Effects of tyrosinase activity on the cytotoxicity of 4-S-cysteaminylphenol and N-acetyl-4-S-cysteaminylphenol in melanoma cells.
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.
Prezioso
J A
JA
Department of Radiation Oncology, University of Pittsburgh, Pittsburgh Cancer Institute, PA.
Epperly
M W
MW
Wang
N
N
Bloomer
W D
WD
D000970:Antineoplastic Agents / Q000378:metabolism*; D019328:Buthionine Sulfoximine; D002455:Cell Division / Q000187:drug effects; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010636:Phenols; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D003543:Cysteamine; C066420:N-acetyl-4-S-cysteaminylphenol; D013806:Theophylline; D014442:Monophenol Monooxygenase; C043037:4-S-cysteaminylphenol