Gene Therapy for Experimental Gliomas Using Chemosensitivity Genes

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，被创建为多种癌症的自杀基因疗法。尿嘧啶磷酸核糖基转移酶（UPRT）基因（在哺乳动物细胞中不存在）可直接将5-氟尿嘧啶（5-FU）转化为5-氟尿嘧啶5 '-单磷酸。我们评估了CD和UPRT基因的共表达是否可以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9 L细胞对5-FU的敏感性是亲本细胞的16倍，CD + UPRT-转导的细胞对5-FC的敏感性是亲本细胞的6，000倍，表明与单独CD相比，CD和UPRT的获得进一步增加了9 L细胞对5-FC的敏感性。在大鼠脑肿瘤模型中，将减少量的CD和UPRT载体接种到肿瘤中以检测UPRT的任何额外作用。CD和UPRT共表达后5-FC给药显示了通过顺序磁共振成像检测到的抗肿瘤作用。这种疗法显著延长了动物的存活时间。结果提示5-FC/CD+UPRT基因治疗可增强5-FC/CD基因治疗的抗肿瘤作用。因此，这种方法可能是治疗恶性脑肿瘤的一种更可行的方式。

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.