紫杉醇-奥曲肽耦连药靶向治疗非小细胞肺癌  

Paclitaxel-octreotide conjugates inhibit growth of human non-small cell lung cancer cells

作　　者：孙美丽[1] 王秀问[1] 王朴[2] 魏军民[1] 李蕾[2] 

机构地区：[1]山东大学齐鲁医院肿瘤防治中心,济南250012 [2]山东大学药学院药物化学研究所,济南250012

出　　处：《中国肿瘤生物治疗杂志》2007年第4期368-372,共5页Chinese Journal of Cancer Biotherapy

基　　金：山东省科技厅科技计划基金资助项目(No2004GG3202017)~~

摘　　要：目的：在合成紫杉醇-奥曲肽（paclitaxel-octreotide,PTX-OCT）耦连药物的基础上,评价耦连药物对人非小细胞肺癌细胞A549和Calu-6的细胞毒性和靶向性。方法：合成并纯化紫杉醇-奥曲肽耦连药物PTX-OCT和2PTX-OCT。RT-PCR法检测人非小细胞肺癌A549和Calu-6细胞及人成纤维细胞中生长抑素受体（somatostatin receptor,SSTR）的表达;设置3种药物浓度为1、100nmol/L和1μmol/L与癌细胞共同培养,培养时间为24~72h,同时设置对照组;MTT法检测药物对A549、Calu-6细胞以及人成纤维细胞的毒性;流式细胞术检测1μmol/L紫杉醇、PTX-OCT和2PTX-OCT作用后A549细胞周期变化。结果：人非小细胞肺癌A549和Calu-6细胞均表达SSTR2和SSTR5 mRNA,在人成纤维细胞中未检测到SSTR亚型mRNA。紫杉醇-奥曲肽耦连药物对A549和Calu-6细胞的杀伤作用与紫杉醇类似,具有浓度依赖性和时间依赖性;1μmol/L紫杉醇及PTX-OCT和2PTX-OCT作用72h,A549细胞生存率分别为（26.9±7.3）%、（26.6±9.2）%和（35.7±4.3）%;Calu-6细胞生存率分别为（29.5±5.0）%、（28.2±9.7）%和（26.5±4.9）%;均低于24h组（P〈0.05）。1μmol/L紫杉醇作用24h后成纤维细胞生存率为（64.7±8.6）%,PTX-OCT和2PTX-OCT组分别为（86.1±1.8）%和（90±5.6）%,均高于紫杉醇组（P〈0.05）。流式细胞术分析PTX-OCT和2PTX-OCT及紫杉醇作用后,A549细胞周期均停滞在G2/M期。结论：紫杉醇-奥曲肽耦连药物具有细胞毒性和靶向性,紫杉醇-奥曲肽耦连药物有希望作为一种新的靶向药物来治疗非小细胞肺癌。Objective： To evaluate the cytotoxicity and targeting ability of self-developed paclitaxel-octreotide （PTX- OCT） conjugates on A549 non-small cell lung cancer （NSCLC） cells and Calu-6 NSCLC cells. Methods： Conjugates PTX-OCT and 2PTX-OCT were synthesized by our school. Reverse transcription-polymerase chain reaction was used to detect mRNA of human somatostatin receptor subtypes （SSTRs） using specific primers. The cells were treated with different concentrations （1, 100 nmol/L and 1 μmol/L） of paclitaxel and the conjugates for different time periods （24-72 h） ; we also set up a control group. MTr assay was used to evaluate the cell viability after treatment; cell cycle perturbations were determined by FAC Scan flow cytometer 24 h after treatment with 1μmol/L paclitaxel, FTX-OCT, and 2PTX-OCT. Restilts： Both A549 cell and Calu-6 cell expressed the mRNA of SSTR2 and SSTR5 ; no SSTR mRNA was detected in the fi- broblasts. The conjugates had a similar eytotoxieity to paelitaxel; they both effectively inhibited the growth of A549 cells and Calu-6 cells in a concentration- and time-dependent manner. After 72 h treatment with 1 μmol/L paelitaxel, PTX- OCT and 2PTX-OCT, the survival rates of A549 cells were （26.9±7.3）%, （26.6 ±9.2）% and （35.7 ±4.3）%, respectively; the survival rates of Calu-6 cells were （29.5 ± 5.0）%, （28.2 ± 9.7 ）% and （26.5 ±4.9）%, respectively. The survival rate A549 cells at 72 h after treatment was lower than that at 24 h after treatment（ P 〈 0.05 ）. The survival rate of fibroblasts was （64.7 ± 8.6）% 24 h after treatment with 1 μmol/L paelitaxel, significantly lower than those trea-ted with PTX-OCT （86.1 ± 1.8） % and 2PTX-OCT （90 ±5.6） % （both P 〈 0.05）. FCA results showed that the conjugates arrested A549 cells at G2/M phase just as paclitaxel did. Conclusion： Paclitaxel-octreotide conjugates possess cytotoxicity and specific targeting ability; they may be used as a new targeting drug for treatment of NSCLC.

关 键 词：非小细胞肺癌 紫杉醇 紫杉醇-奥曲肽耦连药 生长抑素 靶向 

分 类 号：R734.2[医药卫生—肿瘤]