title: A further insight into the mechanism of action of anthracycline antibiotics.
abstract: The uptake of Adriamycin (ADM) by eucaryotic and procaryotic cells and the interaction of the antibiotic with structurally organized DNA were investigated. The aim of this work was to understand why ADM is endowed with very low antibiotic activity in spite of being highly cytotoxic for mammalian cells, and to get a further insight into the mechanism of action of this compound. Spectrophotometric, fluorometric, chiroptical, and electron microscopic techniques were used. The drug was shown to concentrate in mammalian cells but failed to do so in bacteria and penetrated rather poorly in Candida albicans. The chromatin binding affinity of ADM appeared to be substantially reduced with respect to the affinity for free DNA. Complex stereochemistry was also influenced by the presence of nucleosomal arrangements in the polynucleotide. In addition, evidence was obtained that the antibiotic tended to accumulate at specific (linker) chromatin regions and to cause extensive compaction of organized DNA. The observed phenomena may play a relevant role in the mode of drug action in eucaryotic cells and help to explain the lack of antibacterial activity by ADM in spite of the apparent attainment of great enough intracellular levels to affect DNA template function.
authors.affiliation: Department of Organic Chemistry, University of Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Palù
authors.forename: S
authors.initials: S
authors.lastname: Valisena
authors.forename: G
authors.initials: G
authors.lastname: Bertoloni
authors.forename: C
authors.initials: C
authors.lastname: Cera
authors.forename: M
authors.initials: M
authors.lastname: Palumbo
mesh_terms: D001419:Bacteria / Q000187:drug effects* / Q000235:genetics; D001665:Binding Sites; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D002942:Circular Dichroism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D013293:Enterococcus faecalis / Q000187:drug effects / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008854:Microscopy, Electron; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics
chemical_list: D002843:Chromatin; D004317:Doxorubicin; D004247:DNA