Effects of tyrosinase activity on the cytotoxicity of 3,4-dihydroxybenzylamine and buthionine sulfoximine in human melanoma cells.
The rationale for melanoma specific dihydroxybenzene containing antitumor agents is based in part upon the ability of the enzyme tyrosinase to oxidize these pro drugs to toxic intermediates. In situ tyrosinase activity was demonstrated to be affected by both cell density and time from plating in pigmented melanoma cells. Phenylthiourea, which completely inhibited tyrosinase activity with minimal cytotoxicity was found to block the growth inhibitory activity of the antitumor dopamine analog 3,4-dihydroxybenzylamine (3,4-DHBA) (NSC 263475). The antioxidant dithioerythritol was also found to inhibit tyrosinase activity and to block the growth inhibitory effects of 3,4-DHBA in pigmented melanoma cell lines. Buthionine sulfoximine (BSO) was shown to be cytotoxic to melanoma cells and its growth inhibitory effects appears to correlate with tyrosinase levels. Furthermore, BSO was shown to potentiate the growth inhibitory effects of 3,4-DHBA on marginally pigmented human melanoma cell lines.
Prezioso
J A
JA
Division of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Fitzgerald
G B
GB
Wick
M M
MM
D000963:Antimetabolites / Q000378:metabolism / Q000633:toxicity*; D019328:Buthionine Sulfoximine; D004156:Catechol Oxidase / Q000378:metabolism*; D002452:Cell Count; D004226:Dithioerythritol / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D014442:Monophenol Monooxygenase / Q000378:metabolism* / Q000494:pharmacology; D010670:Phenylthiourea / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000963:Antimetabolites; D008717:Methionine Sulfoximine; C022133:3,4-dihydroxybenzylamine; D019328:Buthionine Sulfoximine; D004226:Dithioerythritol; D010670:Phenylthiourea; D004156:Catechol Oxidase; D014442:Monophenol Monooxygenase; D005978:Glutathione; D004298:Dopamine