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Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1
BACKGROUND AND OBJECTIVE: Side effects of irinotecan treatment can be dose limiting and may impair quality of life. In this study, we investigated the correlation between single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in the irinotecan metabolism and transport, outside UGT...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582127/ https://www.ncbi.nlm.nih.gov/pubmed/37715926 http://dx.doi.org/10.1007/s40262-023-01279-7 |
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author | de With, Mirjam van Doorn, Leni Kloet, Esmay van Veggel, Anne Matic, Maja de Neijs, Micha J. Oomen - de Hoop, Esther van Meerten, Esther van Schaik, Ron H. N. Mathijssen, Ron H. J. Bins, Sander |
author_facet | de With, Mirjam van Doorn, Leni Kloet, Esmay van Veggel, Anne Matic, Maja de Neijs, Micha J. Oomen - de Hoop, Esther van Meerten, Esther van Schaik, Ron H. N. Mathijssen, Ron H. J. Bins, Sander |
author_sort | de With, Mirjam |
collection | PubMed |
description | BACKGROUND AND OBJECTIVE: Side effects of irinotecan treatment can be dose limiting and may impair quality of life. In this study, we investigated the correlation between single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in the irinotecan metabolism and transport, outside UGT1A1, and irinotecan-related toxicity. We focused on carboxylesterases, which are involved in formation of the active metabolite SN-38 and on drug transporters. METHODS: Patients who provided written informed consent at the Erasmus Medical Center Cancer Institute to the Code Geno study (local protocol: MEC02-1002) or the IRI28-study (NTR-6612) were enrolled in the study and were genotyped for 15 SNPs in the genes CES1, CES2, SLCO1B1, ABCB1, ABCC2, and ABCG2. RESULTS: From 299 evaluable patients, 86 patients (28.8%) developed severe irinotecan-related toxicity. A significantly higher risk of toxicity was seen in ABCG2 c.421C>A variant allele carriers (P = 0.030, OR 1.88, 95% CI 1.06–3.34). Higher age was associated with all grade diarrhea (P = 0.041, OR 1.03, 95% CI 1.00–1.06). In addition, CES1 c.1165-41C>T and CES1 n.95346T>C variant allele carriers had a lower risk of all-grade thrombocytopenia (P = 0.024, OR 0.42, 95% CI 0.20–0.90 and P = 0.018, OR 0.23, 95% CI 0.08–0.79, respectively). CONCLUSION: Our study indicates that ABCG2 and CES1 SNPs might be used as predictive markers for irinotecan-induced toxicity. |
format | Online Article Text |
id | pubmed-10582127 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-105821272023-10-19 Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1 de With, Mirjam van Doorn, Leni Kloet, Esmay van Veggel, Anne Matic, Maja de Neijs, Micha J. Oomen - de Hoop, Esther van Meerten, Esther van Schaik, Ron H. N. Mathijssen, Ron H. J. Bins, Sander Clin Pharmacokinet Original Research Article BACKGROUND AND OBJECTIVE: Side effects of irinotecan treatment can be dose limiting and may impair quality of life. In this study, we investigated the correlation between single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in the irinotecan metabolism and transport, outside UGT1A1, and irinotecan-related toxicity. We focused on carboxylesterases, which are involved in formation of the active metabolite SN-38 and on drug transporters. METHODS: Patients who provided written informed consent at the Erasmus Medical Center Cancer Institute to the Code Geno study (local protocol: MEC02-1002) or the IRI28-study (NTR-6612) were enrolled in the study and were genotyped for 15 SNPs in the genes CES1, CES2, SLCO1B1, ABCB1, ABCC2, and ABCG2. RESULTS: From 299 evaluable patients, 86 patients (28.8%) developed severe irinotecan-related toxicity. A significantly higher risk of toxicity was seen in ABCG2 c.421C>A variant allele carriers (P = 0.030, OR 1.88, 95% CI 1.06–3.34). Higher age was associated with all grade diarrhea (P = 0.041, OR 1.03, 95% CI 1.00–1.06). In addition, CES1 c.1165-41C>T and CES1 n.95346T>C variant allele carriers had a lower risk of all-grade thrombocytopenia (P = 0.024, OR 0.42, 95% CI 0.20–0.90 and P = 0.018, OR 0.23, 95% CI 0.08–0.79, respectively). CONCLUSION: Our study indicates that ABCG2 and CES1 SNPs might be used as predictive markers for irinotecan-induced toxicity. Springer International Publishing 2023-09-16 2023 /pmc/articles/PMC10582127/ /pubmed/37715926 http://dx.doi.org/10.1007/s40262-023-01279-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by-nc/4.0/Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Original Research Article de With, Mirjam van Doorn, Leni Kloet, Esmay van Veggel, Anne Matic, Maja de Neijs, Micha J. Oomen - de Hoop, Esther van Meerten, Esther van Schaik, Ron H. N. Mathijssen, Ron H. J. Bins, Sander Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1 |
title | Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1 |
title_full | Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1 |
title_fullStr | Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1 |
title_full_unstemmed | Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1 |
title_short | Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1 |
title_sort | irinotecan-induced toxicity: a pharmacogenetic study beyond ugt1a1 |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582127/ https://www.ncbi.nlm.nih.gov/pubmed/37715926 http://dx.doi.org/10.1007/s40262-023-01279-7 |
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