胃癌人源异种移植模型的建立及其在药效学研究中的应用

Establishment of a patient-derived xenotransplantation model of gastric cancer and its application in pharmacodynamics study

目的建立胃癌的人源肿瘤异种移植(PDX)动物模型,探讨化疗药物在该模型中的抑瘤效果。方法将人胃癌组织接种于NOG小鼠两侧腋窝皮下,传3代。挑选第3代NOG小鼠肿瘤组织,接种于21只重度联合免疫缺陷-非肥胖糖尿病(SCID-NOD)小鼠左腋皮下,建立胃癌PDX小鼠模型。将接种后的小鼠分为对照组(仅用0.9%氯化钠注射液处理)、奥沙利铂组、顺铂组、紫杉醇组、氟尿嘧啶组、替吉奥组、卡培他滨组,每组3只,给予相应药物。记录不同时间小鼠存活情况、瘤体积及瘤质量,给药第61天后处死小鼠,评价6种化疗药物对该胃癌PDX模型的肿瘤抑制效果。结果胃癌组织传3代后PDX动物模型传瘤稳定性提高,肿瘤生长初期均一性良好。该模型用药前期对奥沙利铂、氟尿嘧啶和卡培他滨较为敏感,第31天的肿瘤生长抑制指数(TGI)分别为63.37%、52.11%和78.48%;用药末期,模型对卡培他滨的敏感性最好,第61天TGI为59.22%,抑瘤率为58.65%。用药后TGI曲线显示,紫杉醇对模型无明显抑瘤效果,顺铂抑瘤效果最差,模型对替吉奥的耐受性较差。结论成功建立胃癌PDX动物模型,卡培他滨对其抑瘤效果最好。

Objective To establish a patient-derived xenotransplantation(PDX)animal model of gastric cancer,and observe the anti-cancer effect of chemotherapeutic drugs on this model.Methods Human gastric cancer tissues were inoculated into the subcutaneous tissues of both axillaries of NOG mice and were subcultured for 3 generations.The tumor tissues of the third-generation NOG mice were selected and inoculated into the subcutaneous tissues of left axillary of 21 severe combined immunodeficiency-non-obese diabetes mellitus(SCID-NOD)mice to establish PDX mouse model of gastric cancer.The inoculated mice were divided into control group(mice received only 0.9%sodium chloride injection),oxaliplatin group,cisplatin group,paclitaxel group,fluorouracil group,tegafur,gimeracil and oteracil porassium capsules group and capecitabine group,with 3 mice in each group,and the corresponding drugs were given.The mice survival status,tumor volume and tumor weight at different times were recorded.Mice were sacrificed on the 61st day of administration,and the tumor inhibition effects of 6 kinds of chemotherapy drugs on the PDX model of gastric cancer were evaluated.Results After being subcultured for 3 generations,the stability of tumor transmission in PDX animal model of gastric cancer was improved,and the homogeneity of tumor growth was good at the initial stage.At the early stage of administration,the model was more sensitive to oxaliplatin,fluorouracil and capecitabine,and the tumor growth inhibition(TGI)values on the 31st day were 63.37%,52.11%and 78.48%,at the end of administration,the model had the best sensitivity to capecitabine with a TGI value of 59.22%and a tumor inhibition rate of 58.65%on the 61st day.The TGI curve after administration showed that paclitaxel had no obvious anti-tumor effect,cisplatin had the worst anti-tumor effect,and the model had poor tolerance to tegafur,gimeracil and oteracil porassium capsules.Conclusion The PDX animal model of gastric cancer is successfully established,and capecitabine has the best tumor suppressive effect on this model.