Interaction of strong DNA-intercalating bioreductive compounds with topoisomerases I and II.
Nitro(imidazole/triazole)-linked acridines (NLAs) have been previously developed in our laboratory as DNA-intercalating bioreductive drugs. Such compounds demonstrate toxicity through the formation of bulky monoadducts with cellular macromolecules upon activation and reductive metabolism under hypoxic conditions. However, NLAs also demonstrate considerable aerobic toxicity. Based on the ability of NLAs to bind strongly to DNA through intercalation, we investigated whether their relatively high aerobic cytotoxicity and their relatively low hypoxic selectivity in vitro are associated with topoisomerases I and II (Topo I and II) inhibition. DNA Topo I or II-mediated activity studies have been performed using supercoiled or kinetoplast DNA plasmids. Calf thymus or human Topo I and human Topo II purified enzymes were used. All NLA derivatives strongly inhibited relaxation of supercoiled DNA catalyzed by either Topo I or II, in a concentration-dependent manner, without stabilization of a cleavable complex. Aerobic toxicity correlated well with the inhibition of Topo II-mediated decatenation of kinetoplast DNA, whereas the intracellular concentrations of NLAs were 27-152-fold greater than those needed for 50% inhibition of Topo-II mediated decatenation of DNA. These results suggest that topoisomerase inhibition accounts for NLAs aerobic toxicity.
Rosenzweig
H S
HS
Department of Radiation Medicine, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA.
Papadopoulou
M V
MV
Bloomer
W D
WD
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000332:Aerobiosis; D000818:Animals; D002417:Cattle; D015687:Cell Hypoxia; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D018105:DNA, Kinetoplast / Q000187:drug effects* / Q000378:metabolism; D004278:DNA, Superhelical / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010957:Plasmids; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors