The in vivo antimelanoma effect of 4-S-cysteaminylphenol and its n-acetyl derivative.
Phenolic melanin precursors can be utilized for the development of anti-melanoma agents. The sulphur homologue of tyrosine, 4-S-cysteinylphenol (CP) and its decarboxylation product, 4-S-cysteaminylphenol (CAP) were shown to be substrates of melanoma tyrosinase, forming melanin-like pigment. Both, but in particular the 4-S-CAP, exhibited a significant in vivo depigmenting effect. Here, we report on the in vivo anti-melanoma effect of 4-S-CP, and 4-S-CAP and its N-acetyl derivative. In a previous in vitro study, it was shown that 4-S-CP and 4-S-CAP required a catalytic amount of dopa for optimal mammalian tyrosinase activity. To enhance the potential anti-melanoma effect of these two compounds. L-dopa and a decarboxylase inhibitor (carbidopa) were given concomitantly. We found that 4-S-CAP showed a significant growth inhibition of B16 melanoma inoculated s.c. into C57BL/6J mice. The anti-melanoma effect was increased significantly by combination of L-dopa and carbidopa. In addition, we tested the in vivo anti-melanoma effect of an N-acetyl derivative of 4-S-CAP (N-Ac-4-S-CAP). We found that N-Ac-4-S-CAP was the tyrosinase substrate and potent inhibitor of melanoma growth. N-acetyl 4-S-CAP showed a marked increase in water solubility. We suggest that N-Ac-4-S-CAP may prove to be a valuable model for the development of anti-melanoma agent using a metabolic pathway of melanin synthesis.
Miura
T
T
Department of Dermatology, Sapporo Medical College, Japan.
Jimbow
K
K
Ito
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002230:Carbidopa / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003543:Cysteamine / Q000494:pharmacology* / Q000031:analogs & derivatives; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005069:Evaluation Studies as Topic; D005260:Female; D007700:Kinetics; D007980:Levodopa / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009368:Neoplasm Transplantation; D010636:Phenols / Q000494:pharmacology*; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D010636:Phenols; D007980:Levodopa; D003543:Cysteamine; C043036:4-S-cysteinylphenol; C066420:N-acetyl-4-S-cysteaminylphenol; D014442:Monophenol Monooxygenase; C043037:4-S-cysteaminylphenol; D003545:Cysteine; D002230:Carbidopa