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|Title:||Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots|
McLuckie, Keith I. E.
Lewis, Paul D.
Farmer, Peter B.
|Publisher:||Oxford University Press|
|Citation:||Nucleic Acids Research, 2008, 36 (18), pp. 5933-5945|
|Abstract:||Tamoxifen elevates the risk of endometrial tumours in women and α-(N²-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-N²-tamoxifen and dG-N²-4-hydroxytamoxifen respectively. Plasmids were replicated in Ishikawa cells then screened in E.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-N²-tam adduct formation in the p53 gene is not a prerequisite for endometrial cancer initiation in women.|
|Rights:||© 2008 The Author(s) 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.|
|Description:||Post-print replaced by version of record 2016-03-09|
|Appears in Collections:||Published Articles, Dept. of Cancer Studies and Molecular Medicine|
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