The dihydropyridine dexniguldipine hydrochloride inhibits cleavage and religation reactions of eukaryotic DNA topoisomerase I.
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.
Straub
T
T
Medizinische Poliklinik, University of Würzburg Medical School, Würzburg, Germany.
Boesenberg
C
C
Gekeler
V
V
Boege
F
F
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
D000970:Antineoplastic Agents; D004095:Dihydropyridines; D011994:Recombinant Proteins; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; C054074:niguldipine