他莫昔芬与雷洛昔芬类似物LY117018：它们对培养细胞中花生四烯酸释放及大鼠肝细胞前列腺素I2生成的影响。

BACKGROUND

Tamoxifen is being used successfully to treat breast cancer. However, tamoxifen also increases the risk of developing endometrial cancer in postmenopausal women. Raloxifene also decreases breast cancer in women at high risk and may have a lower risk at developing cancer of the uterus. Tamoxifen has been shown to stimulate arachidonic acid release from rat liver cells. I have postulated that arachidonic acid release from cells may be associated with cancer chemoprevention.

METHODS

Rat liver, rat glial, human colon carcinoma and human breast carcinoma cells were labelled with [3H] arachidonic acid. The release of the radiolabel from these cells during incubation with tamoxifen and the raloxifene analog LY117018 was measured. The prostaglandin I2 produced during incubation of the rat liver cells with microM concentrations of tamoxifen and the raloxifene analog was quantitatively estimated.

RESULTS

Tamoxifen is about 5 times more effective than LY117018 at releasing arachidonic acid from all the cells tested. In rat liver cells only tamoxifen stimulates basal prostaglandin I2 production and that induced by lactacystin and 12-O-tetradecanoyl-phorbol-13-acetate. LY117018, however, blocks the tamoxifen stimulated prostaglandin production. The stimulated prostaglandin I2 production is rapid and not affected either by preincubation of the cells with actinomycin or by incubation with the estrogen antagonist ICI-182,780.

CONCLUSIONS

Tamoxifen and the raloxifene analog, LY117018, may prevent estrogen-independent as well as estrogen-dependent breast cancer by stimulating phospholipase activity and initiating arachidonic acid release. The release of arachidonic acid and/or molecular reactions that accompany that release may initiate pathways that prevent tumor growth. Oxygenation of the intracellularly released arachidonic acid and its metabolic products may mediate some of the pharmacological actions of tamoxifen and raloxifene.

背景

他莫昔芬正成功用于治疗乳腺癌。然而，他莫昔芬也会增加绝经后女性患子宫内膜癌的风险。雷洛昔芬也能降低高危女性患乳腺癌的风险，且患子宫癌的风险可能较低。已表明他莫昔芬能刺激大鼠肝细胞释放花生四烯酸。我推测细胞释放花生四烯酸可能与癌症化学预防有关。

方法

用[3H]花生四烯酸标记大鼠肝脏、大鼠神经胶质、人结肠癌细胞和人乳腺癌细胞。测量在与他莫昔芬和雷洛昔芬类似物LY117018孵育期间这些细胞中放射性标记物的释放。定量估计大鼠肝细胞在与微摩尔浓度的他莫昔芬和雷洛昔芬类似物孵育期间产生的前列腺素I2。

结果

在从所有测试细胞中释放花生四烯酸方面，他莫昔芬的效果约为LY117018的5倍。仅在大鼠肝细胞中，他莫昔芬能刺激基础前列腺素I2的产生以及由乳胞素和12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯诱导的前列腺素I2的产生。然而，LY117018会阻断他莫昔芬刺激的前列腺素产生。刺激产生的前列腺素I2迅速，且不受细胞先用放线菌素预孵育或与雌激素拮抗剂ICI - 182,780孵育的影响。