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中华普通外科学文献(电子版) ›› 2020, Vol. 14 ›› Issue (02) : 84 -88. doi: 10.3877/cma.j.issn.1674-0793.2020.02.002

所属专题: 文献

论著

细胞内伊马替尼浓度在胃肠道间质瘤耐药过程中的作用
盛友纯1, 张强1, 陈铭1, 徐康菁1, 徐皓1,()   
  1. 1. 210029 南京医科大学第一附属医院普外科
  • 收稿日期:2019-05-09 出版日期:2020-04-01
  • 通信作者: 徐皓
  • 基金资助:
    江苏省自然科学基金资助项目(BK20141493)

Role of intracellular imatinib concentration in drug resistance of gastrointestinal stromal tumor

Youchun Sheng1, Qiang Zhang1, Ming Chen1, Kangjing Xu1, Hao Xu1,()   

  1. 1. Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
  • Received:2019-05-09 Published:2020-04-01
  • Corresponding author: Hao Xu
  • About author:
    Corresponding author: Xu Hao, Email:
引用本文:

盛友纯, 张强, 陈铭, 徐康菁, 徐皓. 细胞内伊马替尼浓度在胃肠道间质瘤耐药过程中的作用[J]. 中华普通外科学文献(电子版), 2020, 14(02): 84-88.

Youchun Sheng, Qiang Zhang, Ming Chen, Kangjing Xu, Hao Xu. Role of intracellular imatinib concentration in drug resistance of gastrointestinal stromal tumor[J]. Chinese Archives of General Surgery(Electronic Edition), 2020, 14(02): 84-88.

目的

探讨细胞内伊马替尼浓度与胃肠道间质瘤(GIST)耐药性的关系。

方法

随机选择南京医科大学第一附属医院2014年12月至2016年4月伊马替尼耐药和敏感的进展期GIST患者各4例,采用液相色谱-串联质谱法(LC-MS/MS)检测细胞内外、组织内与血浆伊马替尼浓度。苏木精-伊红染色和免疫组织化学法观察细胞的形态特征。

结果

伊马替尼耐药患者组织内药物浓度比敏感患者的组织内药物浓度低(P<0.05)。与亲代敏感细胞株相比,伊马替尼耐药GIST细胞株中细胞内伊马替尼浓度显著降低,同时细胞形态也发生了变化。

结论

低细胞内药物浓度可能是伊马替尼耐药的重要原因,细胞内伊马替尼浓度可能是治疗GIST过程中的关键要素。

Objective

To investigate the relationship between intracellular imatinib concentration and drug resistance of gastrointestinal stromal tumor (GIST).

Methods

Eight advanced GIST patients with imatinib-resistant and -susceptible were randomly selected from the First Affiliated Hospital of Nanjing Medical University from December 2014 to April 2016. Concentrations of imatinib in cells, tissues and plasma were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The morphological characteristics of cells were observed by hematoxylin-eosin staining and immunohistochemistry.

Results

The imatinib concentration in tissues of imatinib-resistant patients was lower than that of imatinib-susceptible patients (P<0.05). Compared with parental sensitive cell lines, imatinib concentration of imatinib-resistant cell lines decreased significantly and cell morphology was also changed.

Conclusion

Low intracellular drug concentration may be an important reason of imatinib resistance, and intracellular imatinib concentration may be a key point in the treatment of GIST.

表1 8例进展期胃肠道间质瘤患者的临床病理特征
图1 伊马替尼的液相色谱-串联质谱(LC-MS/MS)色谱图和标准曲线 A为伊马替尼总离子色谱图;B为内标总离子色谱图,伊马替尼-d8(内标);C为患者血浆伊马替尼浓度标准曲线;D为细胞内和组织伊马替尼浓度标准曲线
图3 耐药与敏感细胞株细胞学形态和免疫组织化学结果(×400) A为经苏木精-伊红染色,敏感细胞多为梭型、单核、边缘光滑,而耐药细胞株形态更加不规则、边缘粗糙、核质比增大,且多为双核甚至多核;B为CD117免疫组化染色均呈阳性
图4 耐药GIST细胞株的建立与细胞内外伊马替尼浓度 A、B为不同伊马替尼浓度下的细胞抑制曲线;C、D为在2 000 μg/L和3 000 μg/L浓度培育后,敏感细胞株的细胞内伊马替尼浓度显著高于耐药细胞株,**P<0.05,***P<0.001;E、F为不论伊马替尼的浓度暴露,耐药和敏感细胞株的细胞外伊马替尼浓度差异无统计学意义
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