[Genotoxic and mutagenic activity of antineoplastic anthracyclines and their aglycones: study in two test-systems].
Mutagenic (Ames tests) and genotoxic (SOS chromotest) activities of highly-efficient natural anthracycline monosaccharides possessing antitumor activity-daunorubicin (also known as daunomycin or rubomycin), doxorubicin (adriamycin), and carminomycin-were studied. At the same time, the hypothesis was tested that intercalation of the antibiotic moiety into the helix of cell DNA, which was mediated by the saccharide amino group, played a crucial role in genotoxicity of these anthracyclines. The hydrolysis products of these antibiotics (the corresponding aglycones) and aclacynomycin A (an anthracycline trisaccharide), as well as aclavinone (its derivative aglycone), were studied. All these compounds lacked the saccharide amino group necessary for intercalation. It was found that all anthracycline monosaccharides studied had a strong mutagenic effect on strain TA98 and a moderate effect on strain TA100 of Salmonella typhimurium. Aclacynomycin A was found to have no mutagenic effect on any strain. Lack of the glycoside amino group did not necessarily result in loss of mutagenic activity in the derivative aglycones of anthracycline monosaccharides: they exhibited moderate mutagenic activity in strain TA98 and low but significant activity in strain TA100. The S9 microsomal fraction did not alter the mutagenic activity of either anthracycline monosaccharides or their aglycones; however, it dramatically increased the mutagenic activity of aclavinone: correspondence between positive responses in Ames tests and the SOS chromotest was found. Apparently, the mutagenic activity of the substances studied in bacterial cells was mediated by inducing the SOS-repair process. If the compound contained the amino glycoside moiety, functional and structural precursors of the SOS response were formed via intercalation of the reagents into the DNA duplex; if the substance did not contain this moiety, the precursors were formed via ionic interaction.
Vasil'eva
S V
SV
Makhova
E V
EV
Efremenkova
O V
OV
Bartoshevich
Iu E
IuE
D015250:Aclarubicin / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002360:Carubicin / Q000633:toxicity; D003630:Daunorubicin / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D007364:Intercalating Agents / Q000633:toxicity; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D009279:Naphthacenes / Q000627:therapeutic use / Q000633:toxicity*; D009690:Nucleic Acid Conformation; D013014:SOS Response, Genetics / Q000187:drug effects*; D012486:Salmonella typhimurium / Q000235:genetics; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D007364:Intercalating Agents; D009153:Mutagens; D009279:Naphthacenes; C027832:aklavinone; D015250:Aclarubicin; D004317:Doxorubicin; D002360:Carubicin; D003630:Daunorubicin
Genotoksicheskaia i mutagennaia aktivnost' protivoopukholevykh antratsiklinov i ikh aglikonov: izuchenie v test-sistemakh.