Chetrite G S, Kloosterboer H J, Philippe J C, Pasqualini J R
Steroid Hormone Research Unit, Institut de Puériculture, Paris, France.
Anticancer Res. 1999 Jan-Feb;19(1A):261-7.
It is well recognized that estradiol (E2) is one of the most important hormones supporting the growth and evolution of breast cancer. Consequently, to block this hormone before it enters the cancer cell, or in the cell itself, has been one of the main targets in recent years. In the present study we explored the effect of Org OD14 (active substance in Livial) and its metabolites (Org 30126, Org 4094, Org OM38) on the 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) activity of MCF-7 and T-47D human breast cancer cells. Using physiological doses of estrone ([3H]-E1: 5 x 10(-9) M) this estrogen is converted in a great proportion to E2 in both cell lines. After 24 hours, Org OD14 significantly inhibits this transformation in a dose-dependent manner, by 32 and 73% at 5 x 10(-7) M and 5 x 10(-5) M respectively, in T-47D cells; the effect is similar in MCF-7 cells. Among the three Org OD14 metabolites tested, Org 4094 and Org 30126 (3 alpha- and 3 beta-hydroxy metabolites) are more potent than their precursor, and Org OM-38 (4-ene isomer) is the weakest of the three steroids. The IC50 values were 0.79, 1.98, 7.12, and 22.84 microM in MCF-7 cells for Org 4094, Org 30126, Org OD14, and Org OM-38, respectively, and 4.83, 1.44, 2.03, and 35.25 microM, respectively, in T-47D cells. As Org OD14 and two of its metabolites, Org 30126 and Org 4094, also strongly decrease the conversion of estrone sulphate to estradiol in the hormone-dependent MCF-7 and T-47D breast cancer cells, it is concluded that the inhibition provoked by these steroids on the enzymes (estrone sulphatase and 17 beta-HSD) involved in the local biosynthesis of the biologically active estrogen estradiol, may reduce the risk of breast cancer in postmenopausal women during long-term hormone replacement treatment with Livial.
众所周知，雌二醇（E2）是支持乳腺癌生长和发展的最重要激素之一。因此，在这种激素进入癌细胞之前或在细胞内阻断它，已成为近年来的主要目标之一。在本研究中，我们探讨了替勃龙（Livial中的活性物质）及其代谢产物（Org 30126、Org 4094、Org OM38）对MCF-7和T-47D人乳腺癌细胞17β-羟基类固醇脱氢酶（17β-HSD）活性的影响。使用生理剂量的雌酮（[3H]-E1：5×10-9 M），在这两种细胞系中，这种雌激素大部分会转化为E2。24小时后，替勃龙以剂量依赖性方式显著抑制这种转化，在T-47D细胞中，5×10-7 M和5×10-5 M时分别抑制32%和73%；在MCF-7细胞中的效果类似。在所测试的替勃龙的三种代谢产物中，Org 4094和Org 30126（3α-和3β-羟基代谢产物）比其前体更有效，而Org OM-38（4-烯异构体）是这三种类固醇中活性最弱的。在MCF-7细胞中，Org 4094、Org 30126、替勃龙和Org OM-38的IC50值分别为0.79、1.98、7.12和22.84 μM，在T-47D细胞中分别为4.83、1.44、2.03和35.25 μM。由于替勃龙及其两种代谢产物Org 30126和Org 4094也能强烈降低激素依赖性MCF-7和T-47D乳腺癌细胞中硫酸雌酮向雌二醇的转化，因此得出结论，这些类固醇对参与生物活性雌激素雌二醇局部生物合成的酶（硫酸雌酮酶和17β-HSD）的抑制作用，可能会降低绝经后女性在长期使用替勃龙进行激素替代治疗期间患乳腺癌的风险。
