Involvement of Hydroxyl Radical Formation and Dna Strand Breakage in the Cytotoxicity of Anthraquinone Antitumour Agents |
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Authors: | G R Fisher J R Brown L H Patterson |
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Institution: |
a Dept. Pharmacy, Leicester Polytechnic, Leicester, UK
b Dept. Pharmaceutical Sciences, Sunderland Polytechnic, Sunderland, UK |
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Abstract: | Four 9,10-anthraquinones (AQ) mono- or bis-substituted with the -NH(CH2)2 NH(CH2)2OH group were studied. 1-AQ, 1,5-AQ and 1,8-AQ but not 1,4-AQ (100°M) 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 °M) 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)2 NH(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 °M), 1-8-AQ (0.5 °M) and 1,5-AQ (12.3 °M) but not the 1,4-AQ (1.2 °M). |
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Keywords: | Hydroxyl radicals anthraquinones DNA strand breaks MCF-7 cells cytotoxicity |
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