In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus
In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus
复制标题
DOI：
10.1038/sj.cgt.7700086
复制
发表时间：
2000-01-01
影响因子：
6.4
通讯作者：
Ohmoto, T
中科院分区：
文献类型：
--
作者：
Ichikawa, T;Tamiya, T;Ohmoto, T
我们评估了腺病毒介导的胞嘧啶脱氨酶（CD）基因和5-氟胞嘧啶（5-FC）转导对实验性恶性脑肿瘤的治疗效果和神经毒性。与对照细胞相比，表达CD的腺病毒载体(AdexCACD)感染的9L细胞中的5-FC敏感性增加了1700倍。对携带 9 L 脑肿瘤的大鼠进行瘤内注射 AdexCACD，然后腹膜内注射 5-FC 进行治疗。通过磁共振成像，这些大鼠显示出对肿瘤生长的显着抑制，10 只大鼠中有 7 只存活了超过 90 天。为了评估 5-FC/CD 基因治疗的潜在副作用，对大鼠进行右侧基底神经节脑内注射 AdexCACD 和 5-FC 治疗。注射后 18 天，磁共振成像显示钆增强 T1 加权图像上有一个高度增强的区域。从病理学上讲，这对应于周围有凋亡细胞的坏死区域。此外，还存在脱髓鞘和神经胶质增生并伴有侧脑室扩大。这些结果表明5-FC/CD基因疗法可能对人类恶性脑肿瘤具有抗癌作用，但也表明对正常脑组织存在神经毒性作用。
We evaluated the therapeutic efficacy and neurotoxicity of adenovirus-mediated transduction of the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) for experimental malignant brain tumors. The 5-FC sensitivity in 9 L cells infected by an adenovirus vector expressing CD (AdexCACD) was increased 1700-fold compared with control cells. Rats bearing 9 L brain tumors were treated with an intratumoral injection of AdexCACD followed by intraperitoneal administration of 5-FC. The rats demonstrated remarkable inhibition of tumor growth by magnetic resonance imaging, and 7 of 10 rats survived for >90 days. To evaluate the potential side-effects of the 5-FC/CD gene therapy, rats were treated with an intracerebral injection of AdexCACD into the right basal ganglia and with 5-FC. The magnetic resonance imaging showed a highly enhanced area on the gadollinium-enhanced T1-weighted image at 18 days postinjection. Pathologically, this corresponded to an area of necrosis with surrounding apoptotic cells. In addition, there was demyelination and gliosis with enlargement of the lateral ventricles. These results suggest that the 5-FC/CD gene therapy may provide an anticancer effect for malignant brain tumors in humans, but also show that there are neurotoxic effects on normal brain tissue.