Intracranial administration of adenovirus expressing HSV-TK in combination with ganciclovir produces a dose-dependent, self-limiting inflammatory response.
Intracranial administration of adenovirus expressing HSV-TK in combination with ganciclovir produces a dose-dependent, self-limiting inflammatory response.
复制标题
颅内给予表达 HSV-TK 的腺病毒与更昔洛韦联合产生剂量依赖性、自限性炎症反应。
DOI：
10.1089/hum.1997.8.8-943
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Eck,SL
中科院分区：
文献类型：
--
作者：
Smith,JG;Raper,SE;Wheeldon,EB;Hackney,D;Judy,K;Wilson,JM;Eck,SL
表达单纯疱疹胸苷激酶基因（H5.010RSVtk）的复制缺陷腺病毒可能有助于治疗人类胶质瘤。为了确定这种治疗策略的毒性，我们将h5.010 rsvtk立体定向注射到Wistar大鼠、棉花大鼠和恒河猴的正常大脑中，并以每天10 mg/kg的剂量将其与系统性更昔洛韦（GCV）一起注射。在Wistar大鼠中，5.7 × 109pfu导致组织病理学损伤，包括局部坏死，轻度胶质增生，明显的软化和局灶星形细胞增生；然而，1.0 × 108pfu仅导致轻度胶质瘤和微量脑膜炎，接近“无毒性作用”的剂量。1.0 × 109pfu剂量对腺病毒免疫棉大鼠和腺病毒幼稚棉大鼠均产生相似的结果。在恒河猴中，1.4 × 108pfu至1.5 × 1011pfu的剂量范围可导致局部胶质瘤、坏死、血管周围弯曲、脑膜炎，其严重程度与剂量的增加大致相关。在非中枢神经系统（CNS）组织中未发现毒性的组织学证据，脑脊液（CSF）、血液、尿液和粪便样本中未发现病毒培养。所有动物都存活到规定的终点，没有出现一般毒性或神经系统症状的迹象，只有2只恒河猴例外，其中一只开始发热，另一只出现大癫痫发作（两者随后消退）。这些毒理学研究确定了开展I期临床试验的参数。
Replication-defective adenovirus expressing the herpes simplex thymidine kinase gene (H5.010RSVtk) may be useful in treating human gliomas. To determine the toxicity of this therapeutic strategy, we injected H5.010RSVtkstereotactically into the normal brain of Wistar rats, cotton rats, and rhesus monkeys in conjunction with systemic ganciclovir (GCV) at 10 mg/kg per day. In the Wistar rat, 5.7 × 109pfu resulted in histopathologic injury consisting of localized necrosis, mild gliosis, marked malacia, and focal astrocytosis; however, 1.0 × 108pfu resulted in only mild gliosis and trace meningitis and approximates a “no toxic effect” dose. A dose of 1.0 × 109pfu in both adenoviral immune and adenoviral naive cotton rats resulted in similar findings. In the rhesus monkey, doses ranging from 1.4 × 108pfu to 1.5 × 1011pfu resulted in localized gliosis, necrosis, perivascular cuffing, meningitis, and roughly correlated in severity with increasing dose. No histologic evidence of toxicity was found in non-central nervous system (CNS) tissues, and no virus could be cultured from cerebrospinal fluid (CSF), blood, urine, and stool samples. All animals survived to prescribed end points without signs of general toxicity or neurologic symptoms, except for 2 of the rhesus monkeys, one of which became febrile and the other of which developed a grand mal seizure (both subsequently resolved). These toxicology studies define the parameters for developing a phase I clinical trial.