ATRA增强HSV_1-TK/GCV系统联合topotecan治疗卵巢癌的动物实验  

ATRA enhances the synergistic effects of HSV-1-TK/GCV system and topotecan in the treatment of ovarian cancer in vivo

作　　者：吴强[1] 徐梅[1] 孙志华[1] 袁红花[2] 朱孝荣[2] 崔涛[3] 

机构地区：[1]江苏省肿瘤医院妇瘤科,南京210009 [2]江苏省开放性动物实验中心徐州医学院实验动物中心,徐州221000 [3]徐州医学院病理教研室,徐州221000

出　　处：《肿瘤》2006年第2期148-151,162,共5页Tumor

基　　金：江苏省科技厅社会发展基金资助项目(编号:BS2002058)

摘　　要：目的探讨全反式维甲酸(all-trans retinoic acid,ATRA)提高Ⅰ型单纯疱疹病毒胸苷激酶(herpes si mplex virus thy-midine kinase,HSV1-TK)/丙氧鸟苷(ganciclovir,GCV)系统联合拓扑替康(topotecan,TPT)对卵巢癌的体内治疗作用。方法首先用携带HSV1-TK基因的重组逆转录病毒上清转染人卵巢癌细胞系SKOV-3,在含有G418的培养液中筛选获得抗性克隆细胞(命名为SKOV-3/TK)。PCR方法检测HSV1-TK基因整合情况;用SKOV-3细胞与SKOV-3/TK细胞按8∶2比例混合建立荷瘤鼠模型,作为HSV1-TK/GCV组、HSV1-TK/GCV+TPT组、ATRA联合HSV1-TK/GCV组及ATRA联合HSV1-TK/GCV+TPT组4个实验组,再单用SKOV-3细胞建立荷瘤鼠模型作为对照组;从用药第1天开始每5d测量肿瘤体积1次,至用药结束后1周,绘制肿瘤生长曲线,计算抑瘤率,并取瘤组织做病理学检查。结果各组肿瘤体积与对照组比较抑瘤率分别为38.8%、53.2%、62.3%及95.7%,差异均有显著性(P<0.01),而且联合ATRA组与未用ATRA组比较差异亦有显著性(P<0.01)。病理结果显示实验组肿瘤组织均出现不同程度的点、片状坏死,以ATRA联合HSV1-TK/GCV+TPT组为重。结论HSV1-TK/GCV系统联合TPT治疗卵巢癌可起到协同作用;ARTA可以提高HSV1-TK/GCV系统联合TPT对卵巢癌的体内杀伤作用。Objective：To study whether all-trans retinoic acid（ATRA）could enhance the killing effect of a suicide gene therapy system of HSV-1-TK/GCV（herpes simplex virus Ⅰ thymidine kinase/ganciclovir） combined with topoisomerase Ⅰ inhibitor topotecan （TPT） on ovarian cancer cells in vivo. Methods： Human ovarian cancer cell line SKOV 3 was transfected with the recombinant retrovirus of HSV-1-TK gene. Resistant clones （named SKOV-3/TK） was obtained by G418 screening. HSV-1-TK expression was identified by PCR. Subcutaneous tumor models were induced in nude mice by subcutaneous injection with mixture of SKOV-3 cells and SKOV-3/TK cells at 8 ： 2 ratio. SKOV-3 cells were subcutaneously injected into nude mice as blank control. The average tumor volumes were measured from d 1 every 5 days until 1 week after therapy. Pathological examination was carried out. Results： Compared with control group, tumor growth was inhibited by 38.8 %, 52.2 %, 62.3 %, and 96. 1% in HSV-1-TK/GCV group,HSV-1-TK/GCV plus TPT group, ATRA plus HSV-1-TK/GCV group,and ATRA plus HSV-1-TK/GCV plus TPT group （P〈0.01）. The difference between HSV-1-TK/GCV plus TPT group and ATRA plus HSV-1 TK/GCV plus TPT group was significant （P〈0.01）. The necrosis was most serious in ATRA plus HSV-1-TK/GCV plus TPT group. Conclusions： HSV-1-TK/GCV combined with TPT have synergistic effects in ovarian cancer therapy in vivo. ATRA increased the synergistic effects of HSV-1 TK/GCV and TPT in killing ovarian cancer cells in vivo.

关 键 词：卵巢肿瘤 胸苷激酶 基因疗法 维甲酸 小鼠 裸 

分 类 号：R737.31[医药卫生—肿瘤] R730.53[医药卫生—临床医学]