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UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer

SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1...

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Autores principales: Marcuello, E, Altés, A, Menoyo, A, del Rio, E, Gómez-Pardo, M, Baiget, M
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2004
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364770/
https://www.ncbi.nlm.nih.gov/pubmed/15280927
http://dx.doi.org/10.1038/sj.bjc.6602042
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author Marcuello, E
Altés, A
Menoyo, A
del Rio, E
Gómez-Pardo, M
Baiget, M
author_facet Marcuello, E
Altés, A
Menoyo, A
del Rio, E
Gómez-Pardo, M
Baiget, M
author_sort Marcuello, E
collection PubMed
description SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P=0.005). These results maintained the statistical significance in logistic regression analysis (P=0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1(*)28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1(*)28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1(*)28 polymorphism showed a trend to a poorer OS (P=0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1(*)28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype.
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spelling pubmed-23647702009-09-10 UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer Marcuello, E Altés, A Menoyo, A del Rio, E Gómez-Pardo, M Baiget, M Br J Cancer Clinical SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P=0.005). These results maintained the statistical significance in logistic regression analysis (P=0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1(*)28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1(*)28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1(*)28 polymorphism showed a trend to a poorer OS (P=0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1(*)28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype. Nature Publishing Group 2004-08-16 2004-07-27 /pmc/articles/PMC2364770/ /pubmed/15280927 http://dx.doi.org/10.1038/sj.bjc.6602042 Text en Copyright © 2004 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits 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 license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license 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 license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Clinical
Marcuello, E
Altés, A
Menoyo, A
del Rio, E
Gómez-Pardo, M
Baiget, M
UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer
title UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer
title_full UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer
title_fullStr UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer
title_full_unstemmed UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer
title_short UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer
title_sort ugt1a1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer
topic Clinical
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364770/
https://www.ncbi.nlm.nih.gov/pubmed/15280927
http://dx.doi.org/10.1038/sj.bjc.6602042
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