Lam H Y, Goldenberg G J, Wong C M
Department of Medicine, University of Manitoba, Winnipeg, Canada.
Biochem Pharmacol. 1988 Jul 1;37(13):2625-31. doi: 10.1016/0006-2952(88)90256-0.
Several estrogen-nitrosourea conjugates have been synthesized with the aim of producing more selective cytotoxic agents. The conjugates were shown to compete with estradiol for binding to cytosolic estrogen receptor in rat uterus; the relative binding affinities for N-(2-chloroethyl)-N'-(3,17 beta-dihydroxyestra-1,3,5(10)-trien-17 alpha-yl)methyl-N-nitrosourea (17 alpha-CNU), N-(2-chloroethyl)-N'-(3-hydroxyestra-1,3,5(10)-trien-17 beta-yl)-N-nitrosourea (17 beta-CNU), and N-(2-chloroethyl)-N'-2,3-di(p-hydroxyphenyl)-pentanyl-N-nitrosoure a (HEX-CNU) were 2, 0.4, and 0.2, respectively, using a binding affinity of 100 for estradiol. In the ligand exchange assay, cytosolic receptors preloaded with 17 alpha-CNU and HEX-CNU were found to lose some of their estradiol (E2) binding sites, suggesting that binding to estrogen receptor (ER) may be irreversible. An increase of nuclear accumulation of ER was observed in the presence of 17 alpha-CNU and HEX-CNU. In the rat system, even at a 10,000-fold excess, these two agents failed to show any antagonism of the uterotrophic effect of E2 in vivo. The low binding affinity and instability of these conjugates may account for their lack of antiestrogen activity. On the other hand, 17 alpha-CNU at 100 or 1000 micrograms/day and HEX-CNU at 1000 micrograms/day demonstrated significant uterotrophic activity. This study did not resolve whether the stimulation of uterine growth was due to the parent estrogen-nitrosourea conjugate or to decomposition and/or metabolic products.
为了制备更具选择性的细胞毒性药物，人们合成了几种雌激素 - 亚硝基脲缀合物。这些缀合物被证明能与雌二醇竞争结合大鼠子宫中的胞质雌激素受体；以雌二醇的结合亲和力为100计算，N-(2-氯乙基)-N'-(3,17β-二羟基雌甾-1,3,5(10)-三烯-17α-基)甲基-N-亚硝基脲(17α-CNU)、N-(2-氯乙基)-N'-(3-羟基雌甾-1,3,5(10)-三烯-17β-基)-N-亚硝基脲(17β-CNU)和N-(2-氯乙基)-N'-2,3-二(对羟基苯基)-戊基-N-亚硝基脲(HEX-CNU)的相对结合亲和力分别为2、0.4和0.2。在配体交换试验中，发现预先加载17α-CNU和HEX-CNU的胞质受体失去了一些雌二醇(E2)结合位点，这表明与雌激素受体(ER)的结合可能是不可逆的。在17α-CNU和HEX-CNU存在的情况下，观察到ER的核积累增加。在大鼠实验系统中，即使存在10000倍的过量，这两种药物在体内也未能显示出对E2子宫营养作用的任何拮抗作用。这些缀合物的低结合亲和力和不稳定性可能是它们缺乏抗雌激素活性的原因。另一方面，17α-CNU每天100或1000微克以及HEX-CNU每天1000微克表现出显著的子宫营养活性。这项研究没有解决子宫生长的刺激是由于母体雌激素 - 亚硝基脲缀合物还是由于分解产物和/或代谢产物。
