GENOTOXIC AND MUTAGENIC EFFECTS OF ANTITU MOR ANTHRACYCLINES AND AGLYCONES - STUDIES WITH 2 TEST SYSTEMS

Mutagenic (Ames tests) and genotoxic (SOS chromotest) activities of hi ghly-efficient natural anthracycline monosaccharides possessing antitu mor activity - daunorubicin (also known as daunomycin or rubomycin), d oxorubicin (adriamycin), and carminomycin - were studied. At the same time, the hypothesis was tested that intercalation of the antibiotic m oiety into the helix of cell DNA, which was mediated by the saccharide amino group, played a crucial role in genotoxicity of these anthracyc lines. The hydrolysis products of these antibiotics (the corresponding aglycones) and aclacynomycin A (an anthracycline trisaccharide), as w ell as aclavinone (its derivative aglycone), were studied. All these c ompounds lacked the saccharide amino group necessary for intercalation . It was found that all anthracycline monosaccharides studied had a st rong mutagenic effect on strain TA98 and a moderate effect on strain T A100 of Salmonella typhimurium. Aclacynomycin A was found to have no m utagenic effect on any strain. Lack of the glycoside amino group did n ot necessarily result in loss of mutagenic activity in the derivative aglycones of anthracycline monosaccharides: they exhibited moderate mu tagenic activity in strain TA98 and low but significant activity in st rain TA100. The S9 microsomal fraction did not alter the mutagenic act ivity of either anthracycline monosaccharides or their aglycones; howe ver, it dramatically increased the mutagenic activity of aclavinone: c orrespondence between positive responses in Ames tests and the SOS chr omotest was found. Apparently, the mutagenic activity of the substance s studied in bacterial cells was mediated by inducing the SOS-repair p rocess. If the compound contained the amino glycoside moiety, function al and structural precursors of the SOS response were formed via inter calation of the reagents into the DNA duplex; if the substance did not contain this moiety, the precursors were formed via ionic interaction .