Lamberts S W, Verleun T
Department of Medicine, Erasmus University, Rotterdam, The Netherlands.
Eur J Cancer Clin Oncol. 1987 Aug;23(8):1117-23. doi: 10.1016/0277-5379(87)90143-x.
Chronic administration of the catecholestrogens 2-OH-estrone (2-OH1) and 2-OH-estradiol (2-OHE2), of tamoxifen and its metabolites and of high concentrations of estradiol have been previously shown to inhibit the growth of the estrogen/progesterone receptor-positive transplantable prolactin (PRL)-secreting rat pituitary tumor 7315a. The mechanism of action of these inhibitory effects on tumor growth is unknown. In the present study we investigated the direct effects of these compounds on PRL release by a tumor cell clone derived from the 7315a tumor. E2 stimulated PRL release in FCSABS (10% estrogen-stripped fetal calf serum)-cultured tumor cells in a biphasic manner: at low concentrations (0.1-100 nM) there was a dose-dependent stimulation of PRL release, which decreased in response to 1 microM E2 and which was greatly inhibited by 10 microM E2. Both 2-OHE2 (100 nM and 1 microM) and 2-OHE2 (1 microM) inhibited PRL release by FCS-cultured tumor cells. In FCSABS-cultured tumor cells, 0.1-10 nM 2-OHE1 and 1 microM 2-OHE2 inhibited PRL release, but 1-100 nM 2-OHE2 stimulated PRL release. Tamoxifen (TMX) and its metabolites dihydroxy (di-OH-TMX) and 4-hydroxytamoxifen (4-OH-TMX) inhibited PRL in a dose-dependent manner. The PRL release inhibiting effect of 4-OH-TMX was 100 times more potent that those of TMX and di-OH-TMX, which were similar in their effect. The inhibitory effects of micromolar concentrations of the catecholestrogens on PRL release could be overcome by estradiol, while the inhibitory effects of high concentrations of tamoxifen were not prevented by estradiol. Both "endogenous" (catecholestrogens) and "exogenous" (tamoxifen and its metabolites) antiestrogens and very high concentrations of estradiol directly inhibit PRL secretion by cultured pituitary tumor cells. The mechanism of their anti-tumor effects, however, seems to differ. The catecholestrogens have direct anti-estrogenic effects on cultured tumor cells, which can be antagonized by estradiol. The final effect of their mixed antagonistic/agonistic action depends on the presence or absence of estrogens in the culture medium. Tamoxifen also affects tumor growth probably mainly via a direct effect, partly involving anti-estrogenic and partly direct toxic effects.
先前的研究表明，长期给予儿茶酚雌激素2-羟基雌酮（2-OH1）和2-羟基雌二醇（2-OHE2）、他莫昔芬及其代谢产物以及高浓度的雌二醇，可抑制雌激素/孕激素受体阳性的可移植性分泌催乳素（PRL）的大鼠垂体肿瘤7315a的生长。这些对肿瘤生长的抑制作用的作用机制尚不清楚。在本研究中，我们研究了这些化合物对源自7315a肿瘤的肿瘤细胞克隆释放PRL的直接影响。E2以双相方式刺激在FCSABS（10%雌激素去除的胎牛血清）培养的肿瘤细胞中PRL的释放：在低浓度（0.1-100 nM）时，PRL释放呈剂量依赖性刺激，在1 microM E2作用下这种刺激作用减弱，而在10 microM E2作用下则受到极大抑制。2-OHE2（100 nM和1 microM）和2-OHE2（1 microM）均抑制FCS培养的肿瘤细胞释放PRL。在FCSABS培养的肿瘤细胞中，0.1-10 nM的2-OHE1和1 microM的2-OHE2抑制PRL释放，但1-100 nM的2-OHE2刺激PRL释放。他莫昔芬（TMX）及其代谢产物二羟基（二-OH-TMX）和4-羟基他莫昔芬（4-OH-TMX）以剂量依赖性方式抑制PRL释放。4-OH-TMX对PRL释放的抑制作用比TMX和二-OH-TMX强100倍，后两者的作用相似。微摩尔浓度的儿茶酚雌激素对PRL释放的抑制作用可被雌二醇克服，而高浓度他莫昔芬的抑制作用则不能被雌二醇阻止。“内源性”（儿茶酚雌激素）和“外源性”（他莫昔芬及其代谢产物）抗雌激素以及非常高浓度的雌二醇均直接抑制培养的垂体肿瘤细胞分泌PRL。然而，它们的抗肿瘤作用机制似乎有所不同。儿茶酚雌激素对培养的肿瘤细胞具有直接的抗雌激素作用，这种作用可被雌二醇拮抗。它们混合的拮抗/激动作用的最终效果取决于培养基中雌激素的存在与否。他莫昔芬也可能主要通过直接作用影响肿瘤生长，部分涉及抗雌激素作用，部分涉及直接毒性作用。
