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Limitations and Off-Target Effects of Tryptophan-Related IDO Inhibitors in Cancer Treatment
Immunooncology is still a growing area in cancer therapy. Drugs within this therapeutic approach do not directly target/attack the tumor but interfere with immune checkpoints and target or reprogram key metabolic pathways critical for anti-cancer immune defense. Indolamine 2,3-dioxygenase 1 (IDO1) a...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682646/ https://www.ncbi.nlm.nih.gov/pubmed/31417567 http://dx.doi.org/10.3389/fimmu.2019.01801 |
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author | Günther, Juliane Däbritz, Jan Wirthgen, Elisa |
author_facet | Günther, Juliane Däbritz, Jan Wirthgen, Elisa |
author_sort | Günther, Juliane |
collection | PubMed |
description | Immunooncology is still a growing area in cancer therapy. Drugs within this therapeutic approach do not directly target/attack the tumor but interfere with immune checkpoints and target or reprogram key metabolic pathways critical for anti-cancer immune defense. Indolamine 2,3-dioxygenase 1 (IDO1) and the tryptophan (TRP)-kynurenine pathway were identified as critical mechanisms in cancer immune escape and their inhibition as an approach with promising therapeutic potential. Particularly, a multitude of IDO1 inhibiting tryptophan analogs are widely applied in several clinical trials. However, this therapy results in a variety of implications for the patient's physiology. This is not only due to the inhibition of an enzyme important in almost every organ and tissue in the body but also because of the general nature of the inhibitor as an analog of a proteinogenic amino acid as well as the initiation of cellular detoxification known to affect inflammatory pathways. In this review we provide a deeper insight into the physiological consequences of an IDO1 inhibiting therapy based on TRP related molecules. We discuss potential side and off-target effects that contribute to the interpretation of unexpected positive as well as negative results of ongoing or discontinued clinical studies while we also highlight the potential of these inhibitors independent of the IDO1 signaling pathway. |
format | Online Article Text |
id | pubmed-6682646 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-66826462019-08-15 Limitations and Off-Target Effects of Tryptophan-Related IDO Inhibitors in Cancer Treatment Günther, Juliane Däbritz, Jan Wirthgen, Elisa Front Immunol Immunology Immunooncology is still a growing area in cancer therapy. Drugs within this therapeutic approach do not directly target/attack the tumor but interfere with immune checkpoints and target or reprogram key metabolic pathways critical for anti-cancer immune defense. Indolamine 2,3-dioxygenase 1 (IDO1) and the tryptophan (TRP)-kynurenine pathway were identified as critical mechanisms in cancer immune escape and their inhibition as an approach with promising therapeutic potential. Particularly, a multitude of IDO1 inhibiting tryptophan analogs are widely applied in several clinical trials. However, this therapy results in a variety of implications for the patient's physiology. This is not only due to the inhibition of an enzyme important in almost every organ and tissue in the body but also because of the general nature of the inhibitor as an analog of a proteinogenic amino acid as well as the initiation of cellular detoxification known to affect inflammatory pathways. In this review we provide a deeper insight into the physiological consequences of an IDO1 inhibiting therapy based on TRP related molecules. We discuss potential side and off-target effects that contribute to the interpretation of unexpected positive as well as negative results of ongoing or discontinued clinical studies while we also highlight the potential of these inhibitors independent of the IDO1 signaling pathway. Frontiers Media S.A. 2019-07-30 /pmc/articles/PMC6682646/ /pubmed/31417567 http://dx.doi.org/10.3389/fimmu.2019.01801 Text en Copyright © 2019 Günther, Däbritz and Wirthgen. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Günther, Juliane Däbritz, Jan Wirthgen, Elisa Limitations and Off-Target Effects of Tryptophan-Related IDO Inhibitors in Cancer Treatment |
title | Limitations and Off-Target Effects of Tryptophan-Related IDO Inhibitors in Cancer Treatment |
title_full | Limitations and Off-Target Effects of Tryptophan-Related IDO Inhibitors in Cancer Treatment |
title_fullStr | Limitations and Off-Target Effects of Tryptophan-Related IDO Inhibitors in Cancer Treatment |
title_full_unstemmed | Limitations and Off-Target Effects of Tryptophan-Related IDO Inhibitors in Cancer Treatment |
title_short | Limitations and Off-Target Effects of Tryptophan-Related IDO Inhibitors in Cancer Treatment |
title_sort | limitations and off-target effects of tryptophan-related ido inhibitors in cancer treatment |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682646/ https://www.ncbi.nlm.nih.gov/pubmed/31417567 http://dx.doi.org/10.3389/fimmu.2019.01801 |
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