新型光敏剂光动力治疗耐药胃癌的实验研究  

Experimental study of a novel photosensitizer mediated photodynamic therapy on resistant gastric cancer

作　　者：陈靖京 洪阁 刘姝萍[3] 刘天军 CHEN Jing-jing;HONG Ge;LIU Shu-ping;LIU Tian-jun(Dept of Pharmacology,Dept of Pharmacy of Changzhi Medical College,Changzhi Shanxi046000,China;MolecularDesign and Nanotechnology Lab of Institute of Biomedical Engineering,Chinese Academy of Medical Sciences,Tianjin300192,China;Dept of Dermatology,Heping Hospital Affiliated to Changzhi Medical College,Changzhi Shanxi046000,China)

机构地区：[1]长治医学院药学系药理学教研室,山西长治046000 [2]中国医学科学院生物医学工程研究所分子设计与纳米技术实验室,天津300192 [3]长治医学院附属和平医院皮肤科,山西长治046000

出　　处：《中国药理学通报》2019年第5期661-667,共7页Chinese Pharmacological Bulletin

基　　金：长治医学院创新团队项目(No cx201419);长治医学院博士启动基金(No BS12001)

摘　　要：目的研究新型光敏剂DTP介导的光动力学治疗(PDT)对人长春新碱(vincristine,VCR)耐药胃癌细胞SGC7901/VCR的治疗作用,并揭示DTP-PDT与P-gp之间的关系及相关机制。方法 MTT法评价DTP-PDT对SGC7901/VCR细胞的杀伤作用及联合治疗作用;建立耐药细胞裸鼠模型,计算瘤体积,观察治疗效果;流式细胞术检测细胞凋亡及坏死情况;检测DTP-PDT后,细胞内单线态氧(~1O_2)产率;流式细胞术和qPCR技术分别检测MDR1 mRNA和P-gp表达。结果 DTP-PDT对SGC7901/VCR细胞及其裸鼠移植瘤均有明显杀伤作用,细胞死亡方式为凋亡;DTP-PDT后,细胞内~1O_2水平增加;DTP-PDT能够抑制耐药细胞MDR1 mRNA转录和P-gp表达,生育酚(α-tocopherol)可以减弱这种抑制;DTP-PDT与VCR合用对耐药细胞有协同治疗作用,生育酚可以减弱这种协同。结论 DTP-PDT产生的~1O_2可以抑制SGC7901/VCR生长,诱发细胞凋亡,而且能够抑制细胞表面P-gp的过表达,减少化疗药物外排,使DTP-PDT与VCR有协同治疗作用。Aim To investigate the therapeutic efficacy of DTP-mediated photodynamic therapy (PDT) on SGC7901/VCR human vincristine(VCR)-resistant gastric cancer cells,and to reveal the relationship between DTP-PDT and P-gp. Methods MTT assay was employed to evaluate the cytotoxicity of DTP-PDT and combination treatment with DTP-PDT and VCR.A SGC7901/VCR-bearing nude mouse model was established,and the tumor volume was measured to draw the growth curve.Cell apoptosis was detected by flow cytometry,and the yield of intracellular singlet oxygen ( 1O 2) was determined after DTP-PDT.The expression of MDR1 mRNA and P-gp was determined by qPCR and flow cytometry,respectively. Results DTP-PDT demonstrated significant cytotoxicity on SGC7901/VCR cells and the nude mice transplanted tumor.DTP-PDT could induce the apoptosis of SGC7901/VCR cells and the generation of intracellular 1O 2.DTP-PDT could inhibit the expression of MDR1 mRNA and P-gp,which could be reduced by α-tocopherol.Combined treatment with DTP-PDT and VCR demonstrated synergistic efficacy on resistant cells,which could be reduced by α-tocopherol. Conclusions 1O 2 generated by DTP-mediated PDT could inhibit the growth of SGC7901/VCR cells and induce cell apoptosis.Meanwhile,it inhibits the over-expression of P-gp on cell membranes,leading to reduced efflux of VCR and synergistic efficacy with DTP-PDT and VCR eventually.

关 键 词：长春新碱耐药胃癌 多药耐药 新型光敏剂 光动力学治疗 单线态氧 P糖蛋白 联合治疗 

分 类 号：R-332[医药卫生] R329.25