EP4受体拮抗剂对前列腺癌骨转移的抑制作用

Inhibitory effect of EP4 antagonist on bone metastasis of prostate cancer

目的炎症与前列腺癌的发生发展关系密切,前列腺素E2受体EP4作为相关炎症反应的下游靶点选择性高。应用EP4受体拮抗剂ONO-AE3-208作用于裸鼠前列腺癌骨转移模型,观察其对前列腺癌骨转移的抑制作用,从动物实验水平初步探讨选择性拮抗EP4受体对前列腺癌全身骨转移的抑制作用。方法将荧光素稳定转染前列腺癌PC3细胞构建PC3/LUC细胞,经裸鼠左心室注射PC3/LUC细胞以构建全身转移模型。于构建术后当天开始按实验组及对照组分别腹腔注射ONO-AE3-208及双蒸水(均为200μL),应用活体生物发光成像系统观察比较术后2组带瘤生长裸鼠模型肿瘤荧光负荷及生存曲线的变化情况。结果裸鼠模型带瘤生长40、45、50、55、60 d后,可见对照组较实验组裸鼠模型骨转移灶荧光负荷[量子数/(s·cm2·球面弧度)]明显增加[(1186899±1844056)vs(372705.6±399 727)、(1 347 038±1 580 655)vs(372 646.7±169 171.5)、(1 760 021±2 274 680)vs(548 350±969 977.4)、(5 056 210±2 265 006)vs(1 045 210±1 980 445)、(12 925 386±2 223 240)vs(1 127 069±2 175 526)],差异均有统计学意义(P<0.05);以2组裸鼠生存率和时间的关系绘制生存曲线并行相关统计学分析可以发现:实验组的生存率为13.3%,对照组的生存率为0%。Log-rank检验表明,实验组的中位生存时间为162 d,对照组为116 d,2组之间的生存率随着时间的变化差异具有统计学意义(P<0.01)。结论 EP4受体拮抗剂ONOAE3-208对前列腺癌裸鼠全身骨转移有抑制作用且可以延长骨转移裸鼠模型的生存时间。

Objective The purpose of this study was to examine the inhibitory effect of ONO-AE3-208,an EP4 antagonist,on prostate cancer with bone metastasis in an animal model.Methods A PC3/LUC cell line was constructed by stably transfecting luciferin to prostate cancer PC3 cells and inoculated into the left ventricle of nude mice to establish an animal model of prostate cancer with bone metastasis.After modeling,the animals in the experimental group and control groups were intraperitoneally given ONO-AE3-208 and double-distilled water,respectively,followed by examination of the metastasis loci and tumor burden by bioluminescence imaging and statistical analysis with survival curves.Results At 60 days after modeling,the animals in the control group exhibited significantly increased metastases and fluorescence burdens as compared with the experimental group（P〈0.01）,and the increase was in a time-dependent manner（P〈0.01）.At 60 days,the controls began to die while the experimental animals remained well alive,and at 180 days,the mice of the control group all died.The survival rate of the animals was significantly higher in the experimental group than in the control（13.3% vs 0%,P〈0.01） and the median survival time remarkably longer in the former than in the latter group（162 d vs 116 d,P〈0.01）.Conclusion The EP4 antagonist ONO-AE3-208 inhibited the bone metastasis of prostate cancer and prolonged the survival time in the model mice.