奥曲肽紫杉醇偶联物靶向治疗小细胞肺癌的实验研究

山东大学学报(医学版) ›› 2011, Vol. 49 ›› Issue (3): 27-32.

奥曲肽紫杉醇偶联物靶向治疗小细胞肺癌的实验研究

王健1，王秀问1，王亚伟1，马道新2，王朴3

山东大学 1.齐鲁医院肿瘤中心化疗科，济南 250012； 2.齐鲁医院肿瘤中心血液科，济南 250012；3.药学院药物化学研究所，济南 250012

收稿日期:2010-12-31 出版日期:2011-03-10 发布日期:2011-03-10
通讯作者: 王秀问（1962- ），男，教授，博士生导师，主要从事肺癌和胃肠道肿瘤的研究。E-mail:wangxw12@yahoo.com 王朴（1962- ），男，教授，主要从事小分子多肽合成方面的研究。E-mail：puwang@sdu.edu.cn
作者简介:王健（1983- ），男，硕士研究生，主要从事肿瘤靶向治疗方面的研究。
基金资助:
山东省自然科学基金资助课题（Y2008C31）。

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

WANG Jian1, WANG Xiu-wen1, WANG Ya-wei1, MA Dao-xin2, WANG Pu3

1. Department of Chemotherapy, Cancer Center, Qilu Hospital of Shandong University, Jinan 250012, China;
2. Department of Blood, Cancer Center, Qilu Hospital of Shandong University, Jinan 250012, China;
3. Institute of Pharmaceutical Science, School of Pharmacy, Shandong University, Jinan 250012, China

Received:2010-12-31 Online:2011-03-10 Published:2011-03-10

摘要/Abstract

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（1～1000nmol/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。

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

Abstract:

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 24h after the treatment with 1000nmol/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-(1-1000nmol/L) and time- (24h, 48h and72h) dependent manner. However, the cytotoxicity of the conjugates to fibroblasts was much lower than that of paclitaxel(P<0. 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.

Key words: Small cell lung cancer; Paclitaxel-octreotide conjugates; Somatostatin receptor; Targeted

中图分类号:

R734.2

王健1，王秀问1，王亚伟1，马道新2，王朴3. 奥曲肽紫杉醇偶联物靶向治疗小细胞肺癌的实验研究[J]. 山东大学学报(医学版), 2011, 49(3): 27-32.

WANG Jian1, WANG Xiu-wen1, WANG Ya-wei1, MA Dao-xin2, WANG Pu3. Paclitaxel-octreotide conjugates inhibit growth of human small cell lung cancer cells[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2011, 49(3): 27-32.

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