米非司酮腹腔内给药对子宫肌瘤模型大鼠的干预作用

The Effect of Intraperitoneally Administered Mifepristone on the Rat with a Model of Hysteromyoma

目的观察米非司酮腹腔内给药对实验性大鼠子宫肌瘤的治疗作用,并探讨其可能的作用机制。方法将SD雌性大鼠75只随机分为5组。正常组15只,其余大鼠以苯甲酸雌二醇和黄体酮诱发子宫肌瘤模型。分为模型组及米非司酮腹腔内给药低、中、高剂量(0.56,1.12,2.24 mg.kg-1.d-1,腹腔内注射)组各15只。正常组、模型组每只每天腹腔内注射等量0.9%氯化钠溶液,共12周。末次用药后24 h将所有大鼠称重,酶标记单克隆抗体法测定血清雌二醇(E2)和孕激素(P)水平,放射免疫法测定血清表皮生长因子(EGF)水平;随后处死大鼠,剖腹先观察子宫大体形状,剪取子宫称重,以子宫重量/体重(mg.g-1)计算子宫系数;免疫组化染色观察子宫平滑肌细胞雌、孕激素受体的表达。结果模型组大鼠血清E2、P和血清EGF水平均明显高于正常组,子宫重量明显增加,子宫系数变大,子宫平滑肌细胞雌、孕激素受体的表达明显升高。米非司酮腹腔内给药可明显降低大鼠血清E2、P及EGF水平,抑制子宫平滑肌细胞雌、孕激素受体的表达,以2.24 mg.kg-1.d-1剂量组的作用最明显。结论米非司酮腹腔内给药对实验性大鼠子宫肌瘤有明显的治疗作用。其抗瘤机制可能为:①降低体内雌、孕激素及其受体水平,直接对抗孕酮活性并产生抗E2作用,从而使雌、孕激素效应显著降低,导致肌瘤体积缩小,子宫重量减轻,子宫系数变小;②降低血清EGF水平,抑制EGF-EGF-R对肿瘤细胞的增殖刺激作用,从而使肌瘤体积缩小。

Objective To study the effect of mifepristone administered intrapeirtoneally on the rat with a model of hysteromyoma and probe into the possible pharmacological mechanisms. Methods 75 female SD rats were randomly divided into 5 equal groups： （1） the normal control group; （2） the model group; （3）, （4）, （5）, low-dose, medium-dose and high-dose mifepristone treatment groups. A model of hysteromyoma was set up in each of the rats of group 2 to group 5 by treatment of the animals with estradiol benzoate （E2 ） and progesterone （P）. Rats of groups （3）, （4） and （5） were given each 0.56,1.12 and 2.24 mg · kg^-1 of mifepristone administered intrapeirtoneally q.d. , respectively, for 12 consecutive weeks. Animals of group （1） and group （2） were given each an equivalent amount of 0.9% sodium chloride solution administered intraperitoneally q.d. for 12 weeks as well. Rats of all 5 groups were weighed 24 h. after the final medication. Serum concentrations of E2 and P were determined with the enzyme-labelled McAb method while serum EGF （epidermal growth factor） level was measured with radioimmunoassay. The animals were then sacrificed. The general appearance of the uterus was kept under observation and the organ was weighed and the uterus coefficient of uterus weight/body weight （mg · g^-1 ） was calculated. The expression of estrogen receptor and progestogen receptor in the hysteromyoma cells was examined with the immunochemical staining method. Results Serum concentration of E2, P and EGF in rats of group （2） （model group） were strikingly higher than those in rats of group （1） （normal control）. The uterus weight , the uterus coefficient and the expression of estrogen receptor and progestogen receptor in the myoma cells were significantly increased in rats of the model group. Mifepristone administered intraperitoneally was shown to dramatically lower the serum levels of E2, P and EGF, inhibit the expression of estrogen receptors and progestogen receptors in the myoma cells. The effect was most prominent when the dose of mifepristone was 2.24 mg · kg^-1 · d^-1. Conclusion Mifepristone administered intraperitoneally was shown to exert definite therapeutic effects on the hystermyoma induced in rats. Mechanisms underlying the effects of the drug may be as follows ： （1） By lowering the serum levels of E2 , P and the expression of their receptors in the myoma cells, the drug displayed a direct antagonistic action against the activities of progesterone and the biological function of estrogen, resulting in a striking alteration of the effects of these hormones and diminution of the size of the tumor and decrease in the weight of the uterus. （2） By lowering the serum EGF level, the drug seems to inhibit the effect of EGF-EGF-R to stimulate the puliferation of tumor cells, leading to a reduction in the size of the tumor.