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)

Cholera toxin (choleragen) and melanocyte stimulating hormone alter within hours the morphology of melanoma cells in culture, and they slow the growth of serum-stimulated cells. After 7-10 days, cells exposed to choleragen or hormone show increased size and a fibroblastic growth pattern. Tyrosinase (EC 1.14.18.1; monophenol monooxygenase) activity increases after 3 days in the presence of 10(-8) M hormone or 10(-10) M choleragen. Binding studies with (125)I-labeled choleragen indicate that although a melanoma cell can bind a maximum of 10(6) molecules of cholera toxin, only about 4000 binding sites must be occupied to achieve maximum stimulation of tyrosinase activity. Melanocyte stimulating hormone and choleragen probably have different membrane-binding sites. After exposure to choleragen for 5 min, membrane adenylate cyclase (EC 4.6.1.1) activity increases dramatically upon further incubation of intact cells for several hours at 37 degrees and falls slowly to basal values over a period of more than 10 days. Hormone stimulation of adenylate cyclase is rapidly reversed by washing the cells, but subsequent restimulation of cyclase by the hormone is impaired. These studies indicate that cAMP mediates the effects of melanocyte stimulating hormone on growth and morphology as well as on tyrosinase activity. Cholera toxin may permanently activate the available adenylate cyclase molecules, and the protracted decay of stimulation that follows may reflect the biological turnover of adenylate cyclase molecules in these cells.
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PMID:Cholera toxin mimics melanocyte stimulating hormone in inducing differentiation in melanoma cells. 436 71

Flunarizine, a drug which binds to calmodulin, was found to inhibit both the growth rate and the survival fraction of a B16 mouse melanoma cell line cultured in vitro. Both of these effects, that are dose and time-dependent, occurred at doses which in vitro cause a 50% inhibition of the calmodulin-activated cyclic nucleotide phosphodiesterase prepared from the tumor. Cyclic AMP was increased in treated B16 melanoma cells, while DNA synthesis was inhibited, though the DNA content/cell was increased. The possible mechanisms of the drug's action are discussed herein.
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PMID:Effects of a calcium-antagonist (flunarizine) on the in vitro growth of B16 mouse melanoma cells. 609 26

It was suggested that the antitumor effect of the interferons is based in part on their ability to stimulate increased cAMP production. We have explored the interaction of human fibroblastic beta interferon (HFIF) with a cAMP decomposition inhibitory pyrimido-pyrimidine derivative, Mopidamole (RA-233) in cultures of neoplastic and normal cell lines. Mopidamole potentiated the growth inhibitory effect of HFIF in cultures of ES-1 malignant melanoma cells, LNCaP prostatic carcinoma cells, RT-4 transitional carcinoma cells, HT-29 colon adenocarcinoma cells and in diploid fibroblast cells.
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PMID:Potentiation of the cell growth inhibitory effect of beta interferon by mopidamole. 609 78

5-Bromodeoxyuridine (BUdR) causes mouse melanoma cells to develop a flattened morphology and simultaneously adhere tenaceously to the substratum on which they are growing. Experiments were done to determine if these events are coupled to increases in cAMP levels and to rearrangements in the cells' cytoskeleton. Cyclic AMP assays revealed that cell flattening and the increase in adhesive properties caused by BUdR is not accompanied by an increase in the cellular concentration of cyclic AMP. However, electron micrographs of cells grown in the presence of BUdR show a striking increase in the number of organized microtubules and microfilaments. Colchicine binding revealed no difference in the amount of tubulin present in untreated or BUdR-treated cells indicating that the increase in the number of microtubules is due to the polymerization of pre-existing tubulin subunits. These results are discussed in light of possible similar mechanisms of action of BUdR and cyclic AMP in regulating the organization of microtubules and microfilaments and the role these structures play in altering cell morphology and adhesive properties.
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PMID:The effects of 5-bromodeoxyuridine on cyclic AMP levels and cytoskeletal organization in malignant melanoma cells. 624 51

