Gene Therapy for Experimental Gliomas Using Chemosensitivity Genes

将胞嘧啶脱氨酶(CD)基因导入肿瘤细胞，然后给予5-氟胞嘧啶(5-FC)，被称为5-FC/CD基因疗法，用于各种癌症的自杀基因治疗。尿嘧啶磷酸核糖基转移酶(UPRT)基因是哺乳动物细胞中不存在的，它直接将5-氟尿嘧啶(5-FU)转化为5-氟尿嘧啶5‘-单磷酸。我们评价了CD和UPRT基因的共同表达是否能对实验性脑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。在大鼠脑瘤模型中，将数量减少的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共表达后给予5-FC，序贯磁共振成像显示有抗肿瘤作用。这种疗法显著延长了动物的存活时间。提示5-FC/CD UPRT基因治疗可增强5-FC/CD基因治疗的抗肿瘤作用。因此，对于恶性脑肿瘤的治疗，这种方法可能是一种更可行的方式。

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.