Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosinase-dependent activation of hydroxybenzenes forms reactive compounds, including catechols and o-quinones, and some of which show antitumor activity against pigmented melanomas. Since VP-16 is a phenoxy-containing antitumor drug, forms free radicals and reactive o-quinones during peroxidative activation, we evaluated the cytotoxicity of VP-16 to both tyrosinase-containing and non-tyrosinase-containing tumor cells. Our results show that VP-16 is significantly more cytotoxic to B-16/F-10 melanoma cells than human MCF-7 breast tumor cells. Phenylthiocarbamide, an inhibitor of tyrosinase activity, selectively decreased VP-16 toxicity only in melanoma cells. Furthermore, VP-16 was readily activated to its phenoxy free radical intermediate by purified tyrosinase, indicating tyrosinase may play a role in VP-16 toxicity in pigmented melanomas.
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PMID:Tyrosinase-induced free radical formation from VP-16,213: relationship to cytotoxicity. 196 66

The lysosomal enzyme beta-hexosaminidase and the melanocyte specific enzyme tyrosinase were examined in human melanoma cell cultures. The beta-hexosaminidase activity of the medium was approximately 40% of the total cellular activity after 24 h, while after 48 h the activity in the medium was twice that of the cells. The tyrosinase activity in the medium was 5% and 19% of the total cellular activity after the 24 h and 48 h incubation, respectively. The low level of lactate dehydrogenase activity in the medium after 24 as well as 48 h of incubation indicated that the release of beta-hexosaminidase and tyrosinase was not due to membrane injury. The data suggest, that 1) beta-hexosaminidase may be a candidate for tumor markers in malignant melanoma, and 2) the tyrosinase activity found in sera of melanoma patients may be due, at least partly, to enzyme release by living cancer cells.
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PMID:Enzyme release from cultured human melanoma cells. 197 50

2-Thiouracil (TU), an antithyroid drug, is receiving growing interest as a specific tumor marker for malignant melanoma, owing to its capability of being selectively accumulated into active melanin-producing tissues. However, up until now, the molecular mechanism of TU uptake by growing melanin has remained largely unknown. In an attempt to fill this gap, we have investigated the effect of TU on the tyrosinase catalyzed oxidation of tyrosine. At a concentration of 0.5 mM, TU was found to totally inhibit melanin formation by tyrosinase catalyzed oxidation of 0.25 mM tyrosine in phosphate buffer at pH 6.8. Polarographical monitoring of oxygen consumption under conditions of complete suppression of melanogenesis revealed a significant tyrosinase activity, with TU acting as a modest non-competitive inhibitor of the enzyme (Ki = 0.6 mM). HPLC and TLC analysis of the tyrosine-tyrosinase reaction in the presence of excess TU showed that the substrate is progressively consumed and a major hitherto unknown product (lambda max = 284 nm), positive to ninhydrin and ferric chloride, is concomitantly formed. This was isolated by repeated gel filtration chromatography of the reaction mixture on Sephadex G-10 and was formulated as the TU-dopa adduct 3,4-dihydroxy-6-(4'-hydroxypyrimidinyl-2'-thio)phenylalanine by spectral analysis. These results suggest that selective TU incorporation in pigmented melanomas and other melanin-producing systems is due to the covalent binding to dopaquinone, produced by tyrosinase catalyzed oxidation of tyrosine.
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PMID:Selective uptake of 2-thiouracil into melanin-producing systems depends on chemical binding to enzymically generated dopaquinone. 212 40

The Glycosylation inhibitors, glucosamine or tunicamycin induced a marked loss of pigment within melanoma cells in addition to their reduced metastatic ability. Electrophoresis of tyrosinase demonstrated the disappearance of or a marked decrease in membrane-bound tyrosinase, T3 in the small and large-granule fractions. Glycoprotein synthesis in the melanogenic subcellular compartments of pigment cells seems to play an integral role in melanogenesis which is principally enhanced in their carcinogenic status. The effect of interferon (IFN) on melanoma metastasis was investigated using B16-F10 melanoma cells. The inhibitory effect was maximal when given 3 h prior to tumor cell inoculation. IFN given 12 and 24 h prior to, as well as simultaneously with, tumor cell inoculation, also reduced metastases, but to a lesser extent. When given 2 h after the inoculation, no effect was shown. The salutary effect of IFN was abolished by anti-asialo GMI, but NK activity was enhanced equally throughout 3 to 24 hrs. This indicates that the effect is substantially dependent on NK cell activity, although the implication of other factors is not excluded.
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PMID:[Control of melanogenesis by glycosylation inhibitors and the inhibitory effect of interferon on melanoma metastasis]. 240 78

