title: Structure-activity relationship of anthracycline-induced genotoxicity in vitro.
abstract: Anthracycline antitumor antibiotics, such as Adriamycin and daunomycin, are potent genotoxic agents and carcinogens. A variety of anthracycline derivatives was investigated in various in vitro short-term tests, i.e., mutagenesis in Salmonella typhimurium and V79 Chinese hamster cells and induction of unscheduled DNA synthesis in primary rat hepatocytes. Compounds containing a daunosamine sugar moiety (Adriamycin, daunomycin, 4-demethoxydaunomycin, 4-demethoxyadriamycin, and carminomycin) were highly active in both mutagenesis assays. Addition of S9 to the bacteria and cocultivation of V79 cells with rat hepatocytes, in general, decreased the mutagenicity of these compounds. In contrast, anthracyclines with N-alkylated sugar moieties (aclacinomycin A, marcellomycin, musettamycin, pyrromycin, rudolfomycin, N,N-dimethyladriamycin, N,N-dimethyldaunomycin, N-benzyldaunomycin, N,N-dibenzyldaunomycin, 3'-deamino-3'-methoxypiperidinodaunomycin, morpholinodaunomycin, cyanomorpholinodaunomycin, and cyanomorpholinoadriamycin) were weakly mutagenic or not mutagenic at all in both bacterial and mammalian cells. The two latter compounds were weakly active in the Salmonella/microsome assay only after addition of S9. Results obtained in the DNA repair studies did not correlate to these mutagenicity data; while most compounds, including Adriamycin and daunomycin, were either weakly active or inactive at inducing unscheduled DNA synthesis in primary rat hepatocytes, morpholinodaunomycin, cyanomorpholinodaunomycin, and cyanomorpholinoadriamycin were extremely active. The results indicate that the mutagenicity of anthracyclines is related more to differences in their sugar moiety than to differences in the chemical structure of their aglycones; N-alkylation of the sugar moiety can abolish or greatly reduce their mutagenic activity. Moreover, induction of unscheduled DNA synthesis, although considered to be due to DNA damage, is not correlated to anthracycline-induced mutations but may possibly indicate covalent DNA interaction.
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004260:DNA Repair; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D009153:Mutagens; D003630:Daunorubicin