Tsai T L, Katzenellenbogen B S
Cancer Res. 1977 May;37(5):1537-43.
This study analyzed the effectiveness of a nonsteroidal antiestrogen, cis-(3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1,2-propanediol (U 23,469) previously shown to be potent in antagonizing estrogen-induced uterine growth, in preventing the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors and in eliciting the regression of established tumors; the study also attempts to elucidate the mechanisms of the tumor antagonism of U 23,469. Virgin female Sprague-Dawley rats that receive DMBA at 47 to 50 days of age and then receive U 23,469 (250 micrograms s.c. in 0.15 M NaCl daily) have a greatly reduced number of mammary tumors and a markedly decreased tumor area. Treatment with U 23,469 for increasing time periods (3, 6, or 12 weeks) beginning 2 weeks after DMBA results in a progressive delay in onset of tumor appearance. U 23,469 treatment beginning 1 week after DMBA or given prior to DMBA is even more effective. The time course of tumor regression (3 months after DMBA) by U 23,469 or ovariectomy is similar, with 50% regression in ca. 2 weeks, and both elicit regression of almost all tumors (greater than 90%). After ovariectomy, cytosol progesterone receptor levels are greatly diminished in tumors and uteri, while cytosol estrogen receptor (ER) levels are high; in both tissues little (ca. one-third) of ER is in the nucleus. During U 23,469 treatment, cytosol ER content is very low in regressing tumor and uterus and over 90% of ER is in the nucleus; cytosol progesterone receptor is slightly depressed in the uterus but is at the untreated level in mammary tumor. These receptor studies suggest that the effectiveness of this antiestrogen in antagonizing mammary tumor development and growth may reside in its ability markedly to perturb the distribution of ER, maintaining over 90% of ER in the nucleus with concomitant low levels of cytoplasmic ER, a situation that may render the mammary tissue insensitive to the animal's own endogenous estrogens.
本研究分析了一种非甾体类抗雌激素药物顺式-（3-[对-（1,2,3,4-四氢-6-甲氧基-2-苯基-1-萘基）苯氧基]-1,2-丙二醇（U 23,469）的有效性。该药物先前已显示出在拮抗雌激素诱导的子宫生长方面具有强效作用，此次研究其在预防7,12-二甲基苯并（a）蒽（DMBA）诱导的大鼠乳腺肿瘤发生以及促使已形成肿瘤消退方面的效果；该研究还试图阐明U 23,469肿瘤拮抗作用的机制。47至50日龄的处女雌性斯普拉格-道利大鼠在接受DMBA后，再接受U 23,469（每日皮下注射250微克于0.15 M氯化钠溶液中），其乳腺肿瘤数量大幅减少，肿瘤面积显著减小。在DMBA注射后2周开始用U 进行不同时长（3、6或12周）的治疗，会使肿瘤出现的起始时间逐渐延迟。在DMBA注射后1周开始用U 23,469治疗或在DMBA注射前给药则效果更佳。U 23,469或卵巢切除术后肿瘤消退的时间进程（DMBA注射后3个月）相似，约2周内有50%的肿瘤消退，且两者都能使几乎所有肿瘤（超过90%）消退。卵巢切除术后，肿瘤和子宫中的胞质孕酮受体水平大幅降低，而胞质雌激素受体（ER）水平较高；在这两种组织中，只有少量（约三分之一）的ER位于细胞核中。在U 23,469治疗期间，正在消退的肿瘤和子宫中的胞质ER含量非常低，超过90%的ER位于细胞核中；子宫中的胞质孕酮受体略有降低，但乳腺肿瘤中的该受体水平与未治疗时相当。这些受体研究表明，这种抗雌激素在拮抗乳腺肿瘤发生和生长方面的有效性可能在于其能够显著扰乱ER的分布，使超过90%的ER维持在细胞核中，同时胞质ER水平较低，这种情况可能使乳腺组织对动物自身的内源性雌激素不敏感。
