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[Cancer Research 59, 2091-2095, May 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 2091-2095, May 1, 1999]
© 1999 American Association for Cancer Research

Carcinogenesis

Mutagenic Potential of {alpha}-(N2-Deoxyguanosinyl)tamoxifen Lesions, the Major DNA Adducts Detected in Endometrial Tissues of Patients Treated with Tamoxifen1

Isamu Terashima, Naomi Suzuki and Shinya Shibutani2

Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651

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.




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Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 1999 by the American Association for Cancer Research.