ANTIMELANOMA EFFECT OF 4-S-CYSTEAMINYLCATECHOL, AN ACTIVATED FORM OF 4-S-CYSTEAMINYLPHENOL

Rational chemotherapy of malignant melanoma could be developed by taki ng advantage of the presence of melanogenic enzymes in melanoma cells. 4-S-Cysteaminylphenol (4-S-CAP) has been evaluated for melanocytotoxi city and antimelanoma effect. Although 4-S-CAP is selectively toxic to pigmented melanoma cells, it is not potent enough when applied as a s ingle agent. To increase the efficacy of 4-S-CAP, we synthesized 4-S-c ysteaminylcatechol (4-S-CAC), an activated form of 4-S-CAP, and compar ed its biochemical properties and antimelanoma effects with those of t he isomers 3-S-cysteaminylcatechol (3-S-CAC) and 2-S-cysteaminylhydroq uinone (2-S-CAH). 4-S-CAC was found to be a better substrate for melan oma tyrosinase than was L-3,4-dihydroxyphenylalanine, the natural cate cholic substrate. 3-S-CAC was a poor substrate, whereas 2-S-CAH was no t a substrate. 4-S-CAC was the most cytotoxic to three lines of melano ma cells in vitro, followed by 2-S-CAH and 3-S-CAC. When applied i.p. for 9 days at a dose of 100 mg/kg, 4-S-CAC . HCl, increased by 46-52% the life span of C57BL/6 mice inoculated i.p. with B16 melanoma; this effect was comparable to that of a 50 mg/kg dose of 3,3-dimethyltriaze nyl)-1H-imidazole-4-carboxamide. 3-S-CAC was marginally effective, whe reas 2-S-CAH was toxic to the host. This systemic toxicity of 2-S-CAH reflected its susceptibility to autoxidation. Growth of B16 melanoma c ells inoculated s.c. was significantly inhibited by i.p. administratio n of 4-S-CAC . HCl (200 mg/kg) for 5 days (P < 0.05). These results su ggest that 4-S-CAC is a potent antimelanoma agent, the effect of which is mostly mediated through tyrosinase oxidation.