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)

Bufalin, which is one of prominent components of Chinese toad venom, was found to decrease the rate of cell proliferation of mouse melanoma clone B16-F10 cells and a concomitant stimulation of expression of its melanotic phenotype. The effect of bufalin on melanogenesis included stimulation of tyrosinase activity and increase of cellular melanin content. These effects became apparent after 48 hr exposure to 10(-4) M bufalin and increased thereafter. Other cardiotonic steroids, such as cinobufagin and ouabain, at the concentration of 10(-4) M for 6 days, also showed the stimulatory effect on melanin synthesis of B16-F10 cells, but not digitoxigenin.
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PMID:Stimulation of melanin synthesis of B16-F10 mouse melanoma cells by bufalin. 161 70

Dopachrome tautomerase (DT) (EC 5.3.2.3) is a melanocyte-specific, membrane-associated, heat-labile, non-dialyzable, protease-sensitive factor which catalyzes the isomeric rearrangement of dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA), apparently through a tautomerization reaction. Metal ions such as Cu, Ni, Co, Zn, Mn, Ca, Al, and Fe can also catalyze the dopachrome/DHICA isomerization. How is the reaction regulated in vivo? An attractive possibility would be that DT is a metalloenzyme. Here we present evidence that this may indeed be the case. Purified preparations of DT and tyrosinase, obtained from Cloudman S91 mouse melanoma cells, were assayed in the presence of a variety of metal chelators including EDTA (predominantly Ca and Mg), EGTA (predominantly Ca), phenylthiourea (PTU) (predominantly Cu), 2,2'-dipyridyl (predominantly Fe); 1,10-phenanthroline (predominantly Fe), and 2,3-dihydroxybenzoic acid (predominantly Fe). In addition, DT activity was assayed in the presence of two non-chelating structural analogs of 1,10-phenanthroline. Results were as follows: (i) iron chelators inhibited DT activity with no effects on tyrosinase activity; (ii) inhibition by the chelators was reversible with the addition of ferrous iron; (iii) 1,10-phenanthroline pre-complexed to ferrous iron was not inhibitory to DT; (iv) non-chelating analogs of phenanthroline were not inhibitory to DT; (v) PTU was inhibitory to tyrosinase but not DT; (vi) Ca2+ and Mg2+ chelators had little effect on either enzyme activity. Finally, studies with glycosylation inhibitors, glycosylase enzymes, and immobilized lectins, indicated that DT is a glycoprotein. The results suggest that DT is a metal-containing glycosylated enzyme, possibly with ferrous iron at its catalytic center.
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PMID:Evidence that dopachrome tautomerase is a ferrous iron-binding glycoprotein. 163 43

New tyrosinase-targeted compounds based on structural variants of the prototype unit 4-aminophenol have been synthesized and screened for their potential as antitumour agents against malignant melanoma. Cytotoxicity assays showed that N-4-hydroxyphenylglycine (NHPG) and its alpha-methyl derivatives methylphenylglycine and dimethylphenylglycine exhibit significant antiproliferative effects on pigmented human melanoma cell lines (HBL), with inhibitory concentrations at 50% (IC50) around 80 micrograms/ml. A marked increase in cytotoxicity was observed with morpholine-containing 4-aminophenols, e.g. N-(2-morpholinoethyl)-4-aminophenol, which showed an IC50 of 20 micrograms/ml of HBL cells. Much more pronounced was the effect of the diacetoxy-derivative, DiAcMoAc, which showed an IC50 of 15 micrograms/ml on HBL cells and as low as 2 micrograms/ml on tyrosinase-containing, non-pigmented human melanoma cells (LND1), with a toxicity response of the same order of magnitude as that of melphalan. These results open interesting perspectives in the design of new targeted pro-drugs against malignant melanoma.
Melanoma Res 1992 May
PMID:Synthesis and cytotoxic properties of new N-substituted 4-aminophenol derivatives with a potential as antimelanoma agents. 164 21

