Involvement of hydroxyl radical formation and DNA strand breakage in the cytotoxicity of anthraquinone antitumour agents.
Four 9,10-anthraquinones (AQ) mono- or bis-substituted with the -NH(CH2)2NH(CH2)2OH group were studied. 1-AQ, 1,5-AQ and 1,8-AQ but not 1,4-AQ (100 microM) generated pBR322 plasmid DNA single strand breaks in the presence of purified NADPH dependent cytochrome P450 reductase. 1-AQ, 1,5-AQ and 1,8-AQ (at 100 microM) stimulated hydroxyl radical formation in MCF-7 S9 cell fraction (as measured by dimethyl pyrolline N-oxide spin trapping) and MCF-7 DNA strand breaks as measured by alkaline filter elution. In contrast 1,4-AQ did not stimulate hydroxyl radical formation and produced considerably less strand breaks in MCF-7 cells compared to the other AQ's. It would appear that the position of the -NH(CH2)2NH(CH2)2OH groups on the chromophore is an important determinant in the metabolic activation of cytotoxic anthraquinones. This may contribute to the cytotoxicity (ID50 values) of 1-AQ (0.06 microM), 1-8-AQ (0.5 microM) and 1,5-AQ (12.3 microM) but not the 1,4-AQ (1.2 microM).
Fisher
G R
GR
Dept. Pharmacy, Leicester Polytechnic, U.K.
Brown
J R
JR
Patterson
L H
LH
D000880:Anthraquinones / Q000494:pharmacology / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000473:pathology*; D004249:DNA Damage; D004270:DNA, Circular / Q000187:drug effects; D005609:Free Radicals; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004270:DNA, Circular; D005609:Free Radicals; D013481:Superoxides; D006861:Hydrogen Peroxide; D009251:NADPH-Ferrihemoprotein Reductase