alexa Is Metabolic Activation of Topoisomerase II Poisons Important In The Mechanism Of Cytotoxicity?
ISSN: 2157-7609

Journal of Drug Metabolism & Toxicology
Open Access

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Review Article

Is Metabolic Activation of Topoisomerase II Poisons Important In The Mechanism Of Cytotoxicity?

Birandra K Sinha* and Ronald P Mason

Immunity, Inflammation and Disease Laboratory, National Institutes of Environmental Health Sciences, NIH, Research Triangle, Park, North Carolina, USA

*Corresponding Author:
Birandra K Sinha
Immunity, Inflammation and Disease Laboratory
National Institutes of Environmental Health Sciences
NIH, Research Triangle, Park, North Carolina, USA
Tel: 919-541-4751
E-mail: [email protected]

Received date: June 24, 2015; Accepted date: July 17, 2015; Published date: July 24, 2015

Citation: Birandra KS, Mason RP (2015) Is Metabolic Activation of Topoisomerase II Poisons Important In The Mechanism Of Cytotoxicity?. J Drug Metab Toxicol 6:186. doi: 10.4172/2157-7609.1000186

Copyright: © 2015 Sinha BK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

Abstract

The antitumor drugs doxorubicin and etoposide, a phodophyllotoxin derivative, are clinically active for the treatment of human malignancies. Because of their extreme effectiveness in the clinic, their modes of actions have been the subject of intense research for over several decades both in the laboratory and in the clinic. It has been found that both doxorubicin and etoposide (VP-16) act on topoisomerase II, induce DNA cleavage, and form double-strand breaks, causing tumor cell death. However, both of these drugs also undergo extensive metabolism in tumor cells and in vivo to various reactive intermediates that bind covalently to cellular DNA and proteins. Moreover, both drugs are metabolized to reactive free radicals that induce lipid peroxidation and DNA damage. However, the role of drug activation in the mechanism of cytotoxicity remains poorly defined. In this review, we critically evaluate the significance of metabolic activation of doxorubicin and etoposide in the mechanism of tumor cytotoxicity.

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