p53基因治疗晚期肝癌的临床观察及生物学监测

Clinical therapeutic effect and biological monitoring of p53 gene in advanced hepatocellular carcinoma

目的 观察经皮下药盒动脉输注p53基因治疗晚期肝癌的疗效及生物学改变.方法 收集2006年6月至2009年6月江苏省肿瘤医院介入科晚期肝癌患者48例,分为治疗组30例,一般化疗组（对照组）18例.经右髂外动脉人路皮下埋植药盒系统,根据造影表现决定灌注药物的靶动脉.治疗组在靶动脉注入p53基因1012VP（今又生,深圳赛百诺公司）,加羟基喜树碱20 mg,每周1次,连用3周为1疗程.对照组给予羟基喜树碱20 mg靶动脉灌注.观察治疗前后患者的甲胎蛋白（AFP）、卡氏评分、病灶的变化（RECIST标准）和生存期等,并采用流式细胞技术、人体微核实验检测治疗组患者介入治疗前后外周血中突变型p53表达及自发微核形成.结果 治疗组接受1～8个疗程的治疗,AFP,KPS治疗前后比较,差异有统计学意义（P〈0.05）.而对照组治疗前后比较差异无统计学意义（P＞0.05）.1个月后,生存率为（治疗组/对照组）96.6%/94.4%,病灶变化根据RECIST标准,两组之间差异有统计学意义（P〈0.05）.3个月后,生存率为（治疗组/对照组）83.3%/55.6%,病灶变化两组之间差异有统计学意义（P〈0.05）.6个月后,生存率为50.0%/11.1%,病灶变化两组之间差异有统计学意义（P〈0.05＝.9个月后,生存率为23.3%/0%,病灶变化两组之间差异有统计学意义（P〈0.05＝.12个月后,生存率为6.67%/0%,病灶变化两组之间差异有统计学意义（P〈0.05）.p53平均表达率治疗前后比较,治疗组差异有统计学意义（P〈0.01）.结论 经肝动脉序贯输注p53基因治疗晚期肝癌是安全的,可以适当延长患者生存期.生物学研究对治疗剂量选择,治疗效果的判断将起到积极的指导和监测作用.

Objective To investigate the therapeutic effect and biological changes of hepatic arterial perfusion of p53 gene via port catheter system （PCS） on advanced hepatocellular carcinoma.Methods A total of 48 cases of advanced hepatocellular carcinoma were divided into the experimental group（30）and the control group（18）.Transiliaca external artery PCS implantation was performed in all cases.p53 gene was perffused into target artery confirmed by angiography.In the experimental group,1012 VP of p53 gene and 20 mg OPT were employed everyweek as a course for 21 days.In the control group,only 20 mg OPT was used.KPS,AFP and the survival period,RECIST （ response evaluation criteria in solid ） tumor were analyzed.Flow cytometry （FCM） and micronucleus （MN） assay in vivo were used to detect p53 gene mutation and spontaneous micronucleus formation in peripheral blood of the experimental group.Results The experimental group were performed 1 to 8 courses.There was a significant difference with AFP level and KPS in the experimental group（ P〈0.05 ）.However there was no significant difference （ P 〉0.05 ） in the control group.After one month,survival rate of the the experimental group and the control group was 96.6% and 94.4%,there was a significant difference between the two groups in objective tumor relieve （P〈0.05）.After three months,survival rate of the the experimental group and the control group was 83.3% and 55.6%,there was a significant difference between the two groups in objective tumor relieve （P〈0.05）.After six months,survival rate of the the experimental group and the control group was 50.0% and 11.1%,there was a significant difference between the two groups in objective tumor relieve （ P〈0.05 ）.After nine months,survival rate of the the experimental group and the control group was 23.3% and 0%,there was a significant difference between the two groups in objective tumor relieve （P〈 0.05 ）.After twelve months,survival rate of the the experimental group and the control group was 6.67% and 0%,there was a significant difference between the two groups in objective tumor relieve （ P〈0.05 ）.The depression of p53 expression was observed in the HCC patients who were employed four times of intervention operations.The difference of p53 expression between before and after interventional rAd-p53 therapy were statistically significant （P 〈0.01 ）.The frequency of MN depressed by the rAd-p53 was seen in the patients,and the differences of the frequency of MN between before and after interventional rAd-p53 therapy were statistically significant （ P 〈0.05）.Conclusion p53 gene sequential infusion via hepatic artery is effective for advanced hepatocellular carcinoma.The biological study will play a important role in selecting the therapeutic dose and judging therapeutic efficacy by means of guiding and monitoring.