Enhanced topoisomerase II-induced DNA breaks and free radical production by a new anthracycline with potent antileukemic activity.
In a previous study we reported that a new anthracycline derivative (moflomycin) exhibited a higher antileukemic activity compared to other anthracyclines, such as daunorubicin and doxorubicin. To explain the superior antileukemic effect of moflomycin and to disclose a possible structure-activity relationship, we investigated the three main mechanisms by which anthracyclines are though to exert their antitumor effect: DNA binding, free radical production and topoisomerase II inhibition. The DNA interaction was assessed both by DNA binding and DNA unwinding assays, free radical generation was studied by electron spin resonance, and topoisomerase II interaction by analysis of the stimulation of enzyme-induced DNA breaks. The results showed a higher free radical production and a greater stimulation of topoisomerase II-mediated DNA cleavage by moflomycin than doxorubicin, associated with a lower DNA affinity. The different biochemical characteristics of moflomycin, particularly its interaction with topoisomerase II, are related to the structural modifications performed on the chromophore. These properties, associated with a higher stability of the molecule induced by the presence of an iodine atom on the sugar moiety, are probably responsible for the higher antileukemic activity of this compound.
Andrivon
W
W
Laboratoire d'Hématologie Cellulaire et Moléculaire, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France.
Saucier
J M
JM
Auclair
C
C
Monneret
C
C
Florent
J C
JC
Guillosson
J J
JJ
Nafziger
J
J
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005609:Free Radicals; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D005609:Free Radicals; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; C063104:moflomycin; D004247:DNA; D003630:Daunorubicin