Tamoxifen Suppresses Tumor Promoter-induced Hydrogen Peroxide Formation by Human Neutrophils1

TraiH-tamoxifen (TAM) has been used successfully in therapy for estrogen-dependent human breast tumors and prevention of their recur rence. The mechanism of this prevention was thought to be due to the interference of TAM with estrogen promotion. TAM has a wider anticarcinogenic action that is similar to other chemopreventive agents in that it suppresses tumor promotion in 2-stage carcinogenesis by inter fering with the action of protein kinase C. We report that TAM (5 JIM) totally inhibits hydrogen peroxide (IM),) formation by 12-0-tetradecanoyl-phorbol-13-acetate (TPA)-treated human neutrophils. Interest ingly, 0-estradiol (10 MM)also slightly inhibits the oxidative burst of neutrophils. Pretreatment of neutrophils with varying amounts of TAM and 0-estradiol caused additive inhibition of H2O2 formation by the 2 agents. 4-Hydroxy-tamoxifen, a metabolite with the highest affinity for the estrogen receptor, was only as inhibitory as /3-estradiol. Other de rivatives (els-, .V-di'smethyl-, and .V-desdinu-thyl-luinoxifon) with low biological activities had a smaller effect on H2O2 formation. TPAtreated neutrophils were shown to contain S-hydroxymethyl uracil (HMU). TAM prevented the TPA-induced formation of HMU in other cells. Like TPA, dietary fat, which is a risk factor for breast cancer, induces formation of HMU in the DNA of human white blood cells. TAM may suppress the dietary fat-induced HMU in the same manner at it does in TPA-induced neutrophils.