutic role in the future.
Melanoma Res 2001 Oct
PMID:Study of the in vitro cytotoxic potential of natural and synthetic coumarin derivatives using human normal and neoplastic skin cell lines. 1159 82

Interferon-gamma (IFNgamma) has been shown to induce apoptosis through the induction of the Fas antigen in certain cell lines. In this study, we used four melanoma cell lines (MMN9, PMP, MAA and HMG) to study the antiproliferative effect of exogenous IFNgamma treatment, the expression of IFNgamma-induced Fas antigen, and the combined effect of IFNgamma and anti-Fas antibody (CH-11). We also investigated the relationship between Fas-mediated apoptosis and the expression of the bcl-2 family, measured using Western blotting. IFNgamma increased the mean fluorescence intensity of Fas in MMN9 and PMP cells as measured by flow cytometry. Combined therapy had a significant antiproliferative effect on MMN9 and PMP cells, as measured by the MTT assay. After exposure to IFNgamma and anti-Fas antibody, cleavage of bcl-2 occurred in apoptotic cells, and the signal intensity of both bcl-2 and bak decreased in surviving MMN9 cells, as shown by Western blotting analysis. Our results indicate that IFNgamma induces overexpression of Fas and consequently enhances the sensitivity of melanoma cells to Fas-mediated apoptosis. Furthermore, it is possible that cleavage of bcl-2 correlates with the induction of apoptosis induced by IFNgamma and anti-Fas antibody in melanoma cells. We conclude that combined therapy with IFNgamma and anti-Fas antibody may provide an alternative and more efficient chemotherapeutic approach against melanoma cells by inducing the overexpression of Fas after exposure to IFNgamma.
Melanoma Res 2003 Apr
PMID:Interferon-gamma and anti-Fas antibody-induced apoptosis in human melanoma cell lines and its relationship to bcl-2 cleavage and bak expression. 1269 Feb 98

Evidence indicating that hybrid steroid compounds of anti-cancer agents produce reduced toxicity, significantly lower than the cytotoxic components alone, and increased anti-cancer activity has prompted the design and development of such steroids, mostly alkylating esters. We investigated the in-vitro and in-vivo activity of a homo-aza-steroidal alkylating ester (HASE), in comparison with dacarbazine (DTIC), cisplatin (CPDD), carmustine (BCNU) and semustine (MeCCNU), in the treatment of malignant melanoma. Cytotoxicity was assessed in vitro by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using a panel of six human malignant melanoma cell lines, with or without the presence of rat liver microsome assay. B16 melanoma-bearing mice were used to evaluate in vivo the anti-tumour activity of the tested compounds. In all cases of in-vitro screening, HASE displayed a significantly higher (P<0.0001) cytostatic and cytotoxic effect than DTIC, BCNU and MeCCNU, but produced significantly lower (P<0.0001) activity than CPDD. HASE exhibited a significantly smaller range than CPDD between concentration levels that produced growth arrest and those that induced a cytotoxic effect against melanoma cells in vitro. The anti-tumour activity of HASE in B16 melanoma-bearing mice, as determined by tumour growth rate inhibition (<42%) and percentage survival prolongation (treated versus control, 167%), was significantly superior (P<0.001) to that achieved by DTIC, BCNU and MeCCNU and was equal to that of CPDD. HASE exhibited a toxicity similar to that of DTIC, BCNU and MeCCNU, but significantly lower than that of CPDD. It can be concluded that HASE displays significant in-vitro and in-vivo activity in the treatment of melanoma.
Melanoma Res 2005 Aug
PMID:Research on the anti-tumour effect of steroid lactam alkylator (NSC-294859) in comparison with conventional chemotherapeutics in malignant melanoma. 1603 5

Standard antineoplastic treatment for metastatic melanoma is ineffective in the large majority of patients. Therefore, alternative approaches need to be investigated. STI571 is a new antineoplastic compound, which selectively inhibits the tyrosine kinase activity of ABL, c-Kit and platelet-derived growth factor receptor (PDGFR). Melanoma may express all of these proteins. The aim of this study was to investigate whether STI571 inhibits the in-vitro growth of melanoma cells. Nineteen cell lines were obtained from four primary and 15 metastatic melanomas of cutaneous origin. The percentages of positive cells for the putative targets of STI571 were as follows: ABL, 41-100%; c-Kit, 8-97%; PDGFR-alpha, 41-98%; PDGFR-beta, 51-99%. 3-(4,5-Dimethylthiazol-yl)-2,5-diphenyltetrazolium (MTT) and viability assays showed that STI571 clearly inhibits the proliferation of eight of the 19 (42.1%) cell lines. No relationship could be established between the expression of c-Kit, ABL, PDGFR-alpha or PDGFR-beta and the response of cell lines to STI571. Our study shows, for the first time, an antiproliferative effect of STI571 on human melanoma cell lines of cutaneous origin, raising the possibility of the future clinical use of STI571. The identification of the target of STI571 in human cutaneous melanoma cells would allow the selection of patients who could benefit from this treatment.
Melanoma Res 2006 Apr
PMID:Antiproliferative effect of STI571 on cultured human cutaneous melanoma-derived cell lines. 1656 68


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