人源性结肠癌组织异种移植模型在个体化药物治疗中的应用研究

The application of human colon cancer patient derived xenograft model in individualized drug therapy

目的 建立结肠癌人源性肿瘤组织异种移植(patient-derived xenograft,PDX)模型并研究其在化疗药物筛选中的应用价值。方法 将新鲜的人结肠癌手术标本移植于BAIB/c裸小鼠皮下建立结肠癌PDX模型,稳定传至第3代;将PDX模型肿瘤组织与人肿瘤组织H&E染色,比较其组织形态特征;免疫组织化学检测肿瘤组织癌胚抗原(carcino-embryonic antigen,CEA)的表达水平;绘制PDX模型肿瘤生长曲线;使用PDX模型评估临床用药伊利替康(Irinotecan,CPT-11)、5-氟尿嘧啶(5-Fluorouracil,5-FU)和奥沙利铂(Oxaliplatin,OXA)的治疗效果及安全性;对比PDX模型对照组与治疗组血浆CEA表达水平。结果 成功建立3例结肠癌PDX模型,肿瘤组织基本保持了原发瘤组织的形态,其CEA表达水平与人肿瘤组织基本一致。3例PDX模型均显示,CPT-11、5-FU、OXA治疗具有显著效果(P<0.05),其中CPT-11组效果最显著,其次是5-FU和OXA。D34562和D34603模型均显示OXA对小鼠体重影响较大,而CPT-11和5-FU相对安全。CPT-11、5-FU和OXA治疗均可降低PDX模型血浆CEA水平(P<0.05),且CPT-11组CEA水平明显低于5-FU和OXA组(P<0.05),样本D34562、D34603的5-FU组血浆CEA水平明显低于OXA组(P<0.05)。结论 结肠癌PDX模型较好地保持了人源肿瘤组织的特征,CPT-11表现出良好的治疗效果且安全性高。

Objective To establish patient-derived xenograft(PDX) model of colon cancer and explore its application value in the screening of chemotherapy drugs.Methods Fresh human colon cancer tissues were transplanted subcutaneously into BAIB/c nude mice to establish colon cancer PDX models,which was passaged stably to the third generation.The morphology character and the expression levels of carcino-embryonic antigen(CEA) were compared between PDX models tumor and human tumor,and the tumor growth curve of the PDX model were draw.PDX models were used to evaluate single-agent chemotherapy effect and safety,including irinotecan(CPT-11),5-fluorouracil(5-FU) and oxaliplatin(OXA).The CEA level in plasma between the control group and the treatment group of the PDX models were detected.Results The three PDX models were successfully established including D34562,D31427 and D34603.The tumor of all PDX models well maintained the morphology and CEA expression level of the original human tumor tissues,and the tumor growth display exponential trend.Treatment with CPT-11,5-FU,or OXA inhibited the tumor growth significantly on those three PDX models(P<0.05),and the CPT-11 showed the best treatment effect,followed by 5-FU and OXA.Treatment with OXA in D34562 or D34603 model greatly impact on the weight of mice,while treatment with CPT-11 or 5-FU has little influence on the weight of mice.After treatment with CPT-11,5-FU or OXA,the CEA level in plasma was significantly decreased(P<0.05),and CPT-11 showed more apparent effect than that of the 5-FU group or OXA group(P<0.05).Conclusion The colon cancer PDX model maintains the heterogeneity of human tumor tissues.CPT-11 displayed the best effect and high safety in the treatment of colon cancer.