藁本内酯联合替莫唑胺体内外抗胶质瘤协同作用及安全性初探  

The synergistic efficacy and preliminary safety exploration of ligustilide and temozolomide against glioma in vitro and in vivo

作　　者：刘豫 张明霞 胡鹏翼 汪莲芳 王佳华 李佳巧 郑琴 LIU Yu;ZHANG Ming-xia;HU Peng-yi;WANG Lian-fang;WANG Jia-hua;LI jia-qiao;ZHENG Qin(Key Laboratory of Modern Chinese Medicine Preparation of the Ministry of Education,Jiangxi University of Chinese Medicine,Nanchang 330004,China)

机构地区：[1]江西中医药大学现代中药制剂教育部重点实验室,南昌330004

出　　处：《中国新药杂志》2024年第17期1805-1812,共8页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(82060719);江西省大学生创新创业项目(202210412232);江西省大学生创新专项基金资助项目(JZYC23S67)。

摘　　要：目的:藁本内酯(ligustilide,LIG)与替莫唑胺(temozolomide,TMZ)联合给药体内、体外协同抗胶质瘤作用,以及初步安全性评价研究。方法:CCK-8法检测TMZ,LIG单用及联用对U251细胞增殖作用的影响,通过金正均法Q值评估两药联用的体外协同抗肿瘤效果。建立C6移植胶质瘤大鼠模型,考察尾静脉注射给药TMZ,LIG单用及联合给药对大鼠皮下移植瘤生长影响,计算抑瘤率,并结合HE染色结果评价体内协同抗肿瘤作用。采用脏器系数及各组织器官HE染色病理观察初步评价联合用药安全性。结果:LIG与TMZ在8∶1~8∶5的比例下对U251细胞存活率有协同抑制作用;当联合给药比例为4∶1时Q值最大,协同作用最强。体内实验结果显示,尾静脉注射18.47 mg·kg^(-1)TMZ和4.61 mg·kg^(-1)LIG组合,对大鼠移植瘤模型的肿瘤生长具有显著抑制作用(P<0.05,0.01)。移植瘤组织切片表明,该剂量联合组肿瘤组织坏死最大。各给药组脏器系数同对照组相比均无显著性差异,HE病理组织观察各组织器官未体现出更强的组织异常程度。结论:TMZ与LIG以质量比为4∶1联合给药,体内体外均有协同抗胶质瘤作用,同时初步显示无明显的脏器损伤。Objective:To investigate the synergistic anti⁃glioma effects of ligustilide(LIG)co⁃administered with temozolomide(TMZ)both in vivo and in vitro and to preliminarily study the safety of the combination.Methods:CCK⁃8 method was used to detect the effects of TMZ and LIG alone or in combination on the proliferation of U251 cells.The synergistic antitumor effect of the combination of the two drugs in vitro was assessed by the Q⁃value of the Jin Jung Mean method.A C6 graft glioma rat model was established to investigate the effects of TMZ and LIG alone and in combination via tail vein administration on the growth of subcutaneous graft tumors in rats.The tumor suppression rate was calculated and the synergistic anti⁃tumor effects in vivo was evaluated in combination with HE staining results.Preliminary safety evaluation of the combination was carried out using organ coefficients and HE staining pathologic observations of each tissue and organ.Results:LIG and TMZ had a synergistic inhibitory effect on U251 cell viability at ratios ranging 8∶1~8∶5.The Q value was highest and the synergistic effect was strongest when the coadministration ratio was 4∶1.The results of in vivo experiments showed that the combination of 18.47 mg·kg^(-1) TMZ and 4.61 mg·kg^(-1) LIG injected intravenously via the tail vein had a significant inhibitory effect on the tumor growth in the rat transplantation tumor model(P<0.05,0.01).Tissue sections of transplanted tumors showed that the necrosis of tumor tissues was the severest in this dose combination group.There was no significant difference in organ coefficients of each dosing group compared with the control group,and HE pathological tissue observation of each tissue and organ did not elucidate stronger tissue abnormality.Conclusion:Co⁃administration of TMZ and LIG at a mass ratio of 4∶1 preliminarily showed synergistic anti⁃glioma effects both in vivo and in vitro as well as unobvious organ damage.

关 键 词：藁本内酯 替莫唑胺 胶质瘤 增殖 联合给药 抗肿瘤 

分 类 号：R965[医药卫生—药理学]