Human tyrosinase (5.5 mg) has been purified from a single human melanotic melanoma metastasis (50.5 g). In the presence of dioxygen, L-tyrosine proved to be a very poor substrate for this enzyme with barely detectable activity compared to L-dopa. However, saturating superoxide anion (i.e., greater than 5 x 10(-3) M) enhanced the oxidation rate of L-tyrosine to dopachrome 40-fold. Hydrogen peroxide was shown to be a competitive inhibitor of tyrosinase when L-tyrosine was the substrate. This reversible inhibition is based on a slow pseudocatalase activity for tyrosinase. Monothiols and dithiols inhibit tyrosinase by different mechanisms. Reduced human thioredoxin and 2,3-dithiopropanol are allosteric inhibitors of tyrosinase yielding bis-cysteinate complexes with one of the copper atoms in the enzyme active site. Bis-cysteinate tyrosinase activity is down-regulated to 30% of native enzyme activity in the L-dopa assay; suggesting a true regulatory role for dithiols. Monothiols such as reduced glutathione and beta-mercaptoethanol are much less reactive with tyrosinase although 10(-3) M monothiol totally inhibits enzyme activity. Reduced thioredoxin inhibits tyrosinase 23-fold more than reduced glutathione under the same experimental conditions.
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PMID:Studies on the reactions between human tyrosinase, superoxide anion, hydrogen peroxide and thiols. 165 10

The effects of three non-myelotoxic cancer drugs on the growth of neuroblastoma cells were investigated in vitro and in vivo: dihydroxyphenylalanine (L-dopa, a drug with selective toxicity for melanoma cells), DL-buthionine sulphoximine (BSO, a drug with radiosensitizing effects), and tamoxifen (a drug used in the treatment of human mammary carcinoma). In vivo these substances significantly reduced the weight of neuroblastoma tumour transplants in the mice (nude/nude) (P less than 0.05). A dose/effect relationship could be established. In vitro, the D50 was determined, using fibroblasts as controls. The growth of neuroblastoma tumours was inhibited by different mechanisms: L-dopa and its metabolite dopamine reduced the activity of tyrosinase, BSO reduced glutathione levels, and L-dopa and tamoxifen raised cAMP concentrations.
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PMID:Non-myelotoxic antitumour effects of L-dopa, buthionine sulphoximine and tamoxifen on neuroblastoma cells in vitro and in vivo. 165 80

It has been shown that alpha-MSH inhibits the growth of amelanotic cells of human malignant melanoma (BRO) without their melanization or the expression of tyrosinase activity. alpha-MSH changed the activity of cytosol and microsomal forms of phosphatidyl inositol kinase and phosphatidyl inositol-4-phosphate kinase determining the concentration of phosphatidyl inositol-4-phosphate and phosphatidyl inositol-4,5-bisphosphate. It also induced an "outburst" in the levels of myo-inositol phosphates (mono-, bis- and 1,4,5-trisphosphates). Changes in the levels of myo-inositol phosphates occurred within seconds, and are suggested to play a certain part in the hormonal regulation of melanoma cell growth.
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PMID:Melanocyte-stimulating hormone (alpha-MSH) inhibits the growth of human malignant melanoma cells with the induction of phosphatidyl inositol and myo-inositol phosphate levels. 166 68

Four fatty acids (FA, palmitic, myristic, decanoic, hexanoic) were individually conjugated to the N-terminus of the alpha-MSH fragment analog, H-Asp5-His6-D-Phe7-Arg8-Trp9-Lys10-NH2. This resulted in enhanced potency of the conjugates (compared to the unconjugated melanotropin analog) as determined in the lizard skin bioassay and in the mouse melanoma cell tyrosinase bioassay. The shorter conjugates of hexanoic and decanoic acid were at least equipotent to alpha-MSH in the lizard skin bioassay, whereas the longer myristoyl and palmitoyl analogs were 100 times less active. The myristoyl and palmitoyl conjugates exhibited a "creeping" potency in the lizard skin bioassay-that is, potency of the peptides increased with time in contact with the skins. These observations may be related to the more lipid nature of these FA-conjugates. In the tyrosinase assay, the conjugates were 10-100 times more active than alpha-MSH or the unconjugated analog. Each of the FA-melanotropic peptide conjugates exhibited prolonged (residual) melanotropic activity in both the lizard skin and melanoma cell bioassays. In other words, after removal of the melanotropin conjugates from contact with the skins or cells, responses were still manifested for hours or days thereafter. As little as 1 hr of contact with melanoma cells resulted in enhanced enzyme activity as measured 48 hr later. Since the conjugates, but not H-[Asp5, D-Phe7, Lys10]alpha-MSH5-10-NH2, exhibited prolonged activity, the conversion of reversible agonists to irreversible agonists was demonstrated.
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PMID:Biological activities of melanotropic peptide fatty acid conjugates. 166 21

