Combined transcriptional and transductional targeting improves the specificity and efficacy of adenoviral gene delivery to ovarian carcinoma
Combined transcriptional and transductional targeting improves the specificity and efficacy of adenoviral gene delivery to ovarian carcinoma
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DOI：
10.1038/sj.gt.3301974
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发表时间：
2003-07-01
期刊：
影响因子：
5.1
通讯作者：
Hemminki, A
中科院分区：
文献类型：
--
作者：
Barker, SD;Dmitriev, IP;Hemminki, A
腺病毒是有效的基因递送载体，但具有广泛的天然嗜性。为此，寻找特异性靶向该病毒的方法已成为癌症基因治疗的重要焦点。转导和转录形式的靶向已经在卵巢癌中得到了有希望的结果。因此，我们结合两种形式的靶向研究对这种疾病中转基因表达的特异性和效率的影响。我们使用了组织特异性SLPI启动子和卵巢癌相关靶向衔接蛋白sCARfC6.5。该双特异性蛋白含有柯萨奇-腺病毒受体胞外域和对c-erbB-2特异性的单链抗体。将含有SLPI或普遍表达的CMV启动子的病毒（有或没有sCARfC6.5）用于感染卵巢癌细胞系、原发性卵巢肿瘤细胞和播散性卵巢癌的原位模型。这种双靶向策略增加了体外报告基因和细胞杀伤试验以及体内转基因表达的效率和特异性。通过同时使用SLPI启动子和sCARfC6.5，转基因表达在卵巢肿瘤中增加，而在正常组织（包括肝脏）中减少。因此，我们表明，结合转录和转导靶向可以提高效率和特异性的腺病毒基因治疗卵巢癌。
Adenoviruses are efficient gene delivery vehicles but have broad native tropism. To this end, finding ways to target this virus specifically to carcinomas has become an important focus of cancer gene therapy. Transductional and transcriptional forms of targeting have been used with promising results in ovarian carcinoma. Therefore, we combined both forms of targeting to investigate the effect on the specificity and efficiency of transgene expression in this disease. We used the tissue-specific SLPI promoter and the ovarian cancer associated targeting adaptor protein, sCARfC6.5. This bispecific protein contains the coxsackie-adenovirus receptor ectodomain and a single-chain antibody specific for c-erbB-2. Viruses containing the SLPI or the ubiquitously expressed CMV promoter, with or without sCARfC6.5, were used for infection of ovarian cancer cell lines, primary ovarian tumor cells, and in an orthotopic model of disseminated ovarian carcinoma. This dual-targeting strategy increased the efficiency and specificity of transgene expression in vitro in reporter and cell-killing assays, and in vivo. By using both the SLPI promoter and sCARfC6.5, transgene expression was increased in ovarian tumors and decreased in normal tissues, including the liver. Thus, we show that combining transcriptional and transductional targeting can increase the efficacy and specificity of adenoviral gene therapy for ovarian carcinoma.