Miscoding Potential of Tamoxifen-Derived DNA Adducts: α-(N2-Deoxyguanosinyl)tamoxifen

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Abstract
The treatment of tamoxifen, widely used as adjuvant chemotherapy for breast cancer, increases significantly the risk of developing endometrial cancer. The miscoding properties of tamoxifen-derived DNA adducts, α-(N2-deoxyguanosinyl)tamoxifens (dG-N2-tamoxifen), have been explored, using an in vitro experimental system to quantify base substitutions and deletions. Site-specifically modified oligodeoxynucleotides containing an epimer of trans- and cis-forms of dG-N2-tamoxifens were prepared postsynthetically and used as templates in primer extension reactions catalyzed by mammalian DNA polymerases α, β, and δ. Pol α catalyzed incorporation of dCMP and dAMP opposite all four stereoisomers of dG-N2-tamoxifen, accompanied by lesser amounts of dGMP. In contrast, pol δ catalyzed preferential incorporation of dCMP, a correct base, opposite the lesions; one of the trans-forms of dG-N2-tamoxifens only promoted incorporation of dTMP. Using pol β, preferential incorporation of dCMP, along with small amounts of incorporation of dAMP and dGMP, was detected. One- and two base deletions were also observed with pol α and pol β. The miscoding specificities and frequencies of dG-N2-tamoxifens varied depending on the DNA polymerase used. In addition, with pol α and pol β, large amounts of 5-base deletions were preferentially formed at the cis-forms of dG-N2-tamoxifen, but not at the trans-forms of dG-N2-tamoxifen. We conclude that dG-N2-tamoxifen adducts have high miscoding potentials.