单纯疱疹病毒I型胸苷激酶基因和更昔洛韦系统的灵长类动物体内毒副作用

Acute and long term toxicity effects of herpes simplex virus I thymidine gene and ganciclovir system in non-human primates

目的在灵长类动物中观察单纯疱疾病毒１型胸苷激酶基因（ＨＳＶ－ＴＫ）及更昔洛韦（ＧＣＶ）系统的短期和长期毒副作用。方法恒河猴７只，其中１只设为正常对照，其余６只动物于右侧额叶白质内注射ＨＳＶ－ＴＫ的包装细胞悬液（ｐＬＴＫｃＳＮ／ＶＰＣ），细胞注射后７天起，其中３只动物经外周浅静脉滴注ＧＣＶ，剂量５ｍｇ／ｋｇ·ｄ，共１４天；另外４只不用药。动物在不同时间点处死，取注射针道周围的脑组织进行ＨＳＶ－ＴＫ序列原位杂交，并取全身各脏器进行全面组织学检查和ＨＳＶ－ＴＫ序列ＰＣＲ检测。结果３个月内，中枢神经系统的主要病理变化为脑干脱髓鞘变。其它病理变化包括心肌间质灶性炎症，肝脏浊肿变性，肾小管浊肿变性甚至水样变性，但这些病理变化在３个月后处死的动物中已不存在。ＨＳＣ－ＴＫ序列原位杂交结果见细胞注射后３周内有阳性细胞存在，３个月后处死的动物呈阴性改变。实验过程中动物的血液和脑脊液各项指标的动态观察未见有特异性改变。结论ＨＳＶ－ＴＫ及ＧＣＶ系统在用药后短期内对灵长类动物的心脏、肝脏和肾脏有一定的毒性损害作用，但是可恢复的。关键词##4脑肿瘤;;胸苷激酶基因;;更昔洛韦;;

Objective To evaluate the acute and long term toxicity effects of HSV-TK/GCV system.Methods Six rhesus monkeys received the vector producing cells (pLTKcSN/VPC)injection into the right frontallobe. After seven days, half of them were given ganciclovir through pripherial vein. At different intervals the animals were sacrificed. Histologic studies, in situ hybridization of HSV-TK sequence and PCK detection of HSV-TKgene in brain and Other organs were carried out. Results During the acute period, brain edema arround the injectingsite, demylinization of brain stem and non-significant pathological changes in heart, liver, lung and kidney were detected. The in situ hybridization of HSV-TK Sequence unveiled that the life sop of the vector producing cells in monkey brain was three weeks, PCR examination of VHSV-TK gene showed negative results in all tissue specimens. Theacute pathological changes vanished three months later. Conclusions The results of our studies disclose that the toxicity effects of HSV-TK/GCV system are slight and acceptable.