Tamoxifen Induced DNA Adduct Formation

Shinya Shibutani, Ph.D.
SUNY Stony Brook
R01ES09418

Background: Tamoxifen is widely used as an antiestrogen therapy for breast cancer patients and as a chemopreventive agent for healthy women at high risk for breast cancer. However, tamoxifen use has been associated with increased incidence of endometrial cancer. It has been characterized as a human carcinogen by the International Agency for Research on Cancer.

Oral dosing of tamoxifen causes liver cancer in laboratory animals. Analysis of liver tumors identified DNA adduct formation induced by the activated metabolites of the drug. Other researchers have tried to detect DNA adduct formation in breast cancer patients receiving tamoxifen; however, results have been mixed and inconclusive.

Advance: Using a newly developed modification of a high performance liquid chromatography laboratory analysis, these investigators report the presence of significant quantities of tamoxifen-induced DNA adducts in the livers, uteri, ovaries, and brains of cynomolgus monkeys orally treated with six times the human equivalent dose of tamoxifen for thirty days.

Implication: These results, though preliminary, suggest that women receiving tamoxifen may form DNA damage in many organs including the uterus and ovary. Additional studies are necessary to determine the genotoxic risk of tamoxifen in humans. These results could have important implications in the use of tamoxifen in breast cancer patients and especially in healthy women taking the drug as a chemopreventive agent.

Citation: Shibutani S, Susuki N, Laxmi YR, Schild LJ, Divi RL, Grollman AP, and Poirier MC. Identification of tamoxifen-DNA adducts in monkeys treated with tamoxifen. Cancer Res. 2003 Aug 1; 63(15):4402-6.