Antimelanoma effect of 4-S-cysteaminylcatechol, an activated form of 4-S-cysteaminylphenol.
Rational chemotherapy of malignant melanoma could be developed by taking advantage of the presence of melanogenic enzymes in melanoma cells. 4-S-Cysteaminylphenol (4-S-CAP) has been evaluated for melanocytotoxicity and antimelanoma effect. Although 4-S-CAP is selectively toxic to pigmented melanoma cells, it is not potent enough when applied as a single agent. To increase the efficacy of 4-S-CAP, we synthesized 4-S-cysteaminylcatechol (4-S-CAC), an activated form of 4-S-CAP, and compared its biochemical properties and antimelanoma effects with those of the isomers 3-S-cysteaminylcatechol (3-S-CAC) and 2-S-cysteaminyl-hydroquinone (2-S-CAH). 4-S-CAC was found to be a better substrate for melanoma tyrosinase than was L-3,4-dihydroxyphenylalanine, the natural catecholic substrate. 3-S-CAC was a poor substrate, whereas 2-S-CAH was not a substrate. 4-S-CAC was the most cytotoxic to three lines of melanoma 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 5-(3,3-dimethyltriazenyl)-1H-imidazole-4-carboxamide. 3-S-CAC was marginally effective, whereas 2-S-CAH was toxic to the host. This systemic toxicity of 2-S-CAH reflected its susceptibility to autoxidation. Growth of B16 melanoma cells inoculated s.c. was significantly inhibited by i.p. administration of 4-S-CAC.HCl (200 mg/kg) for 5 days (P < 0.05). These results suggest that 4-S-CAC is a potent antimelanoma agent, the effect of which is mostly mediated through tyrosinase oxidation.
Inoue
S
S
School of Health Sciences, Fujita Health University, Aichi, Japan.
Hasegawa
K
K
Ito
S
S
Ozeki
H
H
Solano
F
F
Jiménez-Cervantes
C
C
Wakamatsu
K
K
Fujita
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D007980:Levodopa / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases; D011506:Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured
C094171:4-S-cysteaminylcatechol; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D011506:Proteins; D007980:Levodopa; D003543:Cysteamine; D010088:Oxidoreductases; C489799:TYRP1 protein, human; C079621:Tyrp1 protein, mouse; C064056:tyrosinase-related protein-1; D014442:Monophenol Monooxygenase; C043037:4-S-cysteaminylphenol