title: The dihydropyridine dexniguldipine hydrochloride inhibits cleavage and religation reactions of eukaryotic DNA topoisomerase I.
abstract: Dexniguldipine hydrochloride (B859-35, a dihydropyridine with antitumor and multidrug resistance-reverting activity) inhibits both the DNA cleavage and religation reactions of purified human DNA topoisomerase I at concentrations >1 microM, whereas at concentrations <1 microM it inhibits selectively the religation step and stabilizes the covalent topoisomerase I-DNA intermediate in a similar fashion as camptothecin. Inhibition of religation by camptothecin can be overcome by increasing the concentration of the DNA substrate in the religation reaction, indicating a competitive type of inhibition. In contrast, dexniguldipine hydrochloride decreases rate constants of topoisomerase I-mediated DNA religation independently of the concentration of the DNA substrate, suggesting a noncompetitive mechanism of inhibition, which is different from that of camptothecin.
authors.affiliation: Medizinische Poliklinik, University of Würzburg Medical School, Würzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Straub
authors.forename: C
authors.initials: C
authors.lastname: Boesenberg
authors.forename: V
authors.initials: V
authors.lastname: Gekeler
authors.forename: F
authors.initials: F
authors.lastname: Boege
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology*; D004795:Enzyme Stability / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D004095:Dihydropyridines; D011994:Recombinant Proteins; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; C054074:niguldipine