Melanin synthesis and the action of L-dopa and 3,4-dihydroxybenzylamine in human melanoma cells.
The toxicity and selectivity of 3,4-dihydroxybenzylamine (DHBA), an experimental antimelanoma agent that cannot enter the melanin pathway, broadly paralleled that of L-dopa in a panel of human melanoma cell lines sensitive or resistant to the latter drug. A human retinoblastoma cell line was found to be sensitive to both compounds. The toxicity and selectivity of both catechols were associated with inhibition of DNA synthesis; DHBA was more potent yet allowed a much greater degree of recovery compared with an equitoxic level of dopa. Dopa and DHBA had similar, dose-dependent effects on the cell cycle, arresting cells in S phase at low doses and in G1 at high doses. Replication of the DNA virus adenovirus was found to be inhibited by both agents. There was no difference between sensitive and resistant cell lines in the manganese or copper/zinc forms of superoxide dismutase, or in iron content and iron-binding capacity. Catechol toxicity was inhibited by the hydrogen peroxide scavenging agents pyruvate and methaemoglobin. Sensitivity to catechols did not correlate with melanin or tyrosinase content, rate of incorporation of tyrosine or dopa, intracellular levels of phenylalanine or tyrosine, or binding of a new monoclonal antibody directed against a melanosomal protein. These results indicate that DHBA and dopa exhibit selective toxicity for neural crest tumor cells independently of the melanisation pathway and of the superoxide scavenging system.
Kable
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Queensland Institute of Medical Research, Herston, Australia.
Parsons
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D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007980:Levodopa / Q000494:pharmacology*; D008543:Melanins / Q000096:biosynthesis*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000032:analysis; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D008543:Melanins; D012334:RNA, Neoplasm; C022133:3,4-dihydroxybenzylamine; D007980:Levodopa; D013482:Superoxide Dismutase; D004298:Dopamine