PURPOSE:Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model. EXPERIMENTAL DESIGN:MCF-7 cells stably expressing STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7STS and wild-type MCF-7 (MCF-7WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly. RESULTS:STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7WT and 3.8-fold for MCF-7STS after 49 days compared with day 0. MCF-7WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7STS tumors, and recovery of these tumors was significantly retarded (P<0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7STS tumors directly correlated with the corresponding STS enzyme activity. CONCLUSIONS:This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition.

译文

用途:类固醇硫酸酯酶(STS)抑制剂可通过硫酸酯酶途径减少或阻止雌激素类固醇的生物合成,可能在乳腺癌的治疗中起重要作用。我们比较了两种有效的STS抑制剂STX64和STX213在异种移植乳腺癌模型中的体内疗效。
实验设计:产生稳定表达STS cDNA(MCF-7STS)的MCF-7细胞。接受皮下切除的卵巢切除的MF-1雌性裸鼠注射雌二醇硫酸盐(E2S)并同时携带MCF-7STS和野生型MCF-7(MCF-7WT)肿瘤的患者,应使用STX64和STX213口服治疗。给予49天的治疗,然后恢复35天,其中动物仅接受E2S。称重小鼠,每周进行一次肿瘤测量。
结果:STX64和STX213在体内表现出有效的STS抑制作用。但是,STX213显示了更长的活动时间。在接受E2S的媒介物治疗的裸鼠中,与第0天相比,在49天后,MCF-7WT的肿瘤体积增加了5.5倍,MCF-7STS的肿瘤体积增加了3.8倍。STX213使MCF-7WT的肿瘤生长比给药减少了56%期间,随后的生长在恢复期受到阻碍。所有治疗均完全抑制MCF-7STS肿瘤的生长,并且这些肿瘤的恢复显着受阻(P <0.01)。所有化合物均完全抑制肝脏和肿瘤STS活性。此外,MCF-7STS肿瘤中的STS mRNA表达与相应的STS酶活性直接相关。
结论:这项研究表明,STS抑制剂可减弱激素依赖性人类乳腺癌的生长,因此可为这种情况提供潜在的新颖治疗方法。

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