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.