多聚凝胶介导IGF-IR反义寡核苷酸治疗体内胶质瘤的实验研究

目的探讨反义寡核苷酸阻断IGF-IR基因表达对裸鼠移植胶质瘤的抑制作用。方法首先建立胶质瘤裸鼠移植模型,随机分为4组:空白对照组、多聚凝胶组、正义核酸组和反义核酸组,反义核酸组在瘤内注射多聚凝胶包裹的反义寡核苷酸,其他每组均作相应的瘤内注射处理。利用多聚凝胶缓释反义寡核苷酸的作用,观察肿瘤的抑制情况、肿瘤病理和IGF-IR表达结果。结果反义核酸组用反义核苷酸开始治疗后的第1周、第2周和第3周,肿瘤的生长速度明显减慢,与空白对照组相比,抑制率分别为65.2%、76.38%和69.6%;而多聚凝胶组和正义核酸组肿瘤生长速度与空白对照组相比无明显差异,其抑制率在各时间点均低于10%。肿瘤的组织病理发现多聚凝胶组、正义核酸组如同空白对照组(野生型),肿瘤细胞密集分布,呈明显的恶性增殖表现,而反义核酸组肿瘤细胞稀疏,可见部分细胞呈凋亡改变,细胞染色质浓聚边缘化。在空白对照组(野生型)、多聚凝胶组和正义核酸组IGF-IR蛋白均呈高表达,而反义核酸组IGF-IR的表达明显减弱。结论IGF-IR的反义寡核苷酸对体内胶质瘤的生长具有明显的抑制作用,并能诱导部分肿瘤细胞凋亡。因此,IGF-IR可作为胶质瘤基因治疗的靶。

Experimental study of an antisese oligodeoxynucleotides directed against IGF-IR in the treatment of glioma xenografts in nude mice

Objective To investigate growth inhibition of glioma xenografts in nude mice by using the controlled-release antisense oligodeoxynucleotides(ODNs) from F-127 pluronic gel. Methods The glioma nude model was established by implanting glioma in nude mice. The established tumor-bearing nude mice were randomized into control, pluronic gel, sense, and antisense groups. In the latter group, each mouse received an intratumal s.c injection of mixture of antisense ODNs and gel. Sense, pluronic gel and control mice received a s.c injection of mixture of sense ODNs and gel, F-127 pluronic gel and PBS respectively. Results Antisense ODNs could inhibit tumor growth in antisense animal, and tumor inhibitory rate at 1, 2, 3 week after treatment was 65.2%, 76.38% and 69.6% respectively. Histological examination of tumor specimens in sense, pluronic gel and control mice showed that tumor cells was dense, whereas tumor cell in antisense animal was sparse and present of apoptotic cells. Immunohitochemical assays showed the protein product of IGF-IR of tumor specimens in sense, pluronic gel and control mice was overexpressed, while the protein product of the receptor in antisense mice was reduced. Conclusion The blockage of IGF-IR can significantly inhibit the growth of xenografts derived from glioma cells after treatment with antisense ODNs to IGF-IR mRNA and can induce tumor cell apoptosis. Therefore, IGF-IR may be selected as target for gene therapy for glioma.