人源性胃癌移植瘤模型的初步建立及其评价

doi:10.3969/j.issn.1674-5817.2014.04.001

实验动物与比较医学 ›› 2014, Vol. 34 ›› Issue (4): 259-265.DOI: 10.3969/j.issn.1674-5817.2014.04.001

• 论著 • 下一篇

人源性胃癌移植瘤模型的初步建立及其评价

许春花^1,2, 杨磊³, 汤旭蓁¹, 胡刚¹, 耿沁⁴, 欧阳可栋¹, 谢付波¹, 王科¹, 秦宵然¹, 刘继斌³, 杨伟敏¹, 陶维康¹, 张一心³, 周禾¹

1.上海睿智化学研究有限公司, 上海 201203;
2.复旦大学, 上海 200433;
3.南通市肿瘤医院, 南通 226361;
4.上海市肿瘤研究所, 上海 200023

收稿日期:2013-12-02 出版日期:2014-08-25 发布日期:2014-08-25
作者简介:许春花(1985-), 女, 硕士研究生,E-mail: chhxu@chempartner.cn;共同第一作者: 杨磊, 女, E-mail: leiyang.53@163.com
基金资助:
上海市科技发展基金项目(No.11140901400)

Initially Establishment and Characterization of Patient Derived Gastric Cancer Xenograft Models

XU Chun-hua^1,2, YANG Lei³, TANG Xu-zhen¹, HU Gang¹, GENG Qin⁴, OU YANG Ke-dong¹, XIE Fu-bo¹, WANG Ke¹, QIN Xiao-ran¹, LIU Ji-bin³, YANG Wei-min¹, TAO Wei-kang¹, ZHANG Yi-xin³, ZHOU He¹

1. Shanghai ChemPartner Co.,Ltd, Shanghai 201203, China;
2. Fudan University, Shanghai 200433, China;
3. Nantong Tumor Hospital, Nantong 226361, China;
4. Shanghai Cancer Institute, Shanghai 200023, China

Received:2013-12-02 Online:2014-08-25 Published:2014-08-25

摘要/Abstract

摘要： 目的将临床胃癌组织皮下移植于免疫缺陷小鼠,以建立人源性胃癌移植瘤模型,并对建成模型进行初步评价。方法将98例手术切除的胃癌组织分别皮下移植于SCID小鼠体内,待移植瘤体积长至500~1000 mm³时,取出肿瘤传代至BALB/c-nu/nu裸小鼠体内,同时进行速冻,石蜡包埋,冻存等样本组织库保藏。对石蜡包埋的组织进行HE染色,观察其病理特征; 选取12例生长良好的模型用5-氟尿嘧啶和顺铂进行药效学实验;选取3例模型进行体外药物敏感性实验。结果 25例胃癌模型移植成功并能够稳定传代,成功率为25.52%。各代移植瘤组织形态学特征与患者肿瘤组织一致。体内药效学结果表明, 5-氟尿嘧啶(25 mg/kg)对2例模型有一定的抑制作用(TGI>60%),对10例模型无明显的抑制作用。顺铂(5 mg/kg)对3例模型有明显的抑制作用(TGI>100%),对4例模型有一定的抑制作用(TGI,60%~90%),对5例模型无明显抑制作用(TGI<60%)。体外药物敏感性实验表明对5-氟尿嘧啶敏感程度依次为GAX001(IC₅₀:3.187 μm)>GAX007(IC₅₀:6.886 μmol)>GAX027(IC₅₀:8.323 μmol), 对顺铂敏感程度依次为GAX027(IC₅₀:2.753 μmol)>GAX001(IC₅₀:3.211 μmol)> GAX007(IC₅₀:8.137 μmol)。结论成功建立了25例人源性胃癌小鼠移植瘤模型,移植瘤保留了临床胃癌的病理特征,对其中12例进行的药效学评价表明对相同的化疗药物敏感性不同,能够反映患者的遗传多样性,可用于抗肿瘤药物的筛选和研究。

关键词: 胃癌, 人源性模型, 肿瘤模型, 皮下移植, 抗肿瘤药物

Abstract: Objective To establish the patient derived gastric cancer xenografts by subcutaneous implantation of clinical gastric cancer specimens in immunodeficient mice, and assess its characters. Methods Ninety-eight fresh human gastric cancer specimens were subcutaneously implanted into SCID mice. They were serially passaged with BALB/c-nu/nu mice when the xenograft tumors reached size 500~1000 mm³. Tumors were cryoperserved in liquid nitrogen for future model recovery, and also snap frozen, paraffin-embedded for future analysis. H&E staining and pathological analyses were also performed. Twelve selected patient derived gastric cancer xenograft models were evaluated by in vivo efficacy studies and in vitro chemo sensitivity studies. Results 25 gastric cancer xenografts successfully developed into tumor and could be continuously passaged to next generations, the engraftment efficency is 25.52%. These xenografts showed similar histological features compared with the original clinical specimen. Efficacy studies in vivo showed individual differences in sensitivity to 5-FU and cisplatin among different models: 2 xenografts were highly inhibited by 5-FU (TGI>60%), the same treatment is less effective in the other 10 xenografts; 3 xenografts were completely inhibited by cisplatin (TGI>100%), 4 xenografts were highly inhibited by cisplatin (TGI, 60%-90%), and 5 other xenografts were relatively insensitive to cisplatin treatment (TGI<60%). Chemo sensitivity studies in vitro were performed with 3 representative models, their sensitivity to 5-FU is GAX001(IC₅₀:3.187 μmol) > GAX007(IC₅₀:6.886 μmol) > GAX027(IC₅₀:8.323 μmol), and their sensitivity to cisplatin is GAX027(IC₅₀:2.753 μmol) > GAX001(IC₅₀:3.211 μmol) > GAX007(IC₅₀:8.137 μmol). Conclusions 25 Patient derived gastric cancer xenograft models were successfully established. The transplanted tumors showed similar histological features compared with the original clinical specimen. From the results of the 12 efficacy study, the xenografts showed differently sensitivity to different chemotherapy, representing different chemo-responses in the clinic. These gastric cancer models are valuable for anti-cancer drug development and research

Key words: Gastric cancer, Patient derived xenograft model, Cancer model, Subcutaneous transplantation, Anti-cancer drugs

中图分类号:

Q95-33

许春花, 杨磊, 汤旭蓁, 胡刚, 耿沁, 欧阳可栋, 谢付波, 王科, 秦宵然, 刘继斌, 杨伟敏, 陶维康, 张一心, 周禾. 人源性胃癌移植瘤模型的初步建立及其评价[J]. 实验动物与比较医学, 2014, 34(4): 259-265.

XU Chun-hua, YANG Lei, TANG Xu-zhen, HU Gang, GENG Qin, OU YANG Ke-dong, XIE Fu-bo, WANG Ke, QIN Xiao-ran, LIU Ji-bin, YANG Wei-min, TAO Wei-kang, ZHANG Yi-xin, ZHOU He. Initially Establishment and Characterization of Patient Derived Gastric Cancer Xenograft Models[J]. Laboratory Animal and Comparative Medicine, 2014, 34(4): 259-265.

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人源性胃癌移植瘤模型的初步建立及其评价

Initially Establishment and Characterization of Patient Derived Gastric Cancer Xenograft Models

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