The B16/C3 mouse melanoma cell line produces L-DOPA, catecholamines and melanin in tissue culture. Growth and development of these cells after transplantation into the rat and mouse brain were studied by immunocytochemical and histological techniques. The implanted cells were localized by prelabelling the cell nuclei with bisbenzimide, a fluorescent marker which binds to DNA. Following transplantation into rats, B16/C3 melanoma cells were found to survive for at least 4-6 weeks. These cells initially expressed tyrosinase and tyrosine hydroxylase immunoreactivity and in some cases contained catecholamines. After 3 weeks, the cytoplasm of the transplanted cells began to accumulate melanin; catecholamines and tyrosinase immunoreactivity were no longer detected. Ultimately the cells became round in shape and densely pigmented. Growth of the tumor in the rats was restricted and the implant was encapsulated within a glial sheath. There was evidence of an immune reaction to the tumor in that cells with Ia antigen immunoreactivity were present surrounding the graft. The rat hosts were not adversely affected by the presence of the tumor, nor did the tumor cell grafts alter rotational behavior consequent to unilateral substantia nigra lesions. In mouse hosts, however, the melanoma grew rapidly, was not encapsulated by glia and led to death of all animals. These data suggest that the tumor was not rapidly destroyed in rats, even though its growth was controlled through immunological mechanisms. Both trophic and immunological mechanisms may therefore be involved in the regulation of survival and differentiation of intracerebral grafts of tumor cells.
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PMID:Transplantation of B16/C3 melanoma cells into the brains of rats and mice. 247 Apr 73

A two-step method was used to purify enzymatically active tyrosinase to apparent homogeneity from B16/C3 mouse melanoma cells. The purification was based on our finding that tyrosinase was highly resistant to sodium dodecyl sulfate-proteinase K digestion. Following treatment with proteinase K, tyrosinase was separated from all detectable contaminants using DEAE-52 ion-exchange chromatography. Using this procedure, tyrosinase was purified to high specific activity and in yields greater than 50%. The purified enzyme was then used to generate high titers of specific polyclonal antibodies in rabbits. These antibodies were used to immunoprecipitate all tyrosinase isozymes from murine melanoma tumor extracts and cultured B16/C3 cells metabolically labeled with [35S]methionine.
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PMID:Purification of tyrosinase to homogeneity based on its resistance to sodium dodecyl sulfate-proteinase K digestion. 251 May 99

Previous studies of the human neuroblastoma cell line SK-N-SH had demonstrated the presence of and phenotypic interconversion (transdifferentiation) between two morphologically and biochemically distinct cell types: N (neuroblastic) cells with properties of noradrenergic neurons and S (substrate-adherent) cells with properties of melanocytes. Current studies have sought to test the generality of these findings among other cultured human neuroblastoma cell lines and to define further the S-cell phenotype and that of a newly identified, morphologically intermediate, I-type cell. Morphologically homogeneous populations (clonal sublines or subpopulations) of N, S, and I cells were isolated from five additional neuroblastoma cell lines and analyzed biochemically for neuronal, glial, and melanocytic marker enzyme activities and norepinephrine uptake. Immunoblot techniques were used to detect intermediate filament proteins (neurofilament protein, vimentin, glial fibrillary acidic protein) and fibronectin. All N-type cells exhibited neuronal marker enzyme activities, specific uptake of norepinephrine, and presence of one or more neurofilament proteins. S-type cells generally lacked neuronal characteristics but contained, instead, tyrosinase activity (a melanocytic marker enzyme), vimentin, and fibronectin. This combination of attributes is suggestive of a multipotent embryonal precursor cell of the neural crest. I-type cells differentially expressed both S- and N-cell properties and could represent either a stem cell or an intermediate in the transdifferentiation process. Studies of the biological significance of human neuroblastoma cell transdifferentiation and the molecular mechanisms underlying this process may be of relevance to the biological and clinical behavior of this tumor in the patient.
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PMID:Phenotypic diversification in human neuroblastoma cells: expression of distinct neural crest lineages. 253 91

