Experimental Analysis and Application of Cancer-selectively Replicating Adenovirus for Gene Therapy of Gallbladder Cancer.

新的治疗方法，如基因治疗，对于晚期胆囊癌（GBC）是必要的，但研究很少。最近的研究引入了El突变腺病毒（ad），它们显示出肿瘤特异性复制和有希望的临床结果。我们研究了El突变ad的有效性和安全性及其在GBC基因治疗中的应用。El突变的Ad在几种GBC细胞系和野生型Ad中选择性复制并引起肿瘤溶解，而在正常细胞中仅引起轻微的细胞病变。El突变的Ads还抑制了GBC异种移植物的生长，延长了腹膜播散性GBC小鼠的存活时间。我们进一步研究了表达尿嘧啶磷酸核糖基转移酶（UPRT）的El突变Ad蛋白AxE1CAUP的作用，该蛋白可大大增强5-氟尿嘧啶（5-FU）的细胞毒性。AxE1CAUP选择性地在GBC细胞中复制，与表达UPRT的非复制性Ad AxCAUP相比，AxE1CAUP具有更强的UPRT表达和更高的5-FU敏感性。AxE1CAUP未改变正常细胞对5-FU的敏感性。如果给药时机适当，AxE1CAUP/5-FU的体内疗效也优于AxCAUP/5-FU。我们的研究显示了El突变的Ads在GBC基因治疗中的有效性、安全性和应用。

New treatments, such as gene therapy, are necessary for advanced gallbladder cancer (GBC) but little has been studied. Recent studies have introduced El mutated adenoviruses (Ads), which show tumor-specific replication and promising clinical results. We studied the efficacy and safety of El mutated Ads and their application to gene therapy for GBC. El mutated Ads selectively replicated in and caused oncolysis of several GBC cell lines as well as wild-type Ad, while they caused only mild cytopathy in normal cells. The El mutated Ads also suppressed the growth of GBC xenografts and prolonged the survival of mice with peritoneally disseminated GBC. We further studied the efficacy of AxE1CAUP, an El mutated Ad expressing uracil phosphoribosyltransferase (UPRT), which greatly enhances the cytotoxicity of 5-fluorouracil (5-FU). AxE1CAUP selectively replicated in and provided GBC cells with stronger UPRT expression and greater 5-FU sensitivity than AxCAUP, a non-replicative Ad expressing UPRT. AxE1CAUP did not change the 5-FU sensitivity in normal cells. In vivo efficacy of AxE1CAUP/5-FU was also superior to that of AxCAUP/5-FU if timing of 5-FU administration was appropriately chosen. Our study showed efficacy, safety, and application of El mutated Ads to gene therapy of GBC.