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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Bentham Science Publishers
2015
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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. |
format | Online Article Text |
id | pubmed-5398089 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Bentham Science Publishers |
record_format | MEDLINE/PubMed |
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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