The reactivity in an avidin-biotin complex immunoperoxidase reaction with a large panel of anti-human melanoma associated antigen (MAA) and anti-HLA monoclonal antibodies of 24 primary and 11 metastatic acral lentiginous melanoma (ALM) lesions was compared to that of 12 primary and 12 metastatic nodular melanoma (NM) lesions. The expression of the membrane bound vitronectin receptor, Mr 110,000 MAA, Mr 97,000 MAA, and intercellular adhesion molecule-1 was significantly lower in both primary and metastatic ALM lesions than in their NM counterparts. Furthermore, primary ALM lesions displayed a significantly lower expression than primary NM lesions of the membrane bound high molecular weight melanoma associated antigen (HMW-MAA), Mr 110,000 MAA, Mr 100,000 MAA, 9-O-acetyl-GD3, GD2-GD3, and GD2, of the cytoplasmic monoclonal antibody 465.12 defined MAA and of transferrin receptor and of HLA-DQ and DP antigens; ALM metastases expressed a significantly lower level of carcinoembryonic antigen-MAA than NM metastases. These antigenic differences do not reflect an antigenic paucity of ALM cells, since ALM lesions express a higher level of T4-tyrosinase than NM lesions and a level of HLA Class I antigens similar to that of NM lesions. In view of the use of HMW-MAA, Mr 97,000 MAA, and GD3 in immunoscintigraphy and/or in immunotherapy, it is noteworthy that the three antigens are expressed in a similar high percentage of ALM metastases and of primary and metastatic NM lesions, while the HMW-MAA is expressed in a markedly lower percentage of primary ALM lesions than Mr 97,000 MAA and GD3. However, the degree of heterogeneity of HMW-MAA within a positive primary ALM lesion, as measured by the percentage of stained melanoma cells, is lower than that of Mr 97,000 MAA and GD3. The expression of the antigens investigated in ALM and NM lesions was not correlated with the presence of lymphocyte infiltrates, melanin content of melanoma cells, and epithelioid and spindle type of melanoma cells in the lesions. On the other hand, the survival of patients with ALM was inversely correlated with the expression of intercellular adhesion molecule 1 or HMW-MAA in their primary lesions. A potential role of HMW-MAA in the course of the disease is suggested by its significantly higher expression in metastatic than in primary ALM lesions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential expression of melanoma associated antigens in acral lentiginous melanoma and in nodular melanoma lesions. 167 29

In cultured human melanoma cells, histamine H1 (mepyramine) and H2 receptor antagonists (cimetidine, ranitidine, impromidine) increased tyrosinase activity, whereas H2 agonists (dimaprit, nordimaprit) decreased activity. Mixtures of agonist and antagonist either decreased or increased tyrosinase activity, depending on the relative concentrations of each drug. Nordimaprit, the most effective inhibitor, lowered tyrosinase activity significantly within 36 h and caused a slower loss of tyrosinase protein as judged by reactivity with two monoclonal antibodies. Prolonged treatment of a melanotic cell line with nordimaprit led to complete loss of pigment, with no loss of the 56-kDa melanosomal antigen 1C11. Cells remained amelanotic for 8 weeks after removal of the drug and, even after 26 weeks, melanin content and tyrosinase expression and activity had not fully recovered. Nordimaprit increased the rate of degradation of tyrosinase and of nordimaprit binding proteins. Whereas nordimprit did not directly inhibit tyrosinase, lysates of treated cells contained an inhibitory activity that partitioned approximately equally across a 10-kDa ultrafiltration membrane. Overall, these results showed that melanogenesis can be controlled via histamine receptors, the mechanism for the H2 agonist nordimaprit consisting of three components: induction of a tyrosinase inhibitor, increased degradation of tyrosinase, and long-term down-regulation of tyrosinase expression.
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PMID:Regulation of tyrosinase expression and activity in human melanoma cells via histamine receptors. 168 Sep 32

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


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