4-S-Cysteaminylphenol (4-S-CAP), a phenolic
thioether, has been evaluated for melanocytotoxicity. We have recently shown that
dihydro-1,4-benzothiazine-6,7-dione (benzothiazine BQ) is the ultimate toxic metabolite produced by
tyrosinase oxidation of 4-SCAP. In this study we compared the antimelanoma effects of 4-SCAP and its two homologues, alpha-methyl-4-S-cysteaminylphenol (alpha-Me-4-SCAP) and
4-S-homocysteaminylphenol (4-S-Homo-CAP). Biochemical experiments showed that upon
tyrosinase oxidation alpha-Me-S-CAP and
4-S-Homo-CAP also produced homologues of BQ which reacted rapidly with
reduced glutathione (GSH) and also inhibited
alcohol dehydrogenase, an SH
enzyme. In vitro experiments showed that 4-S-CAP and its two homologues were taken up into B16-F1
melanoma cells at comparable rates but that
4-S-Homo-CAP was least effective in GSH deprivation, which was reflected in the low cytotoxicity of this
phenol, and that the cytotoxicity of the
phenols was
tyrosinase dependent, as proved by the negligible effects on B16-G4F cells which have a much lower
tyrosinase activity. In vivo experiments showed that direct intratumoral administration of these
phenols inhibited the subcutaneous growth of
B16 melanoma, with
4-S-Homo-CAP being the least effective, and that indirect Intraperitoneal administration of 4-S-CAP inhibited
melanoma growth much more effectively than the two homologues. These results indicate that 4-S-CAP is the most promising antimelanoma agent among the three
phenols examined.