肝动脉灌注AdVEGF-tk治疗大鼠肝癌

Vascular endothelial growth factor promoter-thymidine kinase gene in treatment of hepatocellular carcinoma by selective administration into hepatic artery in r ats

目的 :研究经肝动脉灌注腺病毒介导的血管内皮生长因子 (VEGF)启动子调控的单纯疱疹病毒胸苷激酶基因(HSV- tk)系统 (Ad VEGF- tk)对大鼠肝癌模型的治疗作用。 方法 :以二乙基亚硝胺 (DEN)诱导建立 Wistar大鼠肝癌模型 ,将32只成瘤鼠随机分成 Ad VEGF- tk/GCV组、Ad/GCV组、Ad CMV- tk/GCV组和生理盐水 /GCV组 ,每组 8只。诱癌后第 1 2 0天时经肝动脉分别给予重组腺病毒或生理盐水 ,次日起连续 1 0 d每天腹腔内给予丙氧鸟苷 (GCV) 1次 ,剂量为 5 0 mg·kg- 1· d- 1。停止注射后第 1 0天剖腹测量肿瘤大小 ,比较各组间肿瘤评分变化及大鼠存活情况。结果 :DEN处理第 1 2 0天后 ,所有大鼠均有典型肿瘤形成 ,病理证实为肝细胞癌。经肝动脉灌注腺病毒载体或生理盐水后 ,Ad CMV- tk/GCV组在腹腔内注射 GCV开始后第 5天陆续死亡 ,灌注后第 2 0天时该组大鼠只剩下 2只 ;其他 3组大鼠均完全存活。肿瘤评分表明 ,Ad VEGF-tk/GCV组处理前后肿瘤评分没有明显差异 [(2 .2 5± 0 .89) vs(2 .2 5± 0 .76 ) ],而 Ad/GCV组 [(2 .0 0± 0 .93) vs(3.89±0 .83) ]和生理盐水 /GCV组 [(2 .1 3± 0 .83) vs(3.75± 0 .89) ]在处理后明显增高 (P<0 .0 1 )。到灌注后第 90天时 ,Ad VEGF-tk/GCV组大鼠的生存时间明显延长。

Objective:To investigate the therapeutic efficacy of HSV tk under the control of VEGF promoter against rat hepatocarcinomas. Methods: Diethylnitrosam ine (DEN) was use d to develop hepatocarcinomas in 32 Wistar rats, which were subsequently divided into 4 groups:AdVEGF tk group,Ad group,AdCMV tk group and saline group. T h en selective administration of recombinant adenovirus or saline via the intr ahep atic artery was performed in all rats 120 d after the first DEN dose. Ganciclovi r (GCV) was given at a dose of 50 mg·kg -1 ·d -1 (ip) started o n th e following day and lasted 10 d. All the treated animals were anesthetized and l aparotomized to evaluate tumor burden 10 d before and after the last GCV dose. T he survival was checked daily in the remaining animals. Results: Af ter the treatment of DEN (120 d), typical liver tumors were found in all laparot omized rats. The deaths were recorded continuously 5 d after GCV treatment in the animals treated with AdCMV tk/GCV, but not in othe r groups. Tumor score remained stable in rats treated with AdVEGF tk/GCV [(2.2 5± 0.89) vs (2.25± 0.76)] , but increased in the rats treated with Ad/GCV [(2.00±0.93) vs (3.89±0.83)] or saline/GCV [( 2.13± 0.83) vs (3.75± 0.89), P <0.01]. Furthermore, treatment with AdVEGF tk/GCV increased the survival of tumor bear ing animals for more than 90 d. Conclusion: The results display a pronounced tumor growth delay and a prolonged survival time when AdVEGF tk is injected by intrahepatic artery route followed by GCV adminis trations.