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Originally published In Press as doi:10.1074/jbc.M212056200 on December 8, 2002

J. Biol. Chem., Vol. 278, Issue 9, 7406-7412, February 28, 2003
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A Two-drug Model for Etoposide Action against Human Topoisomerase IIalpha *

Kenneth D. BrombergDagger §, Alex B. Burgin, and Neil Osheroff||**

From the Departments of Dagger  Biochemistry and || Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146 and  BioStructures Group, deCODE Genetics, Bainbridge Island, Washington 98110

The widely used anticancer drug etoposide kills cells by increasing levels of topoisomerase II-mediated DNA breaks. While it is known that the drug acts by inhibiting the ability of topoisomerase II to ligate cleaved DNA molecules, the precise mechanism by which it accomplishes this action is not well understood. Because there are two scissile bonds per enzyme-mediated double-stranded DNA break, it has been assumed that there are two sites for etoposide in every cleavage complex. However, it is not known whether the action of etoposide at only one scissile bond is sufficient to stabilize a double-stranded DNA break or whether both drug sites need to be occupied. An oligonucleotide system was utilized to address this important issue. Results of DNA cleavage and ligation assays support a two-drug model for the action of etoposide against human topoisomerase IIalpha . This model postulates that drug interactions at both scissile bonds are required in order to increase enzyme-mediated double-stranded DNA breaks. Etoposide actions at either of the two scissile bonds appear to be independent of one another, with each individual drug molecule stabilizing a strand-specific nick rather than a double-stranded DNA break. This finding suggests (at least in the presence of drug) that there is little or no communication between the two promoter active sites of topoisomerase II. The two-drug model has implications for cancer chemotherapy, the cellular processing of etoposide-stabilized enzyme-DNA cleavage complexes, and the catalytic mechanism of eukaryotic topoisomerase II.

* This work was supported in part by National Institutes of Health Grants GM33944 (to N. O.) and GM58596 (to A. B. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Trainee under National Institutes of Health Grant 5 T32 CA09385.

** To whom correspondence should be addressed: Dept. of Biochemistry, 654 Robinson Research Bldg., Vanderbilt University School of Medicine, Nashville, TN 37232-0146. Tel.: 615-322-4338; Fax: 615-343-1166; E-mail: osheron@ctrvax.vanderbilt.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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