Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rationale for melanoma-specific antitumor agents containing phenolic amines is based in part on the ability of the enzyme tyrosinase to oxidize these prodrugs to toxic intermediates. The phenolic amine compounds 4-S-cysteaminylphenol (4-S-CAP) and N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) inhibited in situ thymidylate synthase activity in pigmented melanoma cell lines but had little or no effect on nonpigmented and nonmelanoma cell lines. Theophylline, a cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor, increased tyrosinase activity and potentiated the inhibition of in situ thymidylate synthase by N-Ac-4-S-CAP. The inhibition of in situ thymidylate synthase by both drugs in pigmented melanoma cells correlated with the inhibition of DNA synthesis and cell growth and was not due to an indirect effect caused by inhibition of the enzyme dihydrofolate reductase. 4-S-CAP inhibition of thymidylate synthase activity in cell free extracts required oxidation of the drug. In the presence of tyrosinase, the concentration causing a 50% inhibition of thymidylate synthase activity (IC50) in cell-free extracts was less than 10 microM, but no inhibition was observed in its absence, even at a drug concentration of 500 microM. Two reducing agents, dithioerythritol and glutathione, effectively blocked the inhibition of thymidylate synthase by oxidized 4-S-CAP. In pigmented melanoma cells containing the enzyme tyrosinase, the quinone-mediated mechanism of inhibition of DNA synthesis via inhibition of thymidylate synthase may be uniquely important in the expression of phenolic amine cytotoxicity.
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PMID:Thymidylate synthase as a target enzyme for the melanoma-specific toxicity of 4-S-cysteaminylphenol and N-acetyl-4-S-cysteaminylphenol. 150 78

The rationale for melanoma specific antitumor agents containing phenolic amines is based in part upon the ability of the enzyme tyrosinase to oxidize these prodrugs to toxic intermediates. Two phenolic amine compounds, N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) and 4-S-cysteaminylphenol (4-S-CAP), demonstrated growth inhibitory activity with a variety of melanoma cell lines and were essentially non-toxic to non-melanoma cell lines. Theophylline, an inhibitor of cyclic nucleotide phosphodiesterase, increased in situ tyrosinase activity and enhanced the antimelanoma effects of 4-S-CAP and N-Ac-4-S-CAP in pigmented melanoma cell lines. Phenylthiourea, a specific inhibitor of tyrosinase activity, partially blocked the growth inhibitory activity of N-Ac-4-S-CAP in human pigmented melanoma cells. Buthionine sulfoximine, an inhibitor of the synthesis of the cellular antioxidant glutathione, potentiated the growth inhibitory activity of N-Ac-4-S-CAP in pigmented melanoma cells.
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PMID:Effects of tyrosinase activity on the cytotoxicity of 4-S-cysteaminylphenol and N-acetyl-4-S-cysteaminylphenol in melanoma cells. 155 10

Systemically administered 4-S-cysteaminylphenol (4-S-CAP) and N-acetyl-4-S-CAP inhibited the growth of xenografts of a human melanoma cell line but not of an ovarian tumour cell line. No selective cytotoxicity for melanoma cells was observed in culture, however. Further study of the in vitro mechanism of 4-S-CAP toxicity showed minimal inhibition of tyrosinase activity or DNA, RNA and protein synthesis, and there was no phase-specific arrest of the cell cycle. However, expression of an 80 kD melanosomal antigen was decreased. Cytotoxicity of 4-S-CAP in culture was decreased by simultaneous treatment with a monoamine oxidase inhibitor. An affinity column prepared from 4-S-CAP retained several proteins from a melanoma cell lysate. One protein, found also in HeLa cells, was identified by N-terminal sequencing as protein disulphide isomerase, a molecule which has multiple roles in the modification of secretory proteins. These results identify a protein target for 4-S-CAP as one possible mechanism of cytotoxicity.
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PMID:Action of cysteaminylphenols on human melanoma cells in vivo and in vitro: 4-S-cysteaminylphenol binds protein disulphide isomerase. 182 29

