应用非小细胞肺癌组织芯片研究新辅助化疗对P-gp、LRP、MRP和GST-π定量表达影响的临床意义

Clinical significance of studying on effects of neoadjuvant chemotherapy on quantitative expression of P-glycoprotein,lung resistance related protein,multidrug resistance-associated protein and glutathione S-transferase with tissue chip of non-small cell

目的探讨新辅助化疗(NACT)对非小细胞肺癌(NSCLC)P-糖蛋白(P-gp)、肺耐药相关蛋白(LRP)、多药耐药相关蛋白(MRP)和谷胱甘肽转移酶S(GST-π)定量表达的影响。方法应用组织芯片、免疫组化及图像定量分析技术,对92例NSCLC标本(其中52例未经化疗的直接手术标本,20例同时具备化疗前活检标本和化疗后手术标本)中P-gp、LRP、MRP和GST-π的表达进行了检测。结果P-gp、LRP、MRP和GST-π在未经化疗的标本中,阳性表达率分别为68.06%,72.22%,81.94%,83.33%;P-gp、LRP和GST-π在腺癌中的表达强度均高于鳞癌(P<0.05,P<0.001,P<0.001),MRP的表达在腺、鳞癌间差异无显著性(P>0.05)。新辅助化疗后,P-gp、GST-π平均光密度与积分光密度在不同临床分期、组织学类型、分化程度、肿瘤大小、年龄以及淋巴结有无转移组中,均高于化疗前(P<0.05或P<0.001);而LRP、MRP平均光密度与积分光密度在上述各组中,在新辅助化疗前、后,差异均无显著性(P>0.05)。结论肺腺癌的原发耐药性可能强于鳞癌;新辅助化疗可能通过诱导耐药蛋白的表达增加肺癌组织的获得性耐药;新辅助化疗的采用与否应视不同病人的具体情况而定,Ⅰ～Ⅱ期NSCLC采用新辅助化疗应慎重,以免影响术后化疗效果;检测NSCLC新辅助化疗前、后耐药蛋白的定量表达,对术前及术后个性化化疗方案的选择和实施具有重要的指导意义。

[Objective] To investigate effects of Neoadjuvant chemotherapy （NACT） on the quantitative expression of P-glycoprotein （P-gp）, lung resistance related protein （LRP）, mulfidrug resistance-associated protein （MRP） and glutathione S-transferase （GST-π） in non-small cell lung cancer （NSCLC）. [Methods] Total 92 specimens from 72 cases of NSCLC patients, including 52 samples of surgery excision from non-NACT-treated patients and 20 paired samples of both biopsy before NACT and surgery excision after NACT from the same patient, were studied. The expression of P-gp, LRP, MRP and GST-π was examined with tissue chip technique and immunohistochemistry. The quantitative analysis was carried out by computer image analysis system. [Resets] In all samples of NSCLC eases before NACT, the positive rate of P-gp, LRP, MRP, GST-π were 68.06%, 72.22%, 81.94%, 83.33%, respectively. The expression of P-gp, MRP and GST-π was significantly higher in adenocarcinoma than in squamous cell carcinoma （P 〈0.05, P 〈0.001, P 〈0.001, respectively）, there was no significant difference with the expression of MRP between adenoeareinoma and squamous cell carcinoma （P 〉0.05）. In samples after treated with NACT, the expression of P-gp, GST-π demonstrated by average optical density and integral optical density were significantly higher （P 〈0.05, P 〈0.001 respeetively） compared with that of biopsy samples taken before NACT. The change in expression of P-gp, GST-π was also showed difference in histopathological types, differentiation, ages, sizes, clinical stages as well as lymph node metastasis or not （P 〈0.05 or P 〈0.001）. There was no significant difference between samples taken before and after NACT （P 〉0.05） with the expression of LRP and MRP demonstrated by both of average optical density and integral optical density. [Conclusions] This study implies that drug resistance in adeno- carcinoma is primarily stronger than that in squamous cell carcinoma. NACT may enhance acquired drug resistance of NSCLC through inducing the expression of drug resistance protein. Results in this study indicate that acquired drug resistance must be considered with the application of NACT to NSCLC patient in clinic, especially to patient in Ⅰ -Ⅱ stage of NSCLC. Since NACT may lead to the enhancement of acquired drug resistance in Ⅰ-Ⅱ stage of NSCLC, this may dwindle the therapeutic effect of chemotherapy after surgery. Comparative examination of drug resistance proteins before and after NACT, combining with comprehensive consideration of chemical regimens of NACT is recommended during chemotherapy of NSCLC for both before and after surgery.