摘要
目的探讨卡培他滨剂量与人源异种移植(PDX)的结直肠癌小鼠模型的疗效、心脏毒性之间的关系。方法将1例结直肠癌患者新鲜癌组织移植至免疫缺陷NOG小鼠双腋皮下,建立PDX模型并稳定传代。对原代和第二代肿瘤组织,采用HE染色观察肿瘤组织细胞形态,采用免疫组织化学法检测肿瘤标志物表达情况,以对模型进行评价。小鼠胃灌注200、300、400 mg/kg卡培他滨,1次/d,分别为低、中、高剂量组,每组5只,对照组胃灌注0.9%NaCl溶液;给药14 d,停药7 d,按此方式连续用药。每天测量小鼠体质量,每3 d测量肿瘤体积。观察100 d后,处死小鼠,剖取瘤块,测量肿瘤质量,计算肿瘤体积、肿瘤体积抑制率和抑瘤率,HE染色观察肿瘤组织细胞形态,采用酶联免疫吸附试验检测小鼠血清中抑瘤效应指标rasP21、环氧合酶2(COX2)、前列腺素E2(PGE2)及心脏毒性指标心肌肌钙蛋白Ⅰ(cTn-Ⅰ)、脑钠尿肽(BNP)蛋白水平。结果成功构建PDX结直肠癌移植小鼠模型,模型较好地保留了原发肿瘤的组织学特性。给药期间,卡培他滨高剂量组1只小鼠死亡,卡培他滨剂量越高,肿瘤体积增大的速度越慢。至处死小鼠时,4组小鼠体质量差异无统计学意义(P>0.05);对剖取的肿瘤组织测量显示,卡培他滨中、高剂量组肿瘤体积和肿瘤质量均较对照组降低(均P<0.05),且随剂量增高降低越明显;低、中、高剂量组肿瘤体积抑制率分别为42.61%、67.61%、77.27%,抑瘤率分别为35.53%、67.77%和75.09%;中、高剂量组血清抑瘤效应指标rasP21、COX2、PGE2蛋白均较对照组降低(均P<0.05),心脏毒性指标cTn-Ⅰ、BNP蛋白水平均较对照组升高(均P<0.05)。结论所构建PDX结直肠癌小鼠模型可以较好地保留原肿瘤的组织学特性。小鼠模型经中、高剂量卡培他滨治疗后,抑瘤效果明显,但有造成心肌损害的风险。
Objective To explore the correlation of the dose of capecitabine with the efficacy and cardiotoxicity in patient-derived tumor xenograft(PDX)model of mice with colorectal cancer.Methods The fresh cancer tissues of 1 colorectal cancer patient were transplanted into the bilateral axillary subcutaneous of immunodeficient NOG mice to establish PDX model and passage stably.And then the morphology of tumor cells in primary generation and the second-generation tumor tissues was observed by using HE staining.The expression of tumor markers was detected by using immunohistochemistry method,and the model was evaluated.Mice were intragastrically infused with 200,300 and 400 mg/kg capecitabine once a day,which were treated as low,middle and high dose groups respectively,5 rats in each group;in the control group,0.9%NaCl solution was perfused into the stomach;14 d in total,use stop for 7 d,consecutively administered in this way.The body weight was measured every day and the tumor volume was measured every 3 days.After 100 days of observation,the mice were killed,and the tumor tissue was taken to measure the tumor weight and then the tumor volume,tumor volume inhibition rate and tumor inhibition rate were calculated.The morphology of tumor tissues was observed by using HE staining.The protein levels of anti-tumor effect indexes like rasP21,cyclooxygenase 2(COX2),prostaglandin E2(PGE2),cardiac troponinⅠ(cTn-Ⅰ)and brain natriuretic peptide(BNP)in serum of mice were detected by using enzyme linked immunosorbent assay(ELISA).Results PDX model of mice with colorectal cancer was successfully constructed,and the histological characteristics of the primary tumor in the model were well preserved.During administration,1 mouse died in the capecitabine high dose group;a slow down in tumor volume growth could be found with the increased dose of capecitabine.There was no statistically significant difference in body weight among 4 groups until all mice were killed(P>0.05).The tumor volume and tumor weight in the low,middle and high dose groups were lower than those in the control group(all P<0.05),and the tumor volume and tumor weight showed an obvious decrease with the increase in dose.The tumor volume inhibition rates of low,middle and high dose groups were 42.61%,67.61%and 77.27%,respectively,and the tumor inhibition rates were 35.53%,67.77%and 75.09%,respectively.The serum anti-tumor effect indexes rasP21,COX2 and PGE2 in the middle and high dose groups were decreased compared with those in the control group(all P<0.05),while cTn-Ⅰand BNP levels were increased compared with those in the control group(all P<0.05).Conclusions The established PDX model of mice with colorectal cancer can better retain the histological characteristics of the original tumor.After treatment of middle and high dose of capecitabine,the tumor inhibition effect is obvious,but the risk of myocardial damage should be noticed.
作者
张宇涛
杨喜花
杨永明
白文启
Zhang Yutao;Yang Xihua;Yang Yongming;Bai Wenqi(Graduate School,Shanxi Medical University,Taiyuan 030001,China;Laboratory Animal Center,Shanxi Province Cancer Hospital,Shanxi Hospital Affiliated to Cancer Hospital,Chinese Academy of Medical Sciences,Cancer Hospital Affiliated to Shanxi Medical University,Taiyuan 030013,China;Department of Colorectal Surgery,Shanxi Province Cancer Hospital,Shanxi Hospital Affiliated to Cancer Hospital,Chinese Academy of Medical Sciences,Cancer Hospital Affiliated to Shanxi Medical University,Taiyuan 030013,China)
出处
《肿瘤研究与临床》
CAS
2023年第4期241-245,共5页
Cancer Research and Clinic
基金
山西省卫生健康委员会科研基金(2021076)。
