| Abstract | The anti-oestrogen tamoxifen is very effective in the treatment and prevention of breast cancer. Tamoxifen is not a pure antagonist, but possesses weak oestrogenic activity that may contribute to a slightly increased risk of endometrial cancer. Whilst this can be incorporated into risk-benefit analysis for the use of the drug, residual concerns exist over the exact mechanism of formation of these tumours. Tamoxifen is a potent hepatocarcinogen in the rat, probably via a genotoxic mechanism. Whilst tamoxifen does not appear to cause liver tumours in humans, DNA adducts have been found in endometrial tissue of women receiving the drug. Hence, there is still a need to establish the mechanism of formation of these tumours. We have therefore determined the molecular nature of mutations induced in vitro by alpha-hydroxytamoxifen, the putative proximate genotoxic metabolite, in a mammalian cell line (V79-rHSTa) with stable expression of rat hydroxysteroid sulfotransferase a, which catalyses the further metabolism of alpha-hydroxytamoxifen to its ultimate genotoxic product. DNA sequence alterations were examined at the Hprt gene in 50 mutant clones. Simple base substitutions, mainly GC-->TA transversions, predominated. However, single G:C base pair deletions and partial/complete exon skippings were also observed. All but one of the mutations involved guanine bases on the non-transcribed strand, probably indicating preferential repair of alpha-hydroxytamoxifen-induced guanine adducts from the transcribed strand. Nearest neighbour analysis of the mutations (on the non-transcribed strand) indicated that thymines (20/40) followed by guanines (13/40) were the most frequent 5' neighbours, with adenines or guanines the most frequent 3' neighbours. Many of the mutations occurred at TTGA/G sequences. Three mutational hot spots accounted for 11 GC-->TA transversions and another site for two single G:C base pair deletions. A search for these characteristic mutations in tumour-related genes of treated rats and humans should help in understanding the mechanism(s) of tamoxifen-induced carcinogenicity. |
| Authors | Masoud Yadollahi-Farsani, Donald S Davies, Alan R Boobis
(Affiliation: Department of Health Toxicology Unit, Section on Clinical Pharmacology, Division of Medicine, Imperial College, London W12 0NN, UK. y.farsani at ic.ac.uk)
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| Journal | Carcinogenesis
(Carcinogenesis)
Vol. 23
Issue 11
Pg. 1947-52
(Nov 2002)
ISSN: 0143-3334 England |
| PMID | 12419845
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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| Chemical References |
- DNA Adducts
- Mutagens
- Recombinant Fusion Proteins
- alpha-hydroxytamoxifen
- Tamoxifen
- Guanine
- Hypoxanthine Phosphoribosyltransferase
- Sulfotransferases
- alcohol sulfotransferase
|
| Topics |
- Animals
- Base Pairing
(drug effects)
- Biotransformation
- Clone Cells
(drug effects)
- Cricetinae
- DNA Adducts
- DNA Damage
- DNA Mutational Analysis
- Genes
(drug effects)
- Guanine
(chemistry)
- Humans
- Hypoxanthine Phosphoribosyltransferase
(genetics)
- Mutagenesis
- Mutagens
(pharmacology)
- Point Mutation
- Rats
- Recombinant Fusion Proteins
(metabolism)
- Species Specificity
- Sulfotransferases
(genetics, metabolism)
- Tamoxifen
(analogs & derivatives, pharmacology)
- Transcription, Genetic
|
