应用GSI药物阻断Notch-1通路对骨肉瘤小鼠模型肿瘤生长及血管形成的影响

Effect of Notchl channel blockers GSI in inhibited tumor growth osteosarcoma model on cytokine secretion: an animal experimental research

[目的]研究Notch-1通道阻断剂γ分泌酶抑制剂(gamma-secretase inhibitor,GSI)在抑制骨肉瘤小鼠模型中肿瘤增长以及其抑制肿瘤血管生成作用,进而探讨Notch-1信号通路在小鼠骨肉瘤模型中的作用及其作用机制。[方法]建立人骨肉瘤荷瘤SCID小鼠模型,将荷瘤成功后小鼠随机分为三组,实验组肿瘤内注射Notch通路阻断药物GSI,对照组注射PBS和DMSO。研究各组小鼠生物学指标、肿瘤增长变化及肿瘤组织检测微血管密度(microvessel density,MVD)的表达情况与差异。[结果]处死小鼠测量瘤体,同对照组相比,GSI治疗组小鼠的生物学指标明显较好,其小鼠的体重、饮食、睡眠、运动情况、精神状态、对刺激的反应及小鼠的皮毛光泽度等优于对照组,其皮下肿瘤体积明显较小,实验组平均体积为(196.3 mm3)较DMSO对照组平均体积(650.3 mm3)及PBS对照组平均体积(694.6 mm3)明显缩小,差别具有统计学意义,P<0.01。实验组及对照组内瘤体切片内血管均见不同程度的CD31表达,其表达于血管内皮细胞内,与对照组相比实验组CD31表达均明显降低,实验组及PBS、DMSO对照组CD31平均秩次分别为4.03、28.9和32.5,P<0.05,差异具有统计学意义。[结论](1)证实GSI可抑制SCID小鼠骨肉瘤动物模型肿瘤的生长;(2)GSI对SCID小鼠骨肉瘤动物模型的治疗作用可通过抑制Notch通路进而干预肿瘤血管形成来实现;(3)应用GSI药物阻断Notch信号通路有望成为骨肉瘤抗肿瘤治疗的新方法。

To research the effect of Notchl channel blockers GSI（ γ- secretase inhibitors） in mice inhibited minor growth osteosarcoma model on cytokine secretion and thus explore the role of Notch 1 signaling pathway in a mouse model of osteosarcoma and mechanism of action. [Methods] Human osteosarcoma tumor- bearing SCID mouse modell was established and the tumor- bearing mice were randomly divided into three groups,mice in the experimental group received injection of Notch pathway blocking drugs GSI,while mice in the two control groups were injected with DMSO and PBS. The changes of biology in tumor bearing SCID mice,the changes of tumor growth and vascular density in tumor bearing SCID mice were recorded and compared between the experiment group and two control groups. [Results] Compared with the ones in control groups,biological indicators in animals of GSI treated group was significantly better,which included the weight of mice,diet,sleep,exercise,the mental state,fur gloss and response to stimuli. The average subcutaneous tumor volume（ 196. 3 mm3） in experimental group was smaller than those in the DMSO control group and PBS control group（ 650. 3 mm3 and 694. 6 mm3respectively）,showing statistically significant difference（ P〈0. 05）. Different levels of CD31 expression were seen in both the experimental group and the control groups in the minor biood vessels slice,and mean rank sum in experimental group expression was 4. 03,also with significant difference compared with the DMSO and PBS groups（ 28. 8 and 32. 5 respectively）. [Conclusion]（ 1） GSI could inhibite the tumor growth of human osteosarcoma in tunaor- bearing SCID mouse model.（ 2） The therapeutic effects of GSI in animal models of osteosarcoma SCID mice is get through inhibiting the Notch pathway and thus interfere the tumor angiogenesis.（ 3）Usage of GSI to block Notch pathway in osteosarcoma is expected to become a new methods for anti- cancer therapy.