We have examined the killing effect of 4-S-cysteaminylphenol (4-S-CAP), a newly synthesised melanin precursor, on B16 melanoma cell lines possessing different melanin-producing activities and found it to be particularly effective in heavily melanised melanoma cells, but less so in moderately melanised melanoma cells, and having no effect on amelanotic melanoma cells and nonmelanoma cells. Thus, it was found that the killing effect of 4-S-CAP is highly dependent upon the synthesis of melanin and tyrosinase in melanoma cells, suggesting that 4-S-CAP may become toxic to melanoma cells only after oxidation by tyrosinase. The killing activity of 4-S-CAP also was found to be associated with a profound inhibition of the thymidine incorporation in pigmented melanoma cells, as compared to the uridine and leucine incorporation. Further, the inhibition of DNA synthesis was most pronounced in heavily melanised melanoma cells, less so in moderately melanised melanoma cells, and not seen in amelanotic melanoma cells. As a possible mechanism that might account for this action, it may be that 4-S-CAP is oxidised by tyrosinase to the o-quinone form via the catechol derivative and that some of the quinones then conjugate with sulfhydryl enzymes including DNA polymerase, thus exerting a killing activity for pigmented melanoma cells. Thus, 4-S-CAP appears to provide a new, effective cytotoxic agent for rational chemotherapy of malignant melanomas.
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PMID:The killing effect of 4-S-cysteaminylphenol, a newly synthesised melanin precursor, on B16 melanoma cell lines. 199 95

Our previous studies have shown that 4-S-cysteaminylphenol (4-S-CAP) causes a significant inhibition of in vivo melanoma growth and a marked depigmentation of black skin and hair follicles. These studies have suggested a role of tyrosinase in the manifestation of these in vivo effects. In this study 4-S-CAP and its analogues were examined for their effects on the growth of human melanoma cells in vitro. 4-S-CAP and 4-S-HomoCAP exhibited strong cytotoxicity with effects much greater than those of alpha-methyl-4-S-CAP and N,N-dimethyl-4-S-CAP. The cytotoxicity of the former two amines was completely prevented by semicarbazide, an inhibitor of plasma monoamine oxidase, while that of the latter two was not prevented by semicarbazide, catalase, and phenylthiourea, a tyrosinase inhibitor. In culture medium 4-S-CAP was rapidly converted by the action of monoamine oxidase present in fetal bovine serum to the aldehyde which was then metabolized to the alcohol and the carboxylic acid when cells were present. alpha-Methyl-4-S-CAP was found to exert higher cytotoxicity to cells with higher tyrosinase activity and melanin content. These results suggest that the in vitro cytotoxicity of 4-S-CAP and 4-S-HomoCAP is mediated through conversion to the aldehydes while that of alpha-methyl-4-S-CAP appears to be dependent on tyrosinase activity to some extent.
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PMID:Mechanism of growth inhibition of melanoma cells by 4-S-cysteaminylphenol and its analogues. 210 82

A phenolic amine compound, 4-S-cysteaminylphenol (4-S-CAP), was found to cause a selective destruction of follicular melanocytes. It was also recently found that 4-S-CAP can be a substrate for both tyrosinase and plasma monoamine oxidase (MAO). Both of these enzymes are capable of producing cytotoxic intermediates through their interaction with 4-S-CAP. To study the mechanism of selective melanocytotoxicity of phenolic amine compounds, we compared the in vivo depigmenting potency of 4-S-CAP and its three analogues; i.e., 4-S-HomoCAP, alpha-methyl(Me)-4-S-CAP and N,N-dimethyl(DiMe)-4-S-CAP, using black hair follicles. All four of these phenolic amine compounds possessed depigmenting potency. In this study we examined the kinetics of tyrosinase and MAO by these four compounds. 4-S-CAP and 4-S-HomoCAP were the substrates of both tyrosinase and MAO, whereas alpha-Me-4-S-CAP and N,N-DiMe-4-S-CAP were the substrates of tyrosinase alone. The rate of o-quinone formation by tyrosinase was not in parallel to the in vivo depigmenting potency of the tested compounds. It is therefore indicated that plasma MAO is not the enzyme directly responsible for the production of the melanocytotoxic intermediates from the phenolic amine compounds. We also found that the observed in vivo depigmentation results from complex processes involving the amount of o-quinone formed and the intracellular interaction of o-quinone with protein species.
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PMID:4-S-cysteaminylphenol and its analogues as substrates for tyrosinase and monoamine oxidase. 212 97

