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Defining functional drug-interaction domains on topoisomerase II by exploiting mechanistic differences between drug classes

  • Session 1: Topoisomerase Basic Science
  • Drug-Interaction Domains, Topoisomerase II, DNA Strand-Break, DNA Strand-Passage
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Topoisomerase II is the primary cellular target for a variety of antineoplastic drugs that are active against human cancers. These drugs exert their cytotoxic effects by stabilizing covalent topoisomerase II-cleaved DNA complexes that are fleeting intermediates in the catalytic cycle of the enzyme. Despite this common feature of drug action, a number of mechanistic differences between drug classes have been described. These mechanistic differences (including effects on DNA cleavage/religation, DNA strand passage, and adenosine triphosphate hydrolysis) were used as the basis for a series of competition experiments to determine whether different compounds share a common site of action on topoisomerase II or interact at distinct sites. Results of the present study strongly suggest that at least four structurally disparate antineoplastic drugs, etoposide, amsacrine, genistein, and the quinolone CP-115,953, share an overlapping interaction domain on the enzyme.

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Abbreviations

SDS:

sodium dodecyl sulfate

APP(NH)P:

adenyl-5′-yl-β,γ-imidodiphosphate

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Author notes

  1. Anita H. Corbett

    Present address: Department of Cellular and Molecular Biology, Dana Farber Cancer Institute, Harvard University School of Medicine, 44 Binney Street, 02115, Boston, MA, USA

Authors and Affiliations

  1. Department of Biochemistry, Vanderbilt University School of Medicine, 654 Medical Research Building, 37232-0146, Nashville, TN, USA

    Neil Osheroff, Anita H. Corbett, Sarah H. Elsea & Majken Westergaard

Authors
  1. Neil Osheroff
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  2. Anita H. Corbett
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  3. Sarah H. Elsea
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  4. Majken Westergaard
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Additional information

This study was supported by grants GM33944 and CA09582 from the National Institutes of Health and by Research Grant NP-812 and Faculty Research Award FRA-370 from the American Cancer Society

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Osheroff, N., Corbett, A.H., Elsea, S.H. et al. Defining functional drug-interaction domains on topoisomerase II by exploiting mechanistic differences between drug classes. Cancer Chemother. Pharmacol. 34 (Suppl 1), S19–S25 (1994). https://doi.org/10.1007/BF00684859

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