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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;;逆转录病毒
Objective To investigate the short-term and long-term toxic side effects of HSV-TK and GCV systems in primates. Methods Seven rhesus monkeys, one of them was used as normal control, and the other six animals were injected with HSV-TK packaging cell suspension (pLTKcSN/VPC) in the right frontal white matter, 7 days after cell injection, of which 3 Animals were infused with GCV via superficial veins at a dose of 5 mg/kg·d for 14 days; the other 4 animals received no medication. The animals were sacrificed at different time points. The brain tissue surrounding the injection needles was used for in situ hybridization of HSV-TK sequences. Whole body organs were taken for comprehensive histological examination and HSV-TK sequence PCR detection. Results Within 3 months, the main pathological changes of the central nervous system was brain stem demyelination. Other pathological changes include myocardial interstitial inflammation, hepatic edema, tubular edema, and even watery degeneration, but these pathological changes are no longer present in animals sacrificed after 3 months. HSC-TK sequence in situ hybridization showed positive cells within 3 weeks after cell injection and animals sacrificed after 3 months showed negative changes. There was no specific change in the dynamic observation of blood and cerebrospinal fluid parameters of animals during the experiment. Conclusion The HSV-TK and GCV systems have certain toxic effects on the heart, liver and kidneys of primates shortly after administration, but they are recoverable. Key words ##4 brain tumor; thymidine kinase gene; ganciclovir; retrovirus