摘要
目的探讨奥希替尼氘代物(RN9591)对肿瘤细胞体外增殖和对荷瘤裸鼠体内肿瘤生长的影响,并与奥希替尼(AZD9291)比较,确定RN9591的开发前景。方法采用MTT比色法观察RN9591、AZD9291对体外培养的A549、H1975、SW9483种不同EGFR表达型癌细胞株体外增殖的影响,计算IC50;建立EGFR双突变吉非替尼耐药非小细胞肺癌细胞H1975的裸鼠移植瘤模型,观察RN9591200、100、50 mg·kg^-13个剂量组,吉非替尼120 mg·kg^-1组,AZD9291100 mg·kg^-1组的治疗作用。观察给药后荷瘤小鼠的肿瘤体积和瘤重,比较药物对肿瘤生长的影响。结果体外抗肿瘤生长结果表明RN9591对A549、H1975、SW948细胞株的IC50分别为11.43、25.61、59.96μmol·L^-1;AZD9291对A549、H1975、SW948细胞株的IC50分别为9.21、25.45、27.05μmol·L^-1。体内抗肿瘤实验结果表明RN9591高、中、低3个剂量组肿瘤相对增殖率(T/C%)分别为60.9%、72.0%、59.6%;吉非替尼组T/C%为63.9%;AZD9291组T/C%为47.6%。结论与AZD9291相比,RN9591保持了对EGFR突变株及吉非替尼耐药株的杀伤力,并降低了对野生型EGFR的抑制作用,体内实验进一步证明RN9591对非小细胞肺癌有明显抑制活性,提示本品具有良好的开发前景。
Objective To determine the effect of osimertinib-deuterium generation(RN9591)on the proliferation of tumor cells in vitro and tumor growing in vivo in nude mice,and to compare with osimertinib(AZD9291)to determine the prospect of RN9591.Methods The effects of RN9591 and AZD9291 on the proliferation of A549(EGFR-Mut),H1975(EGFR-T790M/L858R)and SW948(EGFR-Wt)cell lines in vitro were observed by MTT colorimetry.IC50 was calculated.A xenograft model of EGFR double mutation gefitinib resistant non-small cell lung cancer cell line H1975 was established in nude mice.The therapeutic effects of RN9591 at 200,100,and 50 mg·kg^-1,Gefitinib at 120 mg·kg^-1 and AZD9291 at 100 mg·kg^-1 were observed.The volume and weight of tumor in tumor bearing mice were observed at different times,and the effects of drugs on the tumor growth were compared.Results The IC50 of RN9591 to A549,H1975 and SW948 cell lines were 11.43,25.61 and 59.96μmol·L^-1.The IC50 of AZD9291 to A549,H1975 and SW948 cell lines were 9.21,25.45 and 27.05μmol·L^-1 respectively.In vivo antitumor test showed that the relative proliferation rate(T/C%)of RN9591 was 60.9%,72.0%and 59.6%in the high,medium and low dose groups,63.9%in the Gefitinib group and 47.6%in the AZD9291 group,respectively.Conclusion Compared with AZD9291,RN9591 maintains the lethality toward EGFR mutant and gefitinib resistant strains,and reduces the inhibition of wild-type EGFR.In vivo test further proves that RN9591 has obvious pharmacological activity on non-small cell lung cancer,suggesting that this product is prospective development.
作者
马仁强
颜乙平
严科池
寇俊萍
朱孝云
张灿锐
MA Ren-qiang;YAN Yi-ping;YAN Ke-chi;KOU Jun-ping;ZHU Xiao-yun;ZHANG Can-rui(Drug Evaluation Center,Guangzhou Boji Medical Biotechnological Co.Ltd.,Guangzhou 510530;China Pharmaceutical University,Nanjing 211100;Changzhou Runnuo Biotechnology Co.Ltd.,Changzhou Jiangsu 213000)
出处
《中南药学》
CAS
2020年第5期785-789,共5页
Central South Pharmacy
基金
广东省科技计划项目(No.2017B020228002)
江苏政策引导专项目基金(No.BZ2016021)。
关键词
奥希替尼氘代物
抗肿瘤
荷瘤裸鼠
奥希替尼
非小细胞肺癌
表皮生长因子受体
osimertinib-deuterium generation
anti-tumor
tumor bearing nude mice
osimertinib
non-small cell lung cance
epidermal growth factor receptor
作者简介
马仁强,男,副主任药师,主要从事药理毒理研究与新药开发研究,E-mail:pony213@163.com。
