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Gene Therapy for Experimental Gliomas Using Chemosensitivity Genes

使用化学敏感性基因治疗实验性神经胶质瘤

基本信息

批准号：
09671425
负责人：
TAMIYA Takashi
金额：
$ 1.66万
依托单位：
OKAYAMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671425/
关键词：
adenovirus vector gene therapy brain tumors cytosine deaminase 5-fluorocytosine 5-fluoruoracil chemosensitivity gene uracil phosphoribosyltransferase adenovirus vector brain tumors gene therapy chemosensitivity gene retrovirus vect

项目摘要

Transduction of the cytosine deaminase (CD) gene into tumor cells followed by administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was created as suicide gene therapy for various cancers. The uracil phosphoribosyltransferase (UPRT) gene, which is absent from mammalian cells, directly converts 5-fluoruoracil (5-FU) to 5-fluoruorridine 5'-monophosphate. We evaluated whether the coexpression of CD and UPRT genes could generate a synergistic antitumor effect on experimental brain tumors. In vitro study showed that UPRT-transduced 9L cells mediated by an adenovirus were 16 times more sensitive to 5-FU, and CD + UPRT-transduced cells were 6,000 times more sensitive to 5-FC than parent cells, indicating that the acquisition of CD and UPRT further increased the 5-FC sensitivity of 9L cells compared to that of CD alone. In a rat brain tumor model, a decreased amount of vectors of CD and UPRT were inoculated into the tumors to detect any additional effect of UPRT. CD and UPRT coexpression followed by 5-FC administration showed an antitumor effect detected by sequential magnetic resonance imaging. This therapy significantly prolonged animal survival. These results suggest that 5-FC/CD+UPRT gene therapy can enhance the antitumor effect of 5-FC/CD gene therapy. Consequently, this approach might be a more feasible modality for the treatment of malignant brain tumors.

将胞嘧啶脱氨酶（CD）基因转导到肿瘤细胞中，然后给予5-氟胞嘧啶（5-FC），称为5-FC/CD基因疗法，是针对各种癌症的自杀基因疗法。哺乳动物细胞中不存在尿嘧啶磷酸核糖基转移酶（UPRT）基因，该基因可直接将5-氟尿嘧啶（5- fu）转化为5-氟吡啶5'-单磷酸。我们评估了CD和UPRT基因的共表达是否能对实验性脑肿瘤产生协同抗肿瘤作用。体外研究表明，腺病毒介导的UPRT转导的9L细胞对5-FU的敏感性提高了16倍，CD + UPRT转导的细胞对5-FC的敏感性比亲本细胞高6000倍，表明CD和UPRT的获得进一步提高了9L细胞对5-FC的敏感性。在大鼠脑肿瘤模型中，减少CD和UPRT载体的接种量，以检测UPRT是否有额外的作用。序列磁共振成像检测5-FC给药后CD和UPRT共表达的抗肿瘤作用。这种疗法显著延长了动物的生存时间。提示5-FC/CD+UPRT基因治疗可增强5-FC/CD基因治疗的抗肿瘤效果。因此，这种方法可能是一种更可行的治疗恶性脑肿瘤的方式。