The purpose of these studies was to investigate the relationship of the host microenvironment to the metastatic and pigmented phenotypes of the SW-1 variant of the murine K-1735 melanoma. The SW-1 subline was isolated from an amelanotic lung metastasis in a C3H/HeN mouse given an s.c. injection of the K-1735 melanoma. Cells of this line were highly metastatic and produced tumor deposits in many organs. In all sites except the brain, these lesions were predominantly amelanotic. K-1735 SW-1 cells were isolated from metastases in various organs and subsequently reinoculated into normal syngeneic recipients. Whereas the metastatic phenotype remained stable and thus was heritable, pigmentation was unstable and appeared to be modulated by the site of tumor growth. Further differences in the phenotype of K-1735 SW-1 cells growing in vivo and in culture were revealed by assays for tyrosinase activity. K-1735 SW-1 cells growing in culture did not produce melanin nor did they respond to agents that can stimulate melanin production in another mouse melanoma, the B16 line. K-1735 SW-1 cells do not, however, lack tyrosinase, since these cells are capable of producing melanin when growing in certain organs in vivo. We conclude that the host organ environment may influence a phenotype of malignant melanoma cells, i.e., pigmentation. These findings also suggest caution when extrapolating the results of in vitro biochemical assays to properties of tumor cells growing in vivo.
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PMID:Influence of organ microenvironment on pigmentation of a metastatic murine melanoma. 283 58

The toxicity and selectivity of 3,4-dihydroxybenzylamine (DHBA), an experimental antimelanoma agent that cannot enter the melanin pathway, broadly paralleled that of L-dopa in a panel of human melanoma cell lines sensitive or resistant to the latter drug. A human retinoblastoma cell line was found to be sensitive to both compounds. The toxicity and selectivity of both catechols were associated with inhibition of DNA synthesis; DHBA was more potent yet allowed a much greater degree of recovery compared with an equitoxic level of dopa. Dopa and DHBA had similar, dose-dependent effects on the cell cycle, arresting cells in S phase at low doses and in G1 at high doses. Replication of the DNA virus adenovirus was found to be inhibited by both agents. There was no difference between sensitive and resistant cell lines in the manganese or copper/zinc forms of superoxide dismutase, or in iron content and iron-binding capacity. Catechol toxicity was inhibited by the hydrogen peroxide scavenging agents pyruvate and methaemoglobin. Sensitivity to catechols did not correlate with melanin or tyrosinase content, rate of incorporation of tyrosine or dopa, intracellular levels of phenylalanine or tyrosine, or binding of a new monoclonal antibody directed against a melanosomal protein. These results indicate that DHBA and dopa exhibit selective toxicity for neural crest tumor cells independently of the melanisation pathway and of the superoxide scavenging system.
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PMID:Melanin synthesis and the action of L-dopa and 3,4-dihydroxybenzylamine in human melanoma cells. 290 84

Des-, mono-, and diacetylated melanotropin (des-, mono-, and di-Ac MSH, respectively) were compared for their dose-related effects on content of adenosine 3':5'-monophosphate (cAMP) and tyrosinase activity in the Cloudman S91 mouse melanoma tumor. Des-Ac MSH was more potent than the acetylated forms of MSH at increasing cellular levels of cAMP; mono- and di-Ac MSHs, however, were more potent than des-Ac MSH at elevating the activity of the enzyme, tyrosinase. Lysine-gamma1 MSH, a melanotropin from the amino terminus of pro-opiomelanocortin, exhibited slight stimulatory effects on tyrosinase and these actions were less than additive to those of mono-Ac MSH. Unlike their actions on amphibian skin-darkening or in mammalian behavior, neither beta-endorphin1-31 nor its derivatives, N-Ac-beta-endorphin1-27 or beta-endorphin30-31 (glycylglutamine), exhibited any influence on tyrosinase activity evoked by mono-Ac MSH in the tumor cells.
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PMID:The effects of pro-opiomelanocortin peptides on cyclic AMP and tyrosinase in melanoma cells. 302 51


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