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

癌症选择性复制腺病毒在胆囊癌基因治疗中的实验分析及应用。

基本信息

批准号：
14370174
负责人：
TANAKA Naomi
金额：
$ 7.87万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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.

新的治疗方法，如基因治疗，是必要的晚期胆囊癌（GBC），但很少有研究。最近的研究已经引入了El突变的腺病毒（Ads），其显示肿瘤特异性复制和有希望的临床结果。我们研究了El突变的Ads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选择性地在几种GBC细胞系以及野生型Ad中复制并引起溶瘤，而它们在正常细胞中仅引起轻度的细胞病变。El突变的Ad还抑制GBC异种移植物的生长，并延长具有腹膜播散的GBC的小鼠的存活。我们进一步研究了AxE 1CAUP的功效，AxE 1CAUP是一种表达尿嘧啶磷酸核糖基转移酶（UPRT）的El突变的Ad，其极大地增强了5-氟尿嘧啶（5-FU）的细胞毒性。AxE 1CAUP在GBC细胞中选择性复制，并提供比AxCAUP（表达UPRT的非复制型Ad）更强的UPRT表达和更高的5-FU敏感性。AxE 1CAUP不改变正常细胞对5-FU的敏感性。如果适当选择5-FU给药时间，AxE 1 CAUP/5-FU的体内疗效也优于AxE 1 CAUP/5-FU的上级疗效。我们的研究表明E1突变的Ads在GBC基因治疗中的有效性、安全性和应用价值。