奥曲肽紫杉醇偶联物靶向治疗小细胞肺癌的实验研究  

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

作　　者：王健[1] 王秀问[1] 王亚伟[1] 马道新[2] 王朴[3] 

机构地区：[1]山东大学齐鲁医院肿瘤中心化疗科,济南250012 [2]山东大学齐鲁医院肿瘤中心血液科,济南250012 [3]山东大学药学院药物化学研究所,济南250012

出　　处：《山东大学学报（医学版）》2011年第3期27-32,共6页Journal of Shandong University:Health Sciences

基　　金：山东省自然科学基金资助课题(Y2008C31)

摘　　要：目的合成奥曲肽紫杉醇偶联物(paclitaxel-octreotide conjugates),探讨偶联物对人小细胞肺癌(SCLC)细胞株H446的细胞毒性和靶向性。方法合成分离并纯化奥曲肽紫杉醇偶联物PTX-OCT、2PTX-OCT、PTX-Tyr-OCT和2PTX-Tyr-OCT,实时定量PCR法检测人SCLC细胞株H446及人成纤维细胞中生长抑素受体(SSTR)的表达,四甲基偶氮唑蓝微量酶反应比色(MTT)法检测不同浓度和时间梯度的偶联药物对H446及人成纤维细胞的抑制率,流式细胞术检测1000nmol/L紫杉醇、PTX-OCT、2PTX-OCT、PTX-Tyr-OCT和2PTX-Tyr-OCT作用后H446细胞周期和凋亡率的变化。结果 H446细胞中SSTR1～5 mRNA均有较高量的表达,而人成纤维细胞中未检测到SSTR mRNA的表达。奥曲肽紫杉醇偶联物对H446细胞的杀伤作用与紫杉醇相似,具有浓度(1～1000 nmol/L)和时间(24、48、72h)依赖性;而对SSTR阴性的成纤维细胞,偶联药物的毒性作用要明显低于紫杉醇(P<0.05)。流式细胞术分析PTX-OCT、2PTX-OCT、PTX-Tyr-OCT和2PTX-Tyr-OCT作用后,H446细胞周期均停滞在G2/M期。结论奥曲肽紫杉醇偶联药物具有较好的靶向性,在SCLC的治疗中具有重要的应用前景。Objective To evaluate the anti-proliferative effect and targeting ability of paclitaxel-octreotide conjugates on H446 small cell lung cancer（SCLC） cells.Methods PTX-OCT,2PTX-OCT,PTX-Tyr-OCT and 2PTX-Tyr-OCT were synthesized by coupling cytotoxic paclixtel（PTX） to somatostatin analog octreotide（OCT）.mRNA expressions of human somatostatin receptor subtypes（SSTRs） were detected in H446 cells and fibroblasts by real-time PCR.The cytotoxicity of paclitaxel and the conjugates（at different treatment concentrations and periods） was determined by MTT assay.Cell cycle variation and apoptosis were analyzed by flow cytometry 24 h after the treatment with 1 000 nmol/L of paclitaxel,PTX-OCT,2PTX-OCT,PTX-Tyr-OCT and 2PTX-Tyr-OCT.Results H446 cells expressed mRNA of the five SSTRs,while no SSTR mRNA expression was detected in fibroblasts.The conjugates had an anti-proliferative effect similar to paclitaxel,inhibiting the growth of H446 cells in a dose-（1-1 000 nmol/L） and time-（24 h,48 h and 72 h） dependent manner.However,the cytotoxicity of the conjugates to fibroblasts was much lower than that of paclitaxel（P0.05）.Flow cytometry results indicated that the conjugates blocked H446 cells at the G2/M phase.Conclusion Paclitaxel-octreotide conjugates have significant prospects in targeted therapy mediated by SSTRs in human SCLC.

关 键 词：小细胞肺癌 奥曲肽紫杉醇偶联物 生长抑素受体 靶向 

分 类 号：R734.2[医药卫生—肿瘤]