Tamoxifen suppresses tumor promoter-induced hydrogen peroxide formation by human neutrophils.
Trans-tamoxifen (TAM) has been used successfully in therapy for estrogen-dependent human breast tumors and prevention of their recurrence. 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 interfering with the action of protein kinase C. We report that TAM (5 microM) totally inhibits hydrogen peroxide (H2O2) formation by 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-treated human neutrophils. Interestingly, beta-estradiol (10 microM) also slightly inhibits the oxidative burst of neutrophils. Pretreatment of neutrophils with varying amounts of TAM and beta-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 beta-estradiol. Other derivatives (cis-, N-desmethyl-, and N-desdimethyl-tamoxifen) with low biological activities had a smaller effect on H2O2 formation. TPA-treated neutrophils were shown to contain 5-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.
Lim
J S
JS
Department of Environmental Medicine, New York University Medical Center, New York 10016-6451.
Frenkel
K
K
Troll
W
W
D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D013629:Tamoxifen / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D004965:Estrogen Antagonists; D053284:Polyunsaturated Alkamides; D013629:Tamoxifen; D004958:Estradiol; C051781:ICI 164384; D006861:Hydrogen Peroxide; D013755:Tetradecanoylphorbol Acetate