米非司酮对乳腺癌动物模型肿瘤生长抑制的实验观察

Inhibitive effects of mifepristone on growth of breast cancer： experiment with rats

目的观察米非司酮对裸鼠乳腺癌（MCF-7，ER＋／PR＋）模型肿瘤生长速度的影响，同时观察其对微血管密度（MVD）、雌激素受体（ER）、激素受体（PR）、血管内皮生长因子（VEGF）、以及bcl-2、Ki67、p53、CerbB-2等相关蛋白的表达的影响，探讨米非司酮对乳腺癌作用的机制。方法将指数生长期乳腺癌细胞系（MCF-7，ER＋／PR＋）接种裸鼠建立乳腺癌动物模型，随机将荷瘤裸鼠分为空白对照组（给予植物油0．5ml／d），米非司酮治疗组（分为25mg、50mg、100mg、200mg／kg·d）共5组，肿瘤直径在0．5～1．0cm时开始干预，每2d测一次肿瘤体积，总共干预3周。于第2周随机处死其中部分动物；其余第3周处死。处死前测肿瘤体积；取肿瘤组织做常规病理学检查；免疫组化检测CD34、ER、PR，VEGF、bcl-2、Ki67、p53、CerbB-2等相关蛋白表达。结果肿瘤直径：与空白对照相比，米非司酮明显减慢肿瘤的生长速度（P〈0．01），各组间呈时间、剂量依赖性（P〈0．01）。肿瘤形态学观察：光镜下对照组裸鼠肿瘤异型性明显，病理性核分裂像多，核浆比例大，胞质深蓝色，间质少，仅肿瘤中央有局灶性坏死区。米非司酮治疗组肿瘤异型性小，异常核分裂像少，核浆比例小，胞质浅蓝，间质明显增多，肿瘤坏死区较大，而且上述变化与药物剂量，治疗时间成线性相关。免疫组织化学：与空白对照相比，治疗后凋亡相关蛋白表达有差异有统计学意义（P〈0．01），微血管密度显著降低（P〈0．01）。结论米非司酮对裸鼠乳腺癌模型肿瘤的生长有抑制作用；其生长抑制与促进细胞凋亡、抑制血管生成有关；且对ER＋／PR＋的乳腺癌细胞效果更明显。

Objective To investigate the effects of mifepristone （MIF） on the growth of breast cancer. Methods Forty female athymic BALB/c-nude mice underwent subcutaneous injection of breast cancer cells of the line MCF-7, ER ＋/PR ＋. Ten days later when tumor nodules were formed, the mice were randomly divided into 4 equal groups to be administered with MIF of the concentrations of 25 mg, 50 mg, 100 mg, and 200 mg/kg · d respectively by gastric perfusion. The tumor size was observed every 3 day till 3 weeks later. Ten mice were used as normal control group, undergoing gastric perfusion of vegetable oil. Parts of the animals were killed 2 weeks later, and the remaining mice were all killed 3 weeks later. The tumors were taken out and underwent immunochemistry to measure the protein expression of CD34, estrogen receptor （ER）, progesterone receptor （PR）, vascular endothelial growth factor （VEGF）, bcl-2, Ki67, p53, and CerbB-2. Microscopy was used to measure the microvessel density （MVD）. Results The growth velocity of tumor of the mice of MIF groups were all slower than that of the control group （ all P 〈 0.01 ）. The MVD levels of the MIF groups all decreased time- and dose-dependently. Microscopy showed that in the tumor tissues heteromorphism was significant, pathological caryomitosis was more remarkable, karyoplasmic ratio was greater, endochylema was deep blue, mesenchyma was sparse, and zone of neoplasm necrosis became lager in comparison with the control group. The expression levels of VEGF, bcl-2, Ki67, p53, and CerbB-2 of the MIF groups were all significantly lower, time and dose-dependently, than those of the control group （ all P 〈 0.05 ）. Conclusion MIF inhibits the growth of breast cancer by the mechanisms related to apoptosis promotion and inhibition of angiogenesis, so it can be used in breast cancer endocrine therapy.