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DNA Damage by Antitumor Acridines Mediated by Mammalian DNA Topoisomerase II¹

Department of Biological Chemistry, Johns Hopkins Medical School, Baltimore, Maryland 21205

Antitumor drugs from many chemical classes have been shown to induce protein-linked DNA breaks in cultured mammalian cells and in vitro in the presence of purified mammalian DNA topoisomerase II. The possibility that mammalian DNA topoisomerase II is an intracellular target which mediates drug-induced DNA breaks is supported by the following studies using 4'-(9-acridinylamino)methane-sulfon-m-anisidide (m-AMSA): (a) a single m-AMSA-dependent DNA cleavage activity copurified with calf thymus DNA topoisomerase II activity at all chromatographic steps of the enzyme purification; (b) m-AMSA-induced DNA cleavage by this purified activity resulted in the covalent attachment of protein to the 5'-ends of the DNA via a tyrosyl phosphate bond. This covalently linked protein has the same reduced molecular weight as purified calf thymus DNA topoisomerase II. The possibility that topoisomerase II-mediated DNA breaks may be responsible for cytotoxicity has also been investigated using a number of m-AMSA-related acridines. The level of topoisomerase II-mediated DNA breaks in vitro strongly correlates with the level of protein-linked DNA breaks in cultured cells and drug-induced cytotoxicity. These results suggest that mammalian DNA topoisomerase II may be a cytotoxic target of antitumor acridines.

¹ This work was supported by NIH Grants GM-27731 and CA-39662.

² American Cancer Society postdoctoral fellow. Present address: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610.

³ To whom requests for reprints should be addressed, at Department of Biological Chemistry, Johns Hopkins Medical School, 725 N. Wolfe St., Baltimore, MD 21205.

Received 9/ 9/85. Revised 1/ 7/86. Accepted 1/ 7/86.

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