Antimelanoma effect of 4-S-cysteaminylcatechol, an activated form of 4-S-cysteaminylphenol.

Abstract

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.

• Authors: S Inoue, K Hasegawa, S Ito, H Ozeki, F Solano, C Jiménez-Cervantes, K Wakamatsu, K Fujita
• Journal: Cancer research (Cancer Res) Vol. 55 Issue 12 Pg. 2603-7 (Jun 15 1995) ISSN: 0008-5472 [Print] United States
• PMID: 7780975 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-S-cysteaminylcatechol
• Antineoplastic Agents
• Membrane Glycoproteins
• Proteins
• Levodopa
• Cysteamine
• Oxidoreductases
• TYRP1 protein, human
• Tyrp1 protein, mouse
• tyrosinase-related protein-1
• Monophenol Monooxygenase
• 4-S-cysteaminylphenol

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biotransformation
• Cell Division (drug effects)
• Cell Line
• Cell Survival (drug effects)
• Cysteamine (analogs & derivatives, metabolism, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Humans
• Kinetics
• Levodopa (pharmacology)
• Melanoma (metabolism, pathology)
• Melanoma, Experimental (drug therapy, pathology)
• Membrane Glycoproteins
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Monophenol Monooxygenase (metabolism)
• Oxidation-Reduction
• Oxidoreductases
• Proteins (metabolism)
• Tumor Cells, Cultured