Levodopa/dopamine analogs as inhibitors of DNA synthesis in human melanoma cells.
Compounds possessing the ortho-dihydroxybenzene moiety and structurally related to levodopa and dopamine appear to belong to a new class of biologically active agents that are capable of inhibiting DNA synthesis in a variety of normal and malignant eukaryotic cells. They appear to work in part through their properties as potent reducing agents, and thereby interfere with several redox reactions that are crucial to the synthesis of cellular DNA. Interestingly, the compounds can then be converted to their oxidized or quinone forms, which are powerful electrophiles, and further disrupt cellular metabolism. This latter mechanism appears to account for the relatively increased cytotoxicity observed in melanin-producing cells. In addition to providing potential new agents for the treatment of advanced malignant melanoma, these compounds might prove to be valuable tools in determining the factors that influence rates of DNA synthesis in normal and malignant cells.
Wick
M M
MM
Dana Farber Cancer Institute, Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02115.
D000818:Animals; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007980:Levodopa / Q000031:analogs & derivatives / Q000494:pharmacology*; D008544:Melanocytes / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
C022133:3,4-dihydroxybenzylamine; D007980:Levodopa; D004247:DNA; D004298:Dopamine