Abstract
We have examined the killing effect of 4-S-cysteaminylphenol (4-S-CAP), a newly synthesised melanin precursor, on B16 melanoma cell lines possessing different melanin-producing activities and found it to be particularly effective in heavily melanised melanoma cells, but less so in moderately melanised melanoma cells, and having no effect on amelanotic melanoma cells and nonmelanoma cells. Thus, it was found that the killing effect of 4-S-CAP is highly dependent upon the synthesis of melanin and tyrosinase in melanoma cells, suggesting that 4-S-CAP may become toxic to melanoma cells only after oxidation by tyrosinase. The killing activity of 4-S-CAP also was found to be associated with a profound inhibition of the thymidine incorporation in pigmented melanoma cells, as compared to the uridine and leucine incorporation. Further, the inhibition of DNA synthesis was most pronounced in heavily melanised melanoma cells, less so in moderately melanised melanoma cells, and not seen in amelanotic melanoma cells. As a possible mechanism that might account for this action, it may be that 4-S-CAP is oxidised by tyrosinase to the o-quinone form via the catechol derivative and that some of the quinones then conjugate with sulfhydryl enzymes including DNA polymerase, thus exerting a killing activity for pigmented melanoma cells. Thus, 4-S-CAP appears to provide a new, effective cytotoxic agent for rational chemotherapy of malignant melanomas.
Highlights
Materials and methodsThe 4-S-CAP used was synthesised at the Fujita-Gakuen Health University, Toyoake, Aichi, Japan, by one of the Correspondence: I
In this report, we have evaluated the killing effects of 4-S-CAP on B16 melanoma cell lines possessing different melanin-producing activities, and have examined its effects on the inhibition of macromolecule synthesis and cell cycle progression, so as to clarify the mechanism of its antimelanoma effects
The effect of 4-S-CAP on the macromolecular synthesis was determined by a method similar to that used by Wick (1978)
Summary
The 4-S-CAP used was synthesised at the Fujita-Gakuen Health University, Toyoake, Aichi, Japan, by one of the Correspondence: I. Four sublines of B16-XI melanoma cells, maintained in our laboratory, were used. L929 mouse fibroblast cells, CHO Chinese hamster ovary cells, and HeLa S3 cells were gifts from Aichi Cancer Center Research Institute, Nagoya, Japan. These cell lines have been maintained in the Ham's F-10 medium, supplemented with 10% calf serum (Flow Laboratories, Rockville, MD), penicillin (100 U ml-'), and streptomycin (100 ytg ml-'), and incubated in a humidified atmosphere of 95% air-5% CO2 at 37°C
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