Accomodation of S-cis-tamoxifen-N-2-guanine adduct within a bent and widened DNA minor groove

The non-steroidal anti-estrogen tamoxifen [TAM] has been in clinical use ov er the last two decades as a potent adjunct chemotherapeutic agent for trea tment of breast cancer. It has also been given prophylactically to women wi th a strong family history of breast cancer. However, tamoxifen treatment h as also been associated with increased endometrial cancer, possibly resulti ng from the reaction of metabolically activated tamoxifen derivatives with cellular DNA. Such DNA adducts can be mutagenic and the activities of isome ric adducts may be conformation-dependent. We therefore investigated the hi gh resolution NMR solution conformation of one covalent adduct (cis-isomer, S-epimer of [TAM]G) formed h-om the reaction of tamoxifen [TAM] to N-2-of guanine in the d(C-[TAM]G-C).d(G-C-G) sequence context at the 11-mer oligon ucleotide duplex level. Our NMR results establish that the S-cis [TAM]G les ion is accomodated within a widened minor groove without disruption of the Watson-Crick [TAM]G.C and flanking Watson-Crick G.C base-pairs. The helix a xis of the bound DNA oligomer is bent by about 30 degrees and is directed a way from the minor groove adduct site. The presence of such a bulky [TAM]G adduct with components of the TAM residue on both the 5'- and the 3'-side o f the modified base could compromise the fidelity of the minor groove polym erase scanning machinery. (C) 2000 Academic Press.