洛铂对结直肠癌类器官的腹腔热灌注药物敏感性检测  

Sensitivity of colorectal cancer organoids to hyperthermic intraperitoneal chemotherapy with lobaplatin

作　　者：刘铎 王辉[2] 邓伟豪 兰坚强 宋志文 朱宇 井建玲 蔡建 Liu Duo;Wang Hui;Deng Weihao;Lan Jianqiang;Song Zhiwen;Zhu Yu;Jing Jianling;Cai Jian(Department of Anorectal Surgery,the Second People's Hospital of Shenzhen(the First Affiliated Hospital of Shenzhen University),Shenzhen 518025,China;Department of Colorectal Surgery,the Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou 510655,China;Department of Pathology,the Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou 510655,China;Guangdong Research Center of Organoid Engineering and Technology,Accurate International Biotechnology Co.,Ltd.,Guangzhou 510650,China)

机构地区：[1]深圳市第二人民医院(深圳大学第一附属医院)肛肠外科,深圳518025 [2]中山大学附属第六医院结直肠外科,广州510655 [3]中山大学附属第六医院病理科,广州510655 [4]广东省类器官工程技术研究中心,创芯国际生物科技(广州)有限公司,广州510650

出　　处：《中华胃肠外科杂志》2024年第5期486-494,共9页Chinese Journal of Gastrointestinal Surgery

基　　金：中山大学附属第六医院“1010”计划(1010CG(2022)-08)。

摘　　要：目的利用结直肠癌患者来源的肿瘤类器官作为临床前模型,对比洛铂与奥沙利铂体外热灌注的药物敏感性,以辅助临床制定腹腔热灌注化疗方案。方法收集2021年7月至2022年12月期间中山大学附属第六医院经病理确诊为结直肠癌的患者手术后切下的部分肿瘤组织及获取的相关临床资料,对肿瘤组织进行类器官培养及传代,对活性良好的类器官进行体外热灌注实验。首先使用10例类器官分别进行6种浓度梯度(1000、250、62.5、15.6、3.9和0.98μmol/L)的奥沙利铂和洛铂体外热灌注实验,奥沙利铂于42℃环境下与类器官接触30 min,洛铂于42℃环境下与类器官接触60 min,根据绘制的剂量反应曲线,评估两种药物体外热灌注剂量反应能力。进一步使用30例类器官进行奥沙利铂和洛铂临床剂量的测试,奥沙利铂浓度为579μmol/L,热灌注温度为42℃,时间为30 min;洛铂浓度为240μmol/L,热灌注温度为42℃,时间为60 min。评估奥沙利铂和洛铂两种药物的体外热灌注敏感性。结果成功培养了32例结直肠癌患者的肿瘤类器官。奥沙利铂消除50%肿瘤细胞所需的浓度(IC_(50))中位数为577.45μmol/L(IQR:1846.09μmol/L);洛铂的IC_(50)中位数为85.04μmol/L(IQR:305.01μmol/L),两者比较差异无统计学意义(Z=1.784,P=0.084);10个类器官中有7个结果显示洛铂体外热灌注IC_(50)大于奥沙利铂。30例类器官在奥沙利铂和洛铂临床剂量下的测试结果显示:奥沙利铂的平均抑制率为39.6%(95%CI:32.1%~47.0%),洛铂的平均抑制率为89.7%(95%CI:87.0%~92.3%),两者比较差异有统计学意义(t=-15.282,P<0.001)。结论洛铂体外热灌注的抑制率优于奥沙利铂,有希望代替奥沙利铂成为更好的腹腔热灌注化疗药物。Objective To investigate the sensitivity of tumor organoids derived from samples of colorectal cancer to lobaplatin and oxaliplatin hyperthermic perfusion in vitro and to assist clinical development of hyperthermic intraperitoneal chemotherapy.Method Tumor samples and relevant clinical data were collected from patients with pathologically confirmed colorectal cancer in the Sixth Affiliated Hospital of Sun Yat-sen University from July 2021 to December 2022.Organoids were cultured and tumor tissue were passaged.In vitro hyperthermic perfusion experiments were performed on organoids with good viability.Firstly,10 organoids were treated with oxaliplatin and lobaplatin at the following six concentrations:1000,250,62.5,15.6,3.9,and 0.98μmol/L.The organoids were exposed to oxaliplatin at 42℃for 30 minutes and to lobaplatin at 42℃for 60 minutes.Dose-response curves of responses to in vitro hyperthermic perfusion with these two drugs were constructed and evaluated.Clinical doses of oxaliplatin and lobaplatin were further tested on 30 organoids.This testing revealed oxaliplatin was effective at 579µmol/L at a hyperthermic perfusion temperature of 42℃for 30 min and lobaplatin was effective at 240µmol/L at a hyperthermic perfusion temperature of 42℃for 60 minutes.Result Thirty-two tumor organoids were cultured from samples of colorectal cancer.The median concentration required for oxaliplatin to eliminate 50%of tumor cells(IC_(50))was 577.45µmol/L(IQR:1846.09µmol/L).The median IC_(50) for lobaplatin was 85.04µmol/L(IQR:305.01µmol/L).The difference between the two groups was not statistically significant(Z=1.784,P=0.084).In seven of 10 organoids,lobaplatin showed a greater IC_(50) after in vitro hyperthermic perfusion than did oxaliplatin.Testing of 30 organoids with clinical doses of oxaliplatin and lobaplatin revealed that oxaliplatin achieved an average inhibition rate of 39.6%(95%CI:32.1%‒47.0%),whereas the average rate of inhibition for lobaplatin was 89.7%(95%CI:87.0%‒92.3%):this difference is statist

关 键 词：结直肠肿瘤 腹膜转移 腹腔热灌注化疗 洛铂 类器官 

分 类 号：R735.34[医药卫生—肿瘤]