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Cytotoxicity and DNA Strand Breaks by 5-Iminodaunorubicin in Mouse Leukemia L1210 Cells: Comparison with Adriamycin and 4'-(9-Acridinylamino)methanesulfon-m-anisidide

Laboratory of Molecular Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205

The effects upon cellular DNA and cytotoxicity produced by the anthracyclines 5-iminodaunorubicin and Adriamycin were studied in mouse leukemia L1210 cells. 5-Iminodaunorubicin produced protein-concealed DNA strand breaks as measured by alkaline elution as had other intercalators including Adriamycin. 5-Iminodaunorubicin produced DNA breaks more efficiently than did Adriamycin despite a lower potency for free radical formation. Many of the 5-iminodaunorubicin breaks measured in this assay may arise from apposed single-strand breaks (i.e., double-strand breaks). 5-Iminodaunorubicin produced breaks which disappeared within 1 to 2 hr following drug removal and were in this way similar to the breaks produced by the acridine intercalator 4'-(9-acridinylamino)-methanesulfon-m-anisidide. Adriamycin produced more persistent breaks. Despite similarities in the kinetics of break disappearance, 5-iminodaunorubicin produced greater cytotoxicity than did 4'-(9-acridinylamino)methanesulfon-m-anisidide when compared at doses producing equal single-strand or double-strand breaks. Differences in the ratio of single-strand breaks to double-strand breaks and the associated cytotoxicity for 5-iminodaunorubicin and 4'-(9-acridinylamino)methanesulfon-m-anisidide indicate that a different mechanism is probably involved in the DNA break production by each agent. Differences between the cytotoxicity associated with the DNA break production by two agents with similar break disappearance kinetics indicate that intercalator-induced DNA breaks cannot be a uniformly lethal DNA lesion.

¹ To whom requests for reprints should be addressed, at Building 37, Room 5D17, National Cancer Institute, 9000 Rockville Pike, Bethesda, Md. 20205.

Received 8/21/81. Accepted 4/ 8/82.

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