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The antimalarial agent chloroquine is known for high affinity for melanin. This 4-aminoquinoline derivative was examined for anti-melanoma activity and uptake into melanoma cells. Chloroquine inhibited growth of cultured melanoma cells; the effect was much greater to a moderately pigmented cell line HMV-II than to a nonpigmented HMV-I. Treatment with chloroquine at a dose of 62 mg/kg i.p. for 12 days prolonged by 71% the life span of mice bearing B16 melanoma, while 24-day treatment at 31 mg/kg resulted in a 81% increase in life span. HMV-II cells showed a two-fold increase in uptake of chloroquine as compared with HMV-I cells. Chloroquine, 24 hr after administration to mice implanted s.c. with B16 melanoma, was selectively accumulated in the pigmented tissues, melanoma and eyes. Other nonpigmented tissues such as the liver, lung, and kidney showed rapid uptake (within 1 hr) and release. These results suggest that chloroquine is toxic to pigmented melanoma cells, the process being partly mediated by binding to melanin.

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Melanogenesis provides a unique target for the development of antitumour agents specific for malignant melanoma. Among the anti-melanoma compounds we have examined, 4-S-cysteaminylphenol (4-S-CAP), a phenolic amine, was found to have the most promising anti-melanoma effects. To further improve its efficacy as an anti-melanoma agent, we synthesized the R- and S-enantiomers (99% enantiomer excess) of alpha-methyl- 4-S-cysteaminylphenol (alpha-Me-4-S-CAP) and alpha-ethyl- 4-S-cysteaminylphenol (alpha-Et-4-S-CAP) by coupling 4-hydroxythiophenol with the oxazolines obtained from the (R)- and (S)-enantiomers of 2-amino-1-propanol and 2-amino-1-butanol, respectively. The enantiomers of alpha-Me-4-S-CAP and alpha-Et-4-S-CAP were found to be better substrates for tyrosinase than the natural substrate, L-tyrosine. In vitro experiments showed that all four enantiomers were highly cytotoxic to pigmented B16-F1 melanoma cells, the effect being 70-fold and 160-fold greater than that on non-pigmented B16-G4F melanoma cells and 3T3 fibroblasts, respectively. The cytotoxic effect against B16-F1 cells was completely inhibited by phenylthiourea, a tyrosinase inhibitor, or by N-acetyl-L-cysteine, which increases the intracellular reduced glutathione (GSH) level. 4-S-CAP and the enantiomers were taken up into B16-F1 cells at comparable rates, but showed varying rates of GSH depletion that were inversely correlated to the cytotoxicity. These results suggest that the use of enantiomers would increase the efficacy of tyrosinase-dependent cytotoxic phenols.