以白细胞介素4-受体为靶标的胰腺癌靶向治疗研究

目的 检测白细胞介素4受体(IL-4R)在胰腺癌组织及人胰腺癌细胞株中的表达,观察以抗白细胞介素-4受体单抗(MAIL4R)为载体构建的免疫毒素MAIL4R-CTX对胰腺癌细胞的靶向杀伤作用.方法 应用免疫组织化学检测IL-4R在26例胰腺癌组织、15例胰腺正常组织中的表达;免疫细胞化学染色检测IL-4R在人胰腺癌PANC-1、BxPC-3细胞和人肺腺癌H1299细胞中的表达;采用噻唑蓝(MTT)法观察MAIL4R、眼镜蛇毒细胞毒素(CTX)、免疫毒素MAIL4R-CTX对体外培养PANC-1,BxPC-3细胞和H1299细胞生长的影响.结果 IL-4R在26例胰腺癌组织中均呈不同程度的阳性表达,而15例胰腺正常组织中仅1例呈弱阳性表达,余均为阴性表达;人胰腺癌PANC-1,BxPC-3细胞均表达IL-4R,H1299细胞不表达IL-4R;CTX对PANC-1,BxPC-3和H1299细胞均有明显抑制作用,但对3株细胞的抑制率差异无统计学意义(P＞0.05);MAIL4R对PANC-1、BxPC-3和H1299细胞均无明显抑制作用;MAIL4R-CTX对过表达IL-4R的BxPC-3和PANC-1细胞的生长具有显著的抑制作用,并且为剂量依赖性,而对低表达IL-4R的H1299细胞不敏感,在浓度为18.75 mg/L,作用4h时PANC-1和BxPC-3细胞分别有86.4%和95.2%被杀伤,H1299细胞仅死亡26.8%(P＜0.01).结论 IL-4R过表达于胰腺癌组织和胰腺癌细胞株,而低表达于正常胰腺组织中,免疫毒素MAIL4R-CTX在体外对过表达IL-4R的细胞株PANC-1、BxPC-3有靶向性杀伤作用.

Targeting interleukin-4 receptors for pancreatic cancer therapy

Objective To detect the expression of interleukin-4 receptors (IL-4R) in pancreatic cancer tissue and cell lines,and test the anti-tumor effects of immunotoxin MAIL4R-CTX composed of a targeting moiety monoclonal anti-IL-4R antibody (MAIL4R) and a cytotoxin from cobra venom (CTX).Methods Immunohistochemistry was performed on 15 normal and 26 pancreatic cancer specimens.The expression of IL-4R was detected in pancreatic cancer cell lines PANC-1,BxPC-3 and non-small cell lung cancer cell line H1299.Using MTr method,cytotoxic activity of MAIL4R,CTX and MAIL4R-CTX was tested in PANC-1,BxPC-3 and H1299 cell lines in vitro respectively.Results All pancreatic cancer specimens expressed IL-4R,in contrast,only one normal pancreas samples were stained with MAIIAR weakly;Both BxPC-3 and PANC-1 cells were stained brown,while H1299 cells were not stained;CTX had rapid killing effects on PANC-1,BxPC-3 and H1299 cells but no obvious difference was found among them ( P＞0.05) ;MAIL4R had no obvious killing effect on the above cells; MAIIAR-CTX significantly inhibited growth of BXPC-3 and PANC-1 cells that had high expression of IL-4R and exhibited obvious dose-dependent effect; At the concentration of 18.75 mg/L,the cell killing rate of MAIL4R-CTX on PANC-1 and BxPC-3 cells was 86.4% and 95.2% respectively,while it was only 26.8% on H1299 cells (P＜0.01 ).Conclusion IL-4R was overexpressed in pancreatic cancer tissues and pancreatic cancer cell lines but not or low in normal pancreatic tissues.The immunotoxin MAIL4R-CTX has selective killing effects on pancreatic cancer cells which have high expression of IL-4R.