title: Mutagenic potential of alpha-(N2-deoxyguanosinyl)tamoxifen lesions, the major DNA adducts detected in endometrial tissues of patients treated with tamoxifen.
abstract: Breast cancer patients treated with the antiestrogen tamoxifen (TAM) show an increased risk of developing endometrial cancer. We have recently detected TAM-DNA adducts in endometrium obtained from patients treated with TAM and identified them as trans- and cis-forms of alpha-(N2-deoxyguanosinyl)tamoxifen (dG-N2-TAM). To explore the mutagenic properties of these TAM-DNA adducts, we prepared site-specifically modified oligodeoxynucleotides containing a single isomer of dG-N2-TAM by reacting a 15-mer oligodeoxynucleotide 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 simian kidney (COS-7) cells. An epimer of dG-N2-trans-TAM showed targeted mutations ranging from 0.7 to 1.5%. The other dG-N2-trans-TAM adduct showed 9.6% G-->T transversions, accompanied by 2.8% G-->A transitions. Both dG-N2-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-N2-TAMs are mutagenic lesions in mammalian cells. The tamoxifen-DNA adducts detected in patient endometrium may cause mutations and initiate endometrial cancer.
authors.affiliation: Department of Pharmacological Sciences, State University of New York at Stony Brook, 11794-8651, USA.
authors.forename: I
authors.initials: I
authors.lastname: Terashima
authors.forename: N
authors.initials: N
authors.lastname: Suzuki
authors.forename: S
authors.initials: S
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects* / Q000494:pharmacology; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy; D019556:COS Cells; D018736:DNA Adducts / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity*; D004717:Endometrium / Q000737:chemistry*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007536:Isomerism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000235:genetics; D017354:Point Mutation; D013629:Tamoxifen / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018736:DNA Adducts; D009838:Oligodeoxyribonucleotides; C105083:alpha-(N(2)-deoxyguanosinyl)tamoxifen; D013629:Tamoxifen