Seeger Harald, Deuringer Fritz-Ulrich, Wallwiener Diethelm, Mueck Alfred O
Section of Endocrinology and Menopause, University Women's Hospital, Calwerstrasse 7, 72 076 Tuebingen, Germany.
Maturitas. 2004 Nov 15;49(3):235-40. doi: 10.1016/j.maturitas.2004.02.004.
Long-term hormone replacement therapy is associated with an increased breast cancer risk. Evidence is accumulating that estradiol metabolites are involved in carcinogenesis. These metabolites may have proliferating and anti-proliferative properties. We have investigated the effect of 14 metabolites on the proliferation of human breast cancer cells and on the proliferation of human vascular endothelial cells.
As cell model, human umbilical vein endothelial cells (HUVEC) and the human breast cancer cell line MCF-7 were used. The relationship between dosage and effect was tested over the pharmacological concentration range of 10(-8) to 10(-5) M.
In HUVECs, all of 10 A-ring metabolites tested stimulated the growth of the endothelial cells at the lower concentrations. At the highest concentration, some A-ring metabolites caused significant inhibitions. The D-ring metabolites showed no marked effects compared to the A-ring metabolites. In MCF-7 cells also, nearly all A-ring metabolites demonstrated a biphasic reaction behaviour on cell proliferation. For the D-ring metabolites, this biphasic pattern was only found for 16 alpha-hydroxyestrone, but the inhibitory effect of this metabolite was weak.
These results indicate that certain endogenous estradiol metabolites are able to stimulate breast cancer cell proliferation, and others may be suitable for breast cancer treatment when used in high dosages, since they inhibit cancer cell growth as well as neoangiogensis. This may be of special importance for therapy, since some of these metabolites are virtually devoid of any oestrogenic activity.
长期激素替代疗法与乳腺癌风险增加相关。越来越多的证据表明雌二醇代谢产物参与致癌过程。这些代谢产物可能具有增殖和抗增殖特性。我们研究了14种代谢产物对人乳腺癌细胞增殖以及人血管内皮细胞增殖的影响。
使用人脐静脉内皮细胞（HUVEC）和人乳腺癌细胞系MCF-7作为细胞模型。在10(-8)至10(-5)M的药理浓度范围内测试剂量与效应之间的关系。
在HUVEC中，所测试的10种A环代谢产物在较低浓度下均刺激内皮细胞生长。在最高浓度时，一些A环代谢产物引起显著抑制。与A环代谢产物相比，D环代谢产物未显示出明显作用。在MCF-7细胞中，几乎所有A环代谢产物对细胞增殖也表现出双相反应行为。对于D环代谢产物，仅在16α-羟基雌酮中发现这种双相模式，但其抑制作用较弱。
这些结果表明，某些内源性雌二醇代谢产物能够刺激乳腺癌细胞增殖，而其他一些代谢产物在高剂量使用时可能适用于乳腺癌治疗，因为它们既能抑制癌细胞生长又能抑制新生血管生成。这对于治疗可能具有特殊重要性，因为其中一些代谢产物几乎没有任何雌激素活性。
