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Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines

Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects. However, this is not the case for the anthracycline class of chemotherapy...

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Autores principales: Edwardson, Derek W., Narendrula, Rashmi, Chewchuk, Simon, Mispel-Beyer, Kyle, Mapletoft, Jonathan P.J., Parissenti, Amadeo M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bentham Science Publishers 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398089/
https://www.ncbi.nlm.nih.gov/pubmed/26321196
http://dx.doi.org/10.2174/1389200216888150915112039
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author Edwardson, Derek W.
Narendrula, Rashmi
Chewchuk, Simon
Mispel-Beyer, Kyle
Mapletoft, Jonathan P.J.
Parissenti, Amadeo M.
author_facet Edwardson, Derek W.
Narendrula, Rashmi
Chewchuk, Simon
Mispel-Beyer, Kyle
Mapletoft, Jonathan P.J.
Parissenti, Amadeo M.
author_sort Edwardson, Derek W.
collection PubMed
description Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects. However, this is not the case for the anthracycline class of chemotherapy drugs. This review describes the various enzymes involved in the one electron (semi-quinone) or two electron (hydroxylation) reduction of anthracyclines, or in their reductive deglycosidation into deoxyaglycones. The effects of these reductions on drug anti-tumor efficacy and toxic side effects are also discussed. Current evidence suggests that the one electron reduction of anthracyclines augments both their tumor toxicity and their toxicity towards the host, in particular their cardiotoxicity. In contrast, the two electron reduction (hydroxylation) of anthracyclines strongly reduces their ability to kill tumor cells, while augmenting cardiotoxicity through their accumulation within cardiomyocytes and their direct effects on excitation/contraction coupling within the myocytes. The reductive deglycosidation of anthracyclines appears to inactivate the drug and only occurs under rare, anaerobic conditions. This knowledge has resulted in the identification of important new approaches to improve the therapeutic index of anthracyclines, in particular by inhibiting their cardiotoxocity. The true utility of these approaches in the management of cancer patients undergoing anthracycline-based chemotherapy remains unclear, although one such agent (the iron chelator dexrazoxane) has recently been approved for clinical use.
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spelling pubmed-53980892017-05-12 Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines Edwardson, Derek W. Narendrula, Rashmi Chewchuk, Simon Mispel-Beyer, Kyle Mapletoft, Jonathan P.J. Parissenti, Amadeo M. Curr Drug Metab Article Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects. However, this is not the case for the anthracycline class of chemotherapy drugs. This review describes the various enzymes involved in the one electron (semi-quinone) or two electron (hydroxylation) reduction of anthracyclines, or in their reductive deglycosidation into deoxyaglycones. The effects of these reductions on drug anti-tumor efficacy and toxic side effects are also discussed. Current evidence suggests that the one electron reduction of anthracyclines augments both their tumor toxicity and their toxicity towards the host, in particular their cardiotoxicity. In contrast, the two electron reduction (hydroxylation) of anthracyclines strongly reduces their ability to kill tumor cells, while augmenting cardiotoxicity through their accumulation within cardiomyocytes and their direct effects on excitation/contraction coupling within the myocytes. The reductive deglycosidation of anthracyclines appears to inactivate the drug and only occurs under rare, anaerobic conditions. This knowledge has resulted in the identification of important new approaches to improve the therapeutic index of anthracyclines, in particular by inhibiting their cardiotoxocity. The true utility of these approaches in the management of cancer patients undergoing anthracycline-based chemotherapy remains unclear, although one such agent (the iron chelator dexrazoxane) has recently been approved for clinical use. Bentham Science Publishers 2015-07 2015-07 /pmc/articles/PMC5398089/ /pubmed/26321196 http://dx.doi.org/10.2174/1389200216888150915112039 Text en © 2015 Bentham Science Publishers https://creativecommons.org/licenses/by-nc/4.0/legalcode This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
spellingShingle Article
Edwardson, Derek W.
Narendrula, Rashmi
Chewchuk, Simon
Mispel-Beyer, Kyle
Mapletoft, Jonathan P.J.
Parissenti, Amadeo M.
Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines
title Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines
title_full Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines
title_fullStr Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines
title_full_unstemmed Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines
title_short Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines
title_sort role of drug metabolism in the cytotoxicity and clinical efficacy of anthracyclines
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398089/
https://www.ncbi.nlm.nih.gov/pubmed/26321196
http://dx.doi.org/10.2174/1389200216888150915112039
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