1,4-Diamino-substituted anthraquinone antitumor agents (mitoxantrone and ametantrone) and structurally related 1,5- and 1,8-diaminosubstituted compounds (AM1 and AM2) were tested for their ability to photosensitize human leukemic cells in culture. Viability was measured using the 3,4,5-dimethylthiazol-2,5-diphenyl tetrazolium bromide assay, and DNA and membrane damage were assessed. Following a 1-h exposure to AM2, a dose of drug required to give 50% loss of cell viability (53 µm) was obtained in the dark, which was reduced to approximately 2.4 µm following illumination for 2 min (λ > 475 nm), a dose of light that was completely nontoxic to the cells in the absence of drug. A shift in the cell viability curve was also observed for AM1 but, under identical conditions, the dose modification was only 8.9. In contrast, neither ametantrone nor mitoxantrone gave a decreased viability upon illumination. DNA single-strand breaks as measured by alkaline elution correlated with cell viability. Frank DNA single-strand breaks were produced by AM2 and light, suggesting the production of free radicals. The strand breaks produced by AM2 in the dark and by mitoxantrone (with or without illumination) were protein concealed. No evidence of photo-induced membrane damage, as determined by transport of the model amino acid cycloleucine, could be observed even at supralethal doses.

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This research was supported in part by a grant (to J. W. L.) from the National Cancer Institute of Canada.

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