The acute in vitro actions of two potent melanocytolytic agents, hydroquinone (HQ) and beta-mercaptoethanolamine (MEA), were determined in the B-16, Cloudman S-91 and Harding-Passey (HP) murine melanomas grown in vivo. Drug treated melanoma dice (5--480 min) were analyzed for tyrosinase activity and cyclic nucleotide levels (cAMP, cGMP). HQ and MEA effects on tyrosinase activity are complex and vary with tumor type, duration of treatment and agent tested. MEA or HQ inhibited B-16 tyrosinase activity. With combined drug therapy, low concentrations of MEA plus HQ stimulate B-16 tyrosinase activity while high concentrations of the drugs have little effect on enzymatic activity. MEA depresses tyrosinase activity while HQ elevates enzymatic activity in the S-19 melanoma. Both high and low concentrations of the combined drugs (MEA plus HQ) elicit the same response, stimulation at 10 min followed by continued depression of tyrosinase activity for the remainder of the 4 h study period. MEA initially stimulates HP tyrosinase activity followed by depression of enzymic activity. In contrast, HQ initially depresses HP tyrosinase activity followed by stimulation of enzyme activity. In combination the drugs inhibit HP tyrosinase activity. The effects of MEA and/or HQ on murine melanoma cyclic nucleotide levels are equally complex. MEA or HQ elevate cAMP and cGMP levels in all three tumors with the exception of S-91 cGMP levels which are not altered. In combination the drugs increase cyclic nucleotide levels in each of the three tumor types but at different times. No correlation is present between cyclic nucleotide levels and tyrosinase activity. Thus, the action of increased cyclic nucleotide levels in melanogenesis can not be separated from the direct actions of MEA and HQ upon melanogenesis. The divergent effects of MEA and/or HQ on tyrosinase activity and cyclic nucleotide levels in these melanomas are not correlated with the known in vivo melanocytolytic activity of these drugs. Thus, these parameters appear to be inadequate indicators of melanoma cell viability in chemotherapeutic screening of drugs effective in destroying malignant melanoma.
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PMID:Acute effects of two melanocytolytic agents, hydroquinone and beta-mercaptoethanolamine, upon tyrosinase activity and cyclic nucleotide levels in murine melanomas. 625 89

Cloudman S91 mouse melanoma cells lose their ability to demonstrate an MSH-induced increase in tyrosinase activity as cell density increases. This loss in hormone responsiveness occurs before confluency is reached and cannot be reversed by exposure of cells to increasing concentrations of MSH. The failure of high-density cultures to respond to MSH is apparently not the result of an inability of MSH to stimulate cAMP production, since either low- or high-density cultures exposed to MSH demonstrate equivalent increases in intracellular levels of cAMP. Further, neither theophylline (1mM), dibutyryl cyclic AMP (10(-4)M), or prostaglandin E1 (10(-6)M) is effective in stimulating tyrosinase activity in melanoma cells cultured at densities exceeding 6 X 10(4) cells/cm2. This finding suggests that the decay of hormone responsiveness occurs at a cellular site distal to cAMP production. The decrease in tyrosinase stimulation by MSH as cell density increases is also apparently not the result of an increase in activity of any soluble inhibitor of the enzyme, for cytosol preparations from high-density cultures (10(5) cells/cm2) fail to inhibit tyrosinase activity in cell homogenates from low-density cultures treated with MSH.
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PMID:Decay of hormone responsiveness in mouse melanoma cells in culture as a function of cell density. 625 96

The effects of theophylline treatment on mouse B-16 melanoma cell growth, metabolism, and membrane antigen expression in vitro were studied. Theophylline treatment inhibited DNA synthesis and the cell growth rate, and caused an elevation of intracellular cAMP levels. Cells treated with theophylline became elongated and assumed a normal fibroblast-like morphology. Theophylline treatment of B-16 cells also reduced the levels of tumor specific antigen and H-2 antigen detectable on the cell membrane.
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PMID:Effects of theophylline treatment on mouse B-16 melanoma cells in vitro. 625 90

