Comparison of Tamoxifen (TAM)-DNA Adduct Levels in Uterine Tissue from Different Species of Monkeys and Humans Exposed to TAM

Tamoxifen (TAM) is a selective estrogen receptor modulator used worldwide for adjuvant therapy and chemoprevention of breast cancer. Women receiving TAM have an increased risk of endometrial and myometrial cancer, which may be due to genotoxicity and/or receptor-related mechanisms. Controversy has surrounded the issue of whether or not TAM-DNA adducts form in humans, and we have examined this question in uterine tissues of aging Erythrocebus patas (patas) and Macaca fascicularis (macaque) monkeys given oral TAM dosing, as well as in endometrial and myometrial samples from women given TAM therapy.  DNA adducts were determined by TAM-DNA chemiluminescence immunoassay (CIA) using an antiserum elicited against DNA modified with (E)-α-(deoxyguanosin-N²-yl)-tamoxifen (dG-TAM). Of 5 female patas, 2 were unexposed and 3 were given oral dosing with 1.7 mgTAM/kg bw/day for 3 months. Macaques were either exposed for 4 months with 1.3 mg TAM/kg bw/day (n=4) or unexposed (n=6). Normal and tumor uterine samples from women who received 20 mg/day (n=8) were analyzed along with samples (n=8) from unexposed women. We found 35.1±11.7 adducts /10⁸nucleotides in the patas monkeys, 17±3.6 adducts /10⁸nucleotides in the macaques, and 3.2-16.5 adducts /10⁸ nucleotides in the women.  None of the tissues from unexposed monkeys or women showed evidence of TAM-DNA adduct formation. Whatever the role played by TAM-DNA adduct formation in human endometrial cancer, these data demonstrate that TAM-DNA adducts are formed in monkey uterus as well as human endometrium, myometrium and endometrial tumor.