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Research ArticleArticle

The Ortho-Quinone Metabolite of the Anticancer Drug Etoposide (VP-16) Is a Potent Inhibitor of the Topoisomerase II/DNA Cleavable Complex

Tsvetan G. Gantchev and Darel J. Hunting
Molecular Pharmacology March 1998, 53 (3) 422-428; DOI: https://doi.org/10.1124/mol.53.3.422
Tsvetan G. Gantchev
Medical Research Council Group in the Radiation Sciences, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada
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Darel J. Hunting
Medical Research Council Group in the Radiation Sciences, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada
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Abstract

Epipodophyllotoxin derivatives, such as etoposide (VP-16), constitute an important class of anticancer agents, the major cytotoxic effects of which are associated with trapping of the topoisomerase II/DNA cleavable complex and formation of protein-DNA cross-links and nicked DNA. VP-16, however, can be metabolized to several highly reactive products, including an ortho-quinone (VPQ). The inhibitory activity of VPQ against purified human topoisomerase II processing of supercoiled DNA was studied and compared with that of the parent compound, VP-16. Our results show that VPQ is a powerful inhibitor of topoisomerase II, which prevents DNA strand passage in the presence of ATP. As with VP-16, trapping of the cleavable complex is highly reversible upon removal of divalent ions, which indicating that VPQ alters the cleavage-reunion equilibrium of topoisomerase II and DNA mainly by noncovalent interactions, as does the parent compound. However, we observed several differences between the effects induced by VP-16 and VPQ, including a strong inhibition of the second DNA strand religation, which implies the involvement of additional (asymmetric) mode(s) of interactions of the VPQ, possibly by interference with ATP binding by the homodimeric enzyme, and/or involving covalent interactions. Reduced or oxidized glutathione prevented trapping of the topoisomerase/DNA cleavable complex by VPQ, but not by VP-16, probably by forming covalent adducts with the former.

Footnotes

    • Received September 5, 1997.
    • Accepted November 12, 1997.
  • Send reprint requests to: Dr. Tsvetan G. Gantchev, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada. E-mail: gantchev{at}courrier.usherb.ca

  • This work was supported by the Medical Research Council of Canada.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (3)
Molecular Pharmacology
Vol. 53, Issue 3
1 Mar 1998
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Research ArticleArticle

The Ortho-Quinone Metabolite of the Anticancer Drug Etoposide (VP-16) Is a Potent Inhibitor of the Topoisomerase II/DNA Cleavable Complex

Tsvetan G. Gantchev and Darel J. Hunting
Molecular Pharmacology March 1, 1998, 53 (3) 422-428; DOI: https://doi.org/10.1124/mol.53.3.422

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Research ArticleArticle

The Ortho-Quinone Metabolite of the Anticancer Drug Etoposide (VP-16) Is a Potent Inhibitor of the Topoisomerase II/DNA Cleavable Complex

Tsvetan G. Gantchev and Darel J. Hunting
Molecular Pharmacology March 1, 1998, 53 (3) 422-428; DOI: https://doi.org/10.1124/mol.53.3.422
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