Comparison of in vivo anti-melanoma effect of enantiomeric alpha-methyl- and alpha-ethyl-4-S-cysteaminylphenol.
Melanogenesis appears to be a unique target to develop anti-tumour agents specific for malignant melanoma. Among the anti-melanoma compounds that 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 the efficacy as anti-melanoma agents, we have recently synthesized enantiomers of alpha-Me-4-S-CAP and alpha-Et-4-S-CAP. The enantiomers were found to be good substrates for tyrosinase. In vitro experiments showed that the enantiomers were highly cytotoxic to B16-F1 melanoma cells, and the cytotoxic effect was proved to be tyrosinase-dependent. In the present study, in vivo cytotoxicity experiments showed that i.p. administration of R-alpha-Me-4-S-CAP and S-alpha-Et-4-S-CAP (and 4-S-CAP) strongly inhibited the subcutaneous growth of B16 melanoma in mice, while the corresponding enantiomers were much less effective. Similarly, i.p. treatment with R-alpha-Me-4-S-CAP or S-alpha-Et-4-S-CAP, but not with 4-S-CAP, caused strong depigmentation of follicular melanocytes in C57BL black mice. Among 4-S-CAP and the enantiomers, only R-alpha-Et-4-S-CAP caused a moderate decrease in blood pressure in spontaneously hypertensive rats. These results confirm that the use of enantiomers increases the efficacy of tyrosinase-dependent cytotoxic phenolic amines.
Yukitake
Jun
J
Department of Clinical Immunology, Fujita Health University School of Health Sciences, Toyoake, Aichi 470-1192, Japan.
Otake
Hiromi
H
Inoue
Shigeki
S
Wakamatsu
Kazumasa
K
Ito
Shosuke
S
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D003543:Cysteamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D007022:Hypotension / Q000097:blood; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010858:Pigmentation / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D012878:Skin Neoplasms / Q000188:drug therapy*; D013237:Stereoisomerism; D023041:Xenograft Model Antitumor Assays
D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; C494919:ethyl-4-S-cysteaminylphenol; C113312:methyl-4-S-cysteaminylphenol; D003543:Cysteamine