A phenolic amine compound, 4-S-cysteaminylphenol (4-S-CAP), is a potent depigmenting agent. To develop more efficacious antimelanoma agents, we synthesized four homologues of 4-S-CAP: N-acetyl-4-S-CAP (N-Ac-4-S-CAP), alpha-methyl-4-S-CAP, 4-S-homo-CAP, and N,N'-dimethyl-4-S-CAP. We tested these five compounds in mice in vivo. After s.c. or i.p. injection of saline solution (in control groups) or one of the compounds, follicular melanocytes were examined by light and electron microscopy to assess the degree of melanocytotoxicity; N-Ac-4-S-CAP induced the most depigmentation (98%), whether given i.p. or s.c. After injection of 4-S-CAP or N-Ac-4-S-CAP, the number of murine B16F10 melanoma colonies formed in the lungs was determined; 4-S-CAP and N-Ac-4-S-CAP were almost equally effective, reducing the colonies to 32 and 25% of mean control, respectively. Metabolic studies of the urine showed 9% of 4-S-CAP and 20% of N-Ac-4-S-CAP injected i.p. were excreted unchanged in 24 h; 1.3% of the N-Ac-4-S-CAP was excreted as 4-S-CAP, indicating some conversion. We conclude that N-Ac-4-S-CAP is a suitable model for developing chemotherapy to treat melanoma characterized by high tyrosinase activity and melanin synthesis.
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PMID:Melanocytotoxicity and antimelanoma effects of phenolic amine compounds in mice in vivo. 234 May 20

We have previously shown that 4-S-cysteaminylphenol (4-S-CAP) causes a significant inhibition of in vivo melanoma growth. To clarify the mechanism of the in vivo antimelanoma effect, this study evaluated the cellular and subcellular changes of follicular melanocytes after s.c. administration of 4-S-CAP on the lumbar areas of black and albino mice. 4-S-CAP produced a prompt, selective swelling and lysis of melanocytes, resulting eventually in the necrosis of melanocytes and the depigmentation of black hair follicles. None of the degenerative changes were seen in melanocytes and keratinocytes of control albino follicles. Comparison of melanocytes in black and albino follicles revealed that melanin synthesis is highly active in the melanocytes of black follicles while melanin and tyrosinase synthesis is not seen in the melanocytes of albino follicles. The findings indicate that the selective melanocytotoxicity of 4-S-CAP is manifested by lysis and necrosis of cells which are actively engaged in melanin synthesis. 4-S-CAP appears to provide a new modality for rational chemotherapy of malignant melanoma.
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PMID:Selective cytotoxicity of 4-S-cysteaminylphenol on follicular melanocytes of the black mouse: rational basis for its application to melanoma chemotherapy. 310 7

Our previous studies showed that 4-S-cysteinylphenol (4-S-CP) and 4-S-cysteaminylphenol (4-S-CAP) inhibit the growth of malignant melanoma and cause depigmentation of black skin. In this study we examined kinetic constants of CP and CAP as substrates for tyrosinases and their properties as sulphydryl scavengers. 4-S-CP and 4-S-CAP were found to be much better substrates for mushroom tyrosinase than L-tyrosine while their 2-S isomers were not the substrates. 4-S-CP and 4-S-CAP were also good substrates for mammalian tyrosinase. Upon tyrosinase oxidation the two phenols conjugated with cysteine to form the cysteinyl derivatives of the corresponding catechols via o-quinone forms. The tyrosinase oxidation product of 4-S-CP had a poor ability to conjugate with alcohol dehydrogenase, a sulphydryl enzyme, while that of 4-S-CAP had a much higher ability. These results suggest that in melanocytes these phenols are oxidised by tyrosinase to the corresponding o-quinone forms, some of which conjugate with sulphydryl enzymes through cysteine residues, thus exerting cytotoxic effects.
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PMID:Mechanism of selective toxicity of 4-S-cysteinylphenol and 4-S-cysteaminylphenol to melanocytes. 310 34

Chloramphenicol-resistant (CAPr) reconstituted cells and cybrids were isolated by fusion of karyoplasts (or intact cells) of mouse amelanotic melanoma B16 cells with cytoplasts of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) -deficient, CAPr rat myoblastic cells, L6TG.CAPr, and double selection in HAT medium containing CAP. Reconstituted cells or cybrids exhibited unique cellular arrangement, and about one third of the isolated clones expressed high tyrosinase activity and marked melanin synthesis, although the parental mouse cells expressed low tyrosinase activity and the parental rat cells did not express tyrosinase activity. These phenotypic changes have been stable for more than a year. The phenotypic reversions of these clonal cells were induced by treatment with a tumor promoter. There were changes in the morphology of the treated cells to that of the mouse B16 cells and extinction of tyrosinase activity and melanin synthesis in pigmented clonal cells. These phenotypic changes and reversions induced by a promoter were repeatedly reversible.
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PMID:Induction of supermelanin synthesis and morphological changes in interspecific reconstituted cells and its reversal by tumor promoter. 681 81


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