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目的观察低频超声(20 kHz)辐照联合静脉注射微泡造影剂SonoVue对裸鼠前列腺癌(Du145)移植瘤的抑瘤效应,并探讨其可能的抑瘤机制。方法通过细胞移植和瘤块移植方法建立24只裸鼠前列腺癌Du145移植瘤模型,随机分为超声微泡组、单纯超声组、单纯微泡组和对照组,每组各6只。超声微泡组:尾静脉注射0.2 mLSonoVue的同时对瘤体行20 kHz超声辐照,辐照强度200 mW/cm2;单纯超声组:尾静脉注射生理盐水0.2 mL,同时超声辐照2 min;单纯微泡组:尾静脉注射SonoVue 0.2 mL同时行假照,各组均隔天1次,共3次,对照组不做任何处理。治疗后测量瘤体大小,绘制瘤体生长曲线,计算抑瘤率。首次治疗后14 d剥离瘤体,通过光学显微镜、电子显微镜观察肿瘤组织病理改变。免疫组织化学方法观察CD34阳性染色血管,计算肿瘤微血管密度(micro vessel density,MVD),比较各组间MVD的差异。结果 24只裸鼠均成功植瘤。治疗后超声微泡组瘤体体积均数明显小于其他3组(P<0.05),抑瘤率为62.7%。光学显微镜下超声微泡组瘤体组织大部分损伤坏死,电子显微镜下超声微泡组肿瘤内微血管的内皮细胞损伤,线粒体肿大,基底膜断裂。超声微泡组瘤体内CD34阳性染色微血管数减少,其MVD值显著低于其他各组。结论 20 kHz低频超声辐照联合微泡造影剂SonoVue可有效抑制裸鼠人前列腺癌移植瘤的生长,其抑瘤机制可能是通过超声空化效应破坏肿瘤的微血管实现的。
Objective To observe the anti-tumor effect of low-frequency ultrasound (20 kHz) irradiation combined with intravenous injection of microbubble contrast agent SonoVue on nude mouse prostate cancer (Du145) xenografts and to explore its possible mechanism. Methods Twenty-four nude mice models of prostate cancer Du145 xenografts were established by cell transplantation and tumor mass transplantation. They were randomly divided into ultrasound microbubbles group, simple ultrasound group, simple microbubble group and control group, with 6 mice in each group. Ultrasound group: tail vein injection 0.2 mLSonoVue at the same time on the tumor 20 kHz ultrasound irradiation, irradiation intensity 200 mW / cm2; simple ultrasound group: tail vein injection of saline 0.2 mL, while ultrasound irradiation for 2 min; simple Micro-bubble group: SonoVue 0.2 mL tail vein injection at the same time under the illumination, each group were 1 day, a total of 3 times, the control group without any treatment. After treatment, the tumor size was measured, the growth curve of the tumor was drawn, and the tumor inhibition rate was calculated. The tumors were dissected 14 days after the first treatment, and the pathological changes of tumor tissues were observed by optical microscope and electron microscope. Immunohistochemistry was used to observe CD34-positive staining vessels and to calculate tumor microvascular density (MVD). MVD differences among groups were compared. Results 24 nude mice were successfully implanted tumor. After treatment, the mean volume of tumor in ultrasound microbubbles group was significantly less than the other three groups (P <0.05), and the tumor inhibition rate was 62.7%. Under the light microscope, most of the tumor tissues in the ultrasound microbubbles group were damaged and necrotic. Endothelial cells of the tumor microvessels in the ultrasound microbubble group under the electron microscope were damaged. The mitochondria were swollen and the basement membrane ruptured. The number of CD34 positive microvessels in the ultrasound microbubble group decreased, and the MVD value was significantly lower than those in other groups. Conclusion 20 kHz low frequency ultrasound irradiation combined with microbubble contrast agent SonoVue can effectively inhibit the growth of human prostate cancer xenografts in nude mice. The antitumor mechanism may be achieved through the destruction of tumor microvessels by ultrasound cavitation.