COMPARISON OF ANTIMELANOMA EFFECTS OF 4-S-CYSTEAMINYLPHENOL AND ITS HOMOLOGS

4-S-Cysteaminylphenol (4-S-CAP), a phenolic thioether, has been evalua ted for melanocytotoxicity. We have recently shown that dihydro-1,4-be nzothiazine-6,7-dione (benzothiazine BQ) is the ultimate toxic metabol ite produced by tyrosinase oxidation of 4-S-CAP. In this study we comp ared the antimelanoma effects of 4-S-CAP and its two homologues, alpha -methyl-4-S-cysteaminylphenol (alpha-Me-4-S-CAP) and 4-S-homocysteamin ylphenol (4-S-Homo-CAP). Biochemical experiments showed that upon tyro sinase oxidation alpha-Me-4-S-CAP and 4-S-Homo-CAP also produced homol ogues of BQ which reacted rapidly with reduced glutathione (GSH) and a lso inhibited alcohol dehydrogenase, an SH enzyme. In vitro experiment s 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 ef fective in GSH deprivation, which was reflected in the low cytotoxicit y of this phenol, and that the cytotoxicity of the phenols was tyrosin ase dependent, as proved by the negligible effects on B16-G4F cells wh ich 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 leas t effective, and that indirect intraperitoneal administration of 4-S-C AP inhibited melanoma growth much more effectively than the two homolo gues. These results indicate that 4-S-CAP is the most promising antime lanoma agent among the three phenols examined. (C) 1998 Lippincott-Rav en Publishers.