Mutagenic potential of alpha-(N2-deoxyguanosinyl)tamoxifen lesions, the major DNA adducts detected in endometrial tissues of patients treated with tamoxifen

Breast cancer patients treated with the antiestrogen tamoxifen (TAM) show a n increased risk of developing endometrial cancer. We have recently detecte d TAM-DNA adducts in endometrium obtained from patients treated with TAM an d identified them as trans- and cis-forms of alpha (N-2-deoxyguanosinyl)tam oxifen (dG-N-2-TAM). To explore the mutagenic properties of these TAM-DNA a dducts, we prepared site-specifically modified oligodeoxynucleotides contai ning a single isomer of dG-N-2-TAM by reacting a 15-mer oligodeoxynucleotid e containing a single dG (5'-TCCTCCTCGCCTCTC) with tamoxifen alpha-sulfate. These modified oligodeoxynucleotides were inserted into a single-stranded shuttle vector to investigate mutagenic specificities of the adducts in sim ian kidney (COS-7) cells. An epimer of dG-N-2-trans-TAM showed targeted mut ations ranging from 0.7 to 1.5%, The other dG-N-2-trans-TAM adduct showed 9 .6% G-->T transversions, accompanied by 2.8% G-->A transitions. Both dG-N-2 -cis-TAM adducts showed similar mutation spectra, where G-->T transversions (11-12%) predominated, along with a small number of G-->A transitions and G-->C transversions. Thus, dG-N-2-TAMs are mutagenic lesions in mammalian t ells. The tamoxifen-DNA adducts detected in patient endometrium may cause m utations and initiate endometrial cancer.