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Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots
Tamoxifen elevates the risk of endometrial tumours in women and α-(N(2)-deoxyguanosinyl)-tamoxifen adducts are reportedly present in endometrial tissue of patients undergoing therapy. Given the widespread use of tamoxifen there is considerable interest in elucidating the mechanisms underlying treatm...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Oxford University Press
2008
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566887/ https://www.ncbi.nlm.nih.gov/pubmed/18805907 http://dx.doi.org/10.1093/nar/gkn586 |
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author | Liapis, Evagelos McLuckie, Keith I.E. Lewis, Paul D. Farmer, Peter B. Brown, Karen |
author_facet | Liapis, Evagelos McLuckie, Keith I.E. Lewis, Paul D. Farmer, Peter B. Brown, Karen |
author_sort | Liapis, Evagelos |
collection | PubMed |
description | Tamoxifen elevates the risk of endometrial tumours in women and α-(N(2)-deoxyguanosinyl)-tamoxifen adducts are reportedly present in endometrial tissue of patients undergoing therapy. Given the widespread use of tamoxifen there is considerable interest in elucidating the mechanisms underlying treatment-associated cancer. Using a combined experimental and multivariate statistical approach we have examined the mutagenicity and potential consequences of adduct formation by reactive intermediates in target uterine cells. pSP189 plasmid containing the supF gene was incubated with α-acetoxytamoxifen or 4-hydroxytamoxifen quinone methide (4-OHtamQM) to generate dG-N(2)-tamoxifen and dG-N(2)-4-hydroxytamoxifen, respectively. Plasmids were replicated in Ishikawa cells then screened in Escherichia coli. Treatment with both α-acetoxytamoxifen and 4-OHtamQM caused a dose-related increase in adduct levels, resulting in a damage-dependent increase in mutation frequency for α-acetoxytamoxifen; 4-OHtamQM had no apparent effect. Only α-acetoxytamoxifen generated statistically different supF mutation spectra relative to the spontaneous pattern, with most mutations being GC→TA transversions. Application of the LwPy53 algorithm to the α-acetoxytamoxifen spectrum predicted strong GC→TA hotspots at codons 244 and 273. These signature alterations do not correlate with current reports of the mutations observed in endometrial carcinomas from treated women, suggesting that dG-N(2)-tam adduct formation in the p53 gene is not a prerequisite for endometrial cancer initiation in women. |
format | Text |
id | pubmed-2566887 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-25668872008-10-17 Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots Liapis, Evagelos McLuckie, Keith I.E. Lewis, Paul D. Farmer, Peter B. Brown, Karen Nucleic Acids Res Genome Integrity, Repair and Replication Tamoxifen elevates the risk of endometrial tumours in women and α-(N(2)-deoxyguanosinyl)-tamoxifen adducts are reportedly present in endometrial tissue of patients undergoing therapy. Given the widespread use of tamoxifen there is considerable interest in elucidating the mechanisms underlying treatment-associated cancer. Using a combined experimental and multivariate statistical approach we have examined the mutagenicity and potential consequences of adduct formation by reactive intermediates in target uterine cells. pSP189 plasmid containing the supF gene was incubated with α-acetoxytamoxifen or 4-hydroxytamoxifen quinone methide (4-OHtamQM) to generate dG-N(2)-tamoxifen and dG-N(2)-4-hydroxytamoxifen, respectively. Plasmids were replicated in Ishikawa cells then screened in Escherichia coli. Treatment with both α-acetoxytamoxifen and 4-OHtamQM caused a dose-related increase in adduct levels, resulting in a damage-dependent increase in mutation frequency for α-acetoxytamoxifen; 4-OHtamQM had no apparent effect. Only α-acetoxytamoxifen generated statistically different supF mutation spectra relative to the spontaneous pattern, with most mutations being GC→TA transversions. Application of the LwPy53 algorithm to the α-acetoxytamoxifen spectrum predicted strong GC→TA hotspots at codons 244 and 273. These signature alterations do not correlate with current reports of the mutations observed in endometrial carcinomas from treated women, suggesting that dG-N(2)-tam adduct formation in the p53 gene is not a prerequisite for endometrial cancer initiation in women. Oxford University Press 2008-10 2008-09-19 /pmc/articles/PMC2566887/ /pubmed/18805907 http://dx.doi.org/10.1093/nar/gkn586 Text en © 2008 The Author(s) http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Genome Integrity, Repair and Replication Liapis, Evagelos McLuckie, Keith I.E. Lewis, Paul D. Farmer, Peter B. Brown, Karen Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots |
title | Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots |
title_full | Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots |
title_fullStr | Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots |
title_full_unstemmed | Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots |
title_short | Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots |
title_sort | mutagenicity of tamoxifen dna adducts in human endometrial cells and in silico prediction of p53 mutation hotspots |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566887/ https://www.ncbi.nlm.nih.gov/pubmed/18805907 http://dx.doi.org/10.1093/nar/gkn586 |
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