肿瘤血管破坏剂5,6-二甲基黄嘌呤-4-乙酸对小鼠Lewis肺癌转移的抑制作用及机制  

Effect of tumor vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid on metastasis of Lewis lung cancer in mice

作　　者：崔霞 何微 肖智勇 王莹 刘峰 周文霞 CUI Xia;HE Wei;XIAO Zhiyong;WANG Ying;LIU Feng;ZHOU Wenxia(Nanjing University of Chinese Medicine,Nanjing 210023,China;State Key Laboratory of National Security Specially Needed Medicines,Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Beijing 100850,China)

机构地区：[1]南京中医药大学,江苏南京210023 [2]军事科学院军事医学研究院毒物药物研究所,国家安全特需药品全国重点实验室,北京100850

出　　处：《中国药理学与毒理学杂志》2024年第3期161-169,共9页Chinese Journal of Pharmacology and Toxicology

基　　金：天津市科技计划项目(22ZYJDSS00080)。

摘　　要：目的探讨肿瘤血管破坏剂5,6-二甲基黄嘌呤-4-乙酸(DMXAA)对小鼠Lewis肺癌(LLC)转移的抑制作用及其机制。方法制备2种小鼠肿瘤模型(LLC异位移植瘤小鼠模型和转移型LLC小鼠模型),评价DMXAA对LLC转移的抑制作用。LLC异位移植瘤小鼠模型制备成功后,随机分为3组:模型组(含1%DMSO的生理盐水,ip,2天1次)、模型+苏尼替尼组(30 mg·kg^(-1),ip,2天1次)和模型+DMXAA组(25 mg·kg^(-1),ip,给药1次)。首次给药后每隔1天测量小鼠移植瘤体积,并绘制移植瘤体积生长曲线和小鼠体重变化曲线;给药后2和5 d剥瘤称取瘤重,并将瘤组织进行免疫荧光染色,测定血小板内皮细胞黏附分子1(CD31)和α平滑肌肌动蛋白(α-SMA)阳性表达,计算α-SMA/CD31荧光强度比值,表示移植瘤组织血管表面周细胞覆盖率;哌莫硝唑(pimonidazole)染色检测瘤组织低氧程度。转移型LLC小鼠模型制备成功后,随机分为3组:模型组(含1%DMSO的生理盐水,ip,1周2次)、模型+苏尼替尼组(60 mg·kg^(-1),ip,1周2次)和模型+DMXAA组(25 mg·kg^(-1),ip,给药1次)。首次给药后2和5周用小动物活体成像系统观察小鼠体内肿瘤转移,并进行荧光定量分析。结果与模型组相比,模型+苏尼替尼组和模型+DMXAA组移植瘤体积和重量均显著减小(P<0.05,P<0.01);模型+苏尼替尼组小鼠体重明显下降(P<0.05),而模型+DMXAA组则无显著差异。与模型组相比,苏尼替尼对LLC转移无影响,而给药后2周DMXAA明显抑制LLC转移(P<0.01)。给药后5 d,模型+苏尼替尼组和模型+DMXAA组移植瘤组织中周细胞覆盖率均显著升高(P<0.05);模型+苏尼替尼组瘤组织低氧面积无明显变化,模型+DMXAA组瘤组织低氧面积显著降低(P<0.01)。结论肿瘤血管破坏剂DMXAA显著抑制小鼠LLC生长和转移,其机制可能与其诱导肿瘤血管正常化和改善瘤组织低氧微环境有关。OBJECTIVE To investigate the inhibitory effect and mechanism of 5,6-dimethylxanthe-none-4-acetic acid(DMXAA)on metastasis of Lewis lung cancer(LLC)in mice.METHODS The inhibi-tory effect of DMXAA on tumor metastasis was analyzed via an LLC xenograft tumor model and LLC metastatic tumor model.The mice of LLC xenograft tumor model were randomly divided into three groups:model group(physiological saline containing 1%DMSO,ip,once every two days),model+suni-tinib group(30 mg·kg^(-1),ip,once every two days),and model+DMXAA group(25 mg·kg^(-1),ip,once).Tumor volume and body mass were measured once every two days after administration.Two and five days after administration,tumor mass was measured by sacrificing the mice,followed by immunofluores-cence staining of tumor tissues.Platelet/endothelial cell adhesion molecule-1(CD31)andα-smooth muscle actin(α-SMA)were used to analyze the vascular structure of tumor tissues.The tumor hypoxia level was detected using the hypoxia probe pimonidazole staining.The mice of LLC metastatic tumor model were randomly divided into three groups:model group(physiological saline containing 1%DMSO,ip,twice a week),model+sunitinib group(60 mg·kg^(-1),ip,twice a week),and model+DMXAA group(25 mg·kg^(-1),ip,once).At the Two and five weeks after administration,the in vivo tumor growth and metastasis were observed and quantified using a small animal live imaging system.RESULTS Compared with the model group,the tumor volume and mass of the model+sunitinib group and model+DMXAA group were significantly reduced(P<0.05,P<0.01),and DMXAA took effect faster and more significantly than sunitinib.At the same time,compared with the model group,the body mass in the model+sunitinib group decreased significantly(P<0.05),but there was no significant difference in body mass the model+DMXAA group.Compared with the model group,model+sunitinib had no effect on tumor metastasis,but model+DMXAA significantly reduced tumor metastasis two weeks after administration(P<0.01).Compared with the model group,the coverag

关 键 词：肿瘤血管破坏剂 5 6-二甲基黄嘌呤-4-乙酸 苏尼替尼 转移 低氧 

分 类 号：R966[医药卫生—药理学] R979.1[医药卫生—药学]