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魏 永.透明细胞肾癌裸鼠模型构建及靶向药物敏感性研究[J].中国比较医学杂志,2020,30(6):98~105.
透明细胞肾癌裸鼠模型构建及靶向药物敏感性研究
Establishment of a clear-cell renal cancer cell tumor xenograft model using patient-derived cells to examine cell sensitivity to molecular-targeting agents
投稿时间:2019-12-02  
DOI:10. 3969 / j.issn.1671-7856. 2020. 06. 015
中文关键词:  透明细胞肾癌  患者来源肿瘤细胞  分子靶向药物  药物敏感性检测
英文关键词:clear-cell renal carcinoma, molecular-targeting agent, patient-derived cell, patient-derived tumor xenograft model, drug sensitivity test
基金项目:
作者单位E-mail
魏 永 1.青岛大学附属医院,泌尿外科,青岛 266000
2.中国人民解放军海军第 971 医院,泌尿外科,青岛 266071 
779550007@ qq.com 
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中文摘要:
      目的 利用患者来源( patients-derived cells,PDCs) 的透明细胞肾癌( clear cell renal cancer cell, ccRCC)细胞建立肿瘤动物模型(patient-derived tumor xenograft model,PDX model),检测 ccRCC PDCs 对分子靶向药 物的敏感性,为临床诊疗提供理论和实验依据。 方法 将 ccRCC PDCs 接种裸鼠皮下建立肿瘤模型,使用分子靶向药物舒尼替尼 ( Sunitinib)、 索拉 非 尼 ( Sorafenib)、 乐 伐 替 尼 ( Lenvatinib)、 瑞 戈 非 尼 ( Regorafenib)、 阿 帕 替 尼 (Apatinib)以及安罗替尼(Anlotinib)口服灌胃给药,确定药物对 ccRCC PDCs 在裸鼠皮下成瘤的抑制作用。 收集细 胞与肿瘤组织标本,利用定量 PCR 技术检测分子靶向药物作用靶标(VEGFR 等受体酪氨酸蛋白激酶以及 ERK、 AKT 等 MAPK 信号通路所属蛋白激酶),确定 ccRCC PDCs 在实验过程中的遗传背景是否保持稳定。 结果 成功 获得了 5 株 ccRCC PDCs 并利用上述 ccRCC PDCs 接种裸鼠获得了肾癌裸鼠皮下肿瘤模型;在体外培养 PDCs 细胞 过程中,分子靶向药物作用靶标等的表达出现下降或丢失等现象,而通过裸鼠成瘤对 PDCs 细胞进行扩增,肿瘤组 织中分子靶向药物作用靶标等的表达相对稳定;分子靶向药物对 ccRCC PDCs 裸鼠皮下成瘤的抑制作用存在明确 患者来源的个体差异,在所选取的分子靶向药物中,Lenvatinib 的抗肿瘤活性强于其他几种分子靶向药物。 结论 本研究利用患者来源的透明细胞肾癌细胞系成功建立了肾癌动物模型并检测了肾癌细胞对分子靶向药物的敏感 性,能够为相关临床诊疗提供理论和实验依据。
英文摘要:
      Objective To examine the sensitivity of clear-cell renal carcinoma cells ( ccRCCs) using patients- derived cells (PDCs) to molecular-targeted drugs in patient-derived tumor xenograft (PDX) models.Method PDCs from ccRCCs were subcutaneously inoculated into nude mice to establish a tumor model. The molecular-targeting drugs, sunitinib, sorafenib, lenvatinib, regorafenib, apatinib and anlotinib, were orally administered to examine the inhibitory effect of the drug on the subcutaneous formation of PDC-derived ccRCCs in nude mice.Cell and tumor tissue samples were analyzed via qPCR. The targets of the molecular-targeting drugs (i.e., receptor tyrosine protein kinases, such as VEGFR, and protein kinases of the MAPK signaling pathway such as ERK and AKT) were examined.Result Five lines of PDC- derived ccRCCs were successfully established, and the nude mice were injected with PDC-derived ccRCC to obtain a subcutaneous tumor model of kidney cancer in nude mice. Expression of the target molecules of these drugs decreased during in vitro PDC culturing. Moreover, expansion of these molecules in the tumor tissues was relatively stable. The inhibitory rates of the molecular-targeting agents differed for each drug, and the antitumor activity of lenvatinib was stronger than that of several of the other drugs.Conclusions PDC-derived ccRCCs can be used to establish a mouse model of kidney cancer and test the sensitivity of renal cancer cells to molecular-targeted drugs. These models can provide a rational and experimental basis for relevant clinical diagnosis and treatment.
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