afimoxifene and alpha-acetoxytamoxifen

afimoxifene has been researched along with alpha-acetoxytamoxifen* in 2 studies

Other Studies

2 other study(ies) available for afimoxifene and alpha-acetoxytamoxifen

ArticleYear
DNA adducts formed from 4-hydroxytamoxifen are more mutagenic than those formed by alpha-acetoxytamoxifen in a shuttle vector target gene replicated in human Ad293 cells.
    Biochemistry, 2002, Jul-16, Volume: 41, Issue:28

    The drug tamoxifen, used to treat breast cancer, causes liver cancer in rats and endometrial cancer in women. Tamoxifen forms liver DNA adducts in both short- and long-term dosing of rodents, and DNA adducts have also been reported in tissues of women undergoing tamoxifen therapy. It is not known if the induction of endometrial cancer in women is through these DNA adducts or through the estrogenic nature of the drug. In this study, we have investigated the mutagenicity of two model reactive intermediates of tamoxifen, alpha-acetoxytamoxifen and 4-hydroxytamoxifen quinone methide (4-OHtamQM). These form the same DNA adducts as those found in tamoxifen-treated rats. The two compounds were used to treat the pSP189 plasmid containing the supF gene, which was replicated in Ad293 cells before being screened in indicator bacteria. Plasmid reacted with 4-OHtamQM was more likely to be mutated (2-7-fold increase) than that reacted with alpha-acetoxytamoxifen, despite having a lower level of DNA damage (12-20-fold less), as assayed by (32)P-postlabeling. The two compounds induced statistically different mutation spectra in the supF gene. The majority of mutations in alpha-acetoxytamoxifen-treated plasmid were GC -->TA transversions while GC-->AT transitions were formed in 4-OHtamQM-treated plasmid. 4-OHTamQM-treated DNA induced a larger proportion of multiple mutations and large deletions compared to alpha-acetoxytamoxifen. Sites of mutational hotspots were observed for both compounds. In conclusion, the quantitatively minor DNA adduct of tamoxifen (dG-N(2)-4-hydroxytamoxifen) is more mutagenic than the major tamoxifen DNA adduct (dG-N(2)-tamoxifen).

    Topics: Adenosine Triphosphate; Animals; Base Sequence; Carcinogens; Cell Line; Cell Survival; DNA Adducts; Genes, Suppressor; Genetic Vectors; Humans; Isomerism; Molecular Sequence Data; Plasmids; Rats; Recombinant Proteins; RNA, Transfer; Tamoxifen

2002
Site-specific tamoxifen-DNA adduct formation: lack of correlation with mutational ability in Escherichia coli.
    Biochemistry, 1999, Aug-24, Volume: 38, Issue:34

    We have mapped sites of tamoxifen adduct formation, in the lacI gene using the polymerase STOP assay, following reaction in vitro with alpha-acetoxytamoxifen and horseradish peroxidase (HRP)/H(2)O(2) activated 4-hydroxytamoxifen. For both compounds, most adduct formation occurred on guanines. However, one adenine, within a run of guanines, generated a strong polymerase STOP site with activated 4-hydroxytamoxifen, and a weaker STOP site with alpha-acetoxytamoxifen at the same location. In Escherichia coli the lac I gene reacted with 4-hydroxytamoxifen was more likely to be mutated (2 orders of magnitude) than when reacted with alpha-acetoxytamoxifen, despite the greater DNA adduct formation by alpha-acetoxytamoxifen. This correlates with the greater predicted ability of activated 4-hydroxytamoxifen adducts to disrupt DNA structure than alpha-acetoxytamoxifen adducts. For lac I reacted with activated 4-hydroxytamoxifen, a hot spot of base mutation was located in the region of the only adenosine adduct. No mutational hot spots were observed with alpha-acetoxytamoxifen. Our data clearly shows a lack of correlation between gross adduct number, as assayed by (32)P-postlabeling and mutagenic potential. These data indicate the importance of minor adduct formation in mutagenic potential and further that conclusions regarding the mutagenicity of a chemical may not be reliably derived from the gross determination of adduct formation.

    Topics: Bacteriophage T4; Base Sequence; DNA Adducts; DNA Mutational Analysis; DNA Polymerase I; DNA-Directed DNA Polymerase; Escherichia coli; Lac Operon; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutagens; Phosphorus Radioisotopes; Tamoxifen; Viral Proteins

1999