title: Amplification of pepleomycin-mediated DNA cleavage and apoptosis by unfused aromatic cations.
abstract: An important approach to improve chemotherapy of members of the bleomycin (BLM) family of antibiotics is to find compounds (amplifiers) that enhance the activity of BLM-mediated DNA cleavage and apoptosis. Using a DNA-sequencing technique and pulsed field gel electrophoresis, we have investigated whether BLM-mediated cleavage of isolated and cellular DNA is amplifed by three compounds (RW-12, LS-20, 1S-5Me) which have a conformationally flexible, unfused polyaromatic system and cationic side chain in the molecules. RW-12 enhanced most effectively both pepleomycin (PEM)-induced cytotoxicity and apoptosis. The order of the maximum enhancing effect of amplifiers on PEM-mediated DNA damage is RW-12 > LS-20 > 1S-5Me. RW-12 amplified PEM-mediated DNA cleavage most effectively not only in vitro but also in cultured cells. We have reported that the order of the DNA binding constants of these compounds is RW-12 > LS-20 > 1S-5Me. In this study, we found a good correlation between PEM-mediated cleavage of isolated DNA and cellular DNA. These results suggest that BLM amplifiers bind to DNA and by doing so enhance drug-mediated DNA degradation, ultimately leading to apoptosis. The present study on amplifiers of anticancer agents shows a novel approach to the potentially effective anticancer therapy.
authors.affiliation: Department of Hygiene, Mie University School of Medicine, Tsu, Mie 514-8507, Japan. kawanisi@doc.medic.mie-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Kawanishi
authors.forename: S
authors.initials: S
authors.lastname: Oikawa
authors.forename: M
authors.initials: M
authors.lastname: Kawanishi
authors.forename: H
authors.initials: H
authors.lastname: Sugiyama
authors.forename: I
authors.initials: I
authors.lastname: Saito
authors.forename: L
authors.initials: L
authors.lastname: Strekowski
authors.forename: W D
authors.initials: WD
authors.lastname: Wilson
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002412:Cations; D004249:DNA Damage / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D017663:Peplomycin / Q000633:toxicity*
chemical_list: D002412:Cations; D007364:Intercalating Agents; D009707:Nucleosomes; D017663:Peplomycin; D019951:DNA Polymerase beta