TY - JOUR
T1 - Enzymatic activation and binding of adriamycin to nuclear dna
AU - Sinha, Birandra K.
AU - Mimnaugh, Edward G.
AU - Trush, Michael A.
AU - Kennedy, Katherine A.
PY - 1984/7/1
Y1 - 1984/7/1
N2 - Rat liver microsomal activation of the anthracycline antitumor drug, Adriamycin, in the presence of reduced pyridine nucleotide under anaerobic conditions produces reactive species that bind covalently to cellular macromolecules including DNA. Since the nuclear membrane contains enzymes capable of activating Adriamycin, we have examined activation of Adriamycin by isolated nuclei. The anaerobic incubation of Adriamycin with rat hepatic nuclei resulted in the formation of the Adriamycin semiquinone free radical. Moreover, this activation resulted in the covalent binding of Adriamycin to nuclear DNA. The binding of Adriamycin to DNA was reduced pyridine nucleotide and time dependent and was significantly decreased in the presence of reduced glutathione or ethylxanthate. Dicumerol, an inhibitor of DT-dia-phorase, in contrast, had no effect on this binding. When the incubation was carried out in the presence of oxygen, no semiquinone radical was detected; however, superoxide and hydroxyl radicals were readily detected by a spin-trapping technique. Furthermore, little binding of Adriamycin to nuclear DNA was observed under aerobic conditions. These observations suggest that the nuclear activation andcovalent binding of Adriamycin to DNA may be important in the biochemical actions of this drug.
AB - Rat liver microsomal activation of the anthracycline antitumor drug, Adriamycin, in the presence of reduced pyridine nucleotide under anaerobic conditions produces reactive species that bind covalently to cellular macromolecules including DNA. Since the nuclear membrane contains enzymes capable of activating Adriamycin, we have examined activation of Adriamycin by isolated nuclei. The anaerobic incubation of Adriamycin with rat hepatic nuclei resulted in the formation of the Adriamycin semiquinone free radical. Moreover, this activation resulted in the covalent binding of Adriamycin to nuclear DNA. The binding of Adriamycin to DNA was reduced pyridine nucleotide and time dependent and was significantly decreased in the presence of reduced glutathione or ethylxanthate. Dicumerol, an inhibitor of DT-dia-phorase, in contrast, had no effect on this binding. When the incubation was carried out in the presence of oxygen, no semiquinone radical was detected; however, superoxide and hydroxyl radicals were readily detected by a spin-trapping technique. Furthermore, little binding of Adriamycin to nuclear DNA was observed under aerobic conditions. These observations suggest that the nuclear activation andcovalent binding of Adriamycin to DNA may be important in the biochemical actions of this drug.
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M3 - Article
C2 - 6327028
AN - SCOPUS:0021263022
SN - 0008-5472
VL - 44
SP - 2892
EP - 2896
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -