| Project/Area Number |
13670229
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Fujita Health University |
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Principal Investigator |
INOUE Shigeki Fujita Health University School of Health Sciences, Departments of Clinical Immunology, Professor, 衛生学部, 教授 (30084601)
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| Co-Investigator(Kenkyū-buntansha) |
YUKITAKE Jun Fujita Health University School of Health Sciences, Departments of Clinical Immunology, Assistant Professor, 衛生学部, 講師 (20288468)
WAKAMATSU Kazumasa Fujita Health University School of Health Sciences, Departments of Chemistry, Associate Professor, 衛生学部, 助教授 (80131259)
ITO Shousuke Fujita Health University School of Health Sciences, Departments of Chemistry, Professor, 衛生学部, 教授 (70121431)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Melanoma / 4-S-Cysteaminylphenol / Enantiomer / Tyrosinase / Melanogenesis / メラニン精製 / 4-S-システアミニールフェノール / メラニン / 抗メラノーマ作用 |
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| Research Abstract |
Melanogenesis appears to be a unique target to develop antitumor agents specific for malignant melanoma. Among the antimelanoma compounds that we have examined, 4-S-cysteaminylphenol (4-S-CAP), a phenolic amine, was found to have the most promising antimelanoma effects. However, one problem with 4-S-CAP is its strong hypotensive effect which limits the dose that can be administered in vivo. In an attempt to overcome this problem, a potentially useful approach would appear to be to use enantiomers of 4-S-CAP homologues. We hoped mat one of the enantiomers would preferentially act as a substrate for melanoma tyrosinase while the other enantiomer might carry the hypotensive effect. Based on this rationale, we synthesized enantiomers (99% enantiomer excess) of α-Me-4-S-CAP and α-Et-4-S-CAP by coupling 4-hydroxythiophenol with the oxazolines obtained from (R)- and (S)- enantiomers of 2-amino-1-propanol and 2-amino-1-butanol, respectively. We examined the efficacy of the enantiomers of α-Me- and Et-4-S-CAP as substrates for mouse tyrosinase. The order of V_<max> values was (R)-α-Me-4-S-CAP > (R)-α-Et-4-Sr-CAP > (S)-α-Me-4-S-CAP > 4-S-CAP > (S)-α-Et-4-S-CAP. In vitro experiments showed that 50% inhibition of melanoma cell growth was achieved by all four enantiomers at ca. 10 μM for pigmented B16-F1 cells while they were 50 times less toxic to non-pigmented B16-G4F cells and were even less toxic to mouse 3T3 fibroblasts. In vivo experiments showed that intraperitoneal administration of (R)-α-Me-4-S-CAP and (S)-α-Et-4-S-CAP for 5 days (days 11-15 after tumor challenge) inhibited the subcutaneous growth of B16 melanoma by 50-60% at days 17-20 (P0.05) while the corresponding enantiomers were much less effective. These results indicate that melanogenesis is a principal mediator of the cytotoxicity of both (R)-α-Me-4-S-CAP and (S)-α-Et-4-S-CAP while tyrosinase plays a major role only in the cytotoxicity of (R)-α-Me-4-S-CAP.
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