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Topoisomerase II-mediated DNA Damage Produced by 4'-(9-Acridinylamino)-methanesulfon-m-anisidide and Related Acridines in L1210 Cells and Isolated Nuclei: Relation to Cytotoxicity

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20892

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) is a DNA intercalating 9-aminoacridine with clinical activity in adult acute leukemia. m-AMSA has been shown to produce protein-linked DNA strand breaks in mammalian cells through an interaction with the nuclear enzyme DNA topoisomerase II. We have compared the effects of m-AMSA and several acridine analogues (9-aminoacridine; A, NSC 343499; B, SN 16507; C, NSC 140701; D, SN 13553) on DNA integrity and cell survival in L1210 leukemia in vitro. Cells (or isolated nuclei) were treated with drugs (0.1–50 µM) for 0.5–1.0 h and subsequently analyzed using the alkaline elution technique. All drugs, except Compound D, produced DNA-protein cross-links (DPC) in L1210 cells. At 1 µM, potency was in the order, C>m-AMSA>B>A>>9-aminoacridine. In isolated nuclei, DPC and single-strand breaks were produced in essentially a 1:1 ratio, which is consistent with topisomerase II-mediated protein-linked DNA breaks. Potency differences were less pronounced in nuclei than in cells. In isolated nuclei, Compound D produced extensive DPC not associated with single-strand breaks, which suggests a more complex activity for this compound. Colony formation assays demonstrated the cytotoxicity of most of these acridine analogues (C>B>Am-AMSA>>D= 9-aminoacridine). Correlation of DPC with cell kill gave similar curves for each compound. These results are evidence for a causal relationship between drug-induced topoisomerase II-mediated DNA breaks and cytotoxicity.

¹ To whom requests for reprints should be addressed, at Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Building 37, Room 5A19, Bethesda, MD 20892.

² Present address: Division of Medical Oncology, Henry Ford Hospital, Detroit, MI 48202.

Received 5/11/87. Revised 9/ 4/87. Accepted 11/13/87.

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