腺病毒介导KDR启动子的胸苷激酶基因治疗小鼠人鼻咽癌模型

Adenovirus-mediated herpes simplex virus thymidine kinase gene transfer under the driving of KDR promoter in treatment of experimental human nasopharyngeal carcinoma in nude mice

目的研究腺病毒介导的KDR启动子-单纯疱疹病毒胸苷激酶(HSV-tk)系统(AdKDR-tk)结合丙氧鸟苷(GCV)对裸鼠人鼻咽癌的治疗作用.方法建立人鼻咽癌裸鼠模型,将36只成瘤鼠随机分成AdKDR-tk/GCV组、AdCMV-tk/GCV组和生理盐水/GCV组,每组12只.采用瘤内注射分别给予重组腺病毒及生理盐水,24h后重复注射1次.次日起连续10d每日ipGCV1次,100mg/kg.治疗结束后处死裸鼠,检测肿瘤质量、组织形态学变化及肿瘤微血管密度.结果Ad-CMV-tk/GCV组裸鼠鼻咽癌瘤体质量(1.81±0.84)g及肿瘤微血管密度(11.54±1.56)个/mm3、AdKDR-tk/GCV组[分别为(1.48±0.88)g,(9.87±2.18)个/mm3]与生理盐水/GCV组[分别为(2.53±1.21)g,(17.78±2.12)个/mm3]相比差异有显著性(P<0.05).AdCMV-tk/GCV组与AdKDR-tk/GCV组比较也存在显著差异(P<0.05).结论癌灶内注射AdK-DR-tk对裸鼠人鼻咽癌生长具有明显抑制作用,为鼻咽癌的治疗提供新的方法.

AIM： To investigate the therapeutic efficacy of adenovirus-mediated herpes simplex virus thymidine kinase （HSV-tk） gene transfer under the driving of KDR promoter （AdKDR-tk） in combination of ganciclovir（GCV） against human nasopharyngeal carcinoma （ NPC ） in nude mice. METHODS： CNE-2 cell line was implanted subcutaneously into 36 nude mice, which were subsequently divided into 3 groups （n = 12 each group）： AdKDR-tk/GCV group, AdCMV-tk/GCV group （under the driving of CMV promoter） and saline/GCV group. Then the selective intratumoral injection of recombinant adeuovirus or saline was performed in all nude mice,and repeated 24 h later. For the following 10 d GCV was given at a dose of 100 mg/（kg · d）, ip. All the treated animals were killed to evaluate the tumor weight and the histopathological changes and the microvessel density of tumors after the treatment finished. RESULTS ： The tumor weight and microvessel density of the saline/GCV group, AdCMV-tk/ GCV group and AdKDR-tk/C, CV were （2. 53 ± 1. 21 ） g and （17.78 ±2. 12） /mm^3, （1.81 ±0.84） gand （11.54±1.56） / mm^3, （1.48 ±0. 88） g and （9.87 ±2.18） /mm^3 respectively. Growth and microvessel density of NPC was significantly inhibited in the AdCMV-tk/GCV group and AdKDR-tk/GCV group as compared with that in the saline/GCV group （ P 〈 0.05 ）. AdKDR- tk/GCV group showed more marked antitumor effect, compared with the AdCMV-tk/GCV group （ P 〈 0.05 ）. CONCLUSION：Intratumoral injection of AdKDR-tk results in the marked inhibition of NPC growth in nude mice. It may be a new treatment approach for human NPC.