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Fisher GR, Brown JR, Patterson LH: Involvement of hydroxyl radical formation and DNA strand breakage in the cytotoxicity of anthraquinone antitumour agents. Free Radic Res Commun. 1990;11(1-3):117-25. 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). |
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