Retinoic acid (RA), which reduces the rate of cell proliferation in S91 mouse melanoma clone C2 cells, was found to stimulate the expression of their melanotic phenotype. RA treatment also induced the extension of long cellular processes. The RA effects on melanogenesis included stimulation of tyrosinase activity and augmentation of cellular melanin content to levels 3- to 4-fold higher than in untreated cultures at similar cell densities. These effects became apparent after 48 hours of exposure to 10(-5) M RA and increased thereafter. Half-maximal stimulation in cells treated for 6 days occurred at 5 X 10(-7) M RA. Although the degrees of melanogenesis enhancement by RA (10(-5) M) and by alpha-melanocyte stimulatory hormone (2 X 10(-7) M) were similar, the former did not alter the intracellular cAMP level, whereas the latter induced a transient 4-fold increase. In high-passage (p28) cells, as well as in low-passage cells (less than p10) treated with tyrosinase inhibitor phenylthiocarbamate, melanin synthesis was suppressed in the absence and presence of RA, yet the ability of RA to inhibit cell proliferation was not compromised. In the presence of the tumor promotor phorbol myristate acetate (greater than 5 X 10(-9) M) melanin synthesis in control as well as in cells exposed to RA was dramatically inhibited. Phorbol which is not active in tumor promotion had no effect on melanogenesis. In addition to RA, other retinoids, such as 13-cis-retinoic acid, retinyl acetate, the TMMP analog of RA and the phenyl analog of RA, but not the pyridyl analog of RA or retinyl palmitate, also inhibited cell growth and enhanced melanin synthesis.
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PMID:Enhancement of melanotic expression in cultured mouse melanoma cells by retinoids. 626 Aug 17

Results of hemacytometer cell counts and of tyrosinase measurements made by the Pomerantz method demonstrate that imidazole added to the medium of cultured B16 mouse melanoma cells can stimulate tyrosinase specific activity and inhibit cell division. These effects are greater than with adenosine 3',5' cyclic monophosphate (cAMP) or the cAMP-phosphodiesterase inhibitor theophylline. The effects of imidazole on cell division and tyrosinase are enhanced by theophylline and antagonized by cAMP. Cyclic AMP-phosphodiesterase activity in cell-free extracts can be inhibited by theophylline and stimulated by imidazole. However, imidazole does not affect cAMP-phosphodiesterase specific activity in vivo, nor does it affect intracellular cAMP concentrations as determined by competitive protein-binding assays. In contrast, the specific activity of cAMP-phosphodiesterase in vivo is stimulated by cAMP and theophylline, supporting the hypothesis that cAMP and agents which increase intracellular cAMP concentrations induce the synthesis of cAMP-phosphodiesterase. Studies with actinomycin-D and cycloheximide support the hypothesis that cAMP can also mediate posttranslational activation of tyrosinase. Similar experiments suggest that imidazole, or a derivative thereof, can induce the synthesis of tyrosinase at the pretranslational level of control. We hypothesize that this type of regulation (pretranslational) by imidazole may define a role for the concept of "Metabolite Gene Regulation" (MGR), in mammalian cells.
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PMID:Regulation of cell division and of tyrosinase in B16 melanoma cells by imidazole: a possible role for the concept of metabolite gene regulation in mammalian cells. 626 Aug 21

Studies were performed for the investigation of endocrine responsiveness in cell lines derived from either normal human melanocytes or human melanoma cells. Alterations in differentiation (tyrosinase activity) were determined in cells exposed to either melanocyte-stimulating hormone (MSH, 10(-7) M), theophylline (10(-3) M), N6,O2'-dibutyryl cyclic AMP (db-cAMP, 10(-4) M), or prostaglandin E1 (PGE1, 10(-6) M). Cultures derived from normal uveal melanocytes demonstrated increased tyrosinase activity upon exposure to either theophylline, db-cAMP, or PGE1, but not to MSH. However, MSH responsiveness was detected in 7 of 11 human melanoma cell lines. Four cell lines demonstrated increased activity of tyrosinase after MSH treatment, whereas three lines showed an MSH-induced inhibition of enzyme activity. PGE1 was effective in stimulating tyrosinase activity in five of nine cell lines examined. Theophylline was the most effective stimulator of tyrosinase in melanoma-derived cell populations and caused increased enzyme activity in eight of eleven cell lines.
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PMID:Endocrine responsiveness in human melanocytes and melanoma cells in culture. 626 56


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