Basic fibroblast growth factor enhancement of adenovirus-mediated delivery of the herpes simplex virus thymidine kinase gene results in augmented therapeutic benefit in a murine model of ovarian cancer.
Basic fibroblast growth factor enhancement of adenovirus-mediated delivery of the herpes simplex virus thymidine kinase gene results in augmented therapeutic benefit in a murine model of ovarian cancer.
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发表时间：
1998-10
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通讯作者：
Claudine Rancourt;Buck E. Rogers;B. Sosnowski;M. Wang;Alain Piché;G. Pierce;R. Alvarez;Gene P. Siegal;J. T. Douglas;David T. Curiel
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作者：
Claudine Rancourt;Buck E. Rogers;B. Sosnowski;M. Wang;Alain Piché;G. Pierce;R. Alvarez;Gene P. Siegal;J. T. Douglas;David T. Curiel
许多使用腺病毒载体的临床前和人类临床基因治疗试验表明，提供足够水平的基因转移所需的病毒颗粒数量可能与显着的载体相关毒性有关。为了减少给定水平的基因转移所需的腺病毒颗粒的数量，我们试图通过在靶细胞上高度表达的受体来重定向腺病毒感染。通过使用碱性成纤维细胞生长因子（FGF 2）作为靶向配体，腺病毒介导的基因转移到人卵巢癌细胞系SKOV3.ip1显着增强，允许通过给定剂量的病毒实现更大数量的靶细胞的转导。在人卵巢癌的小鼠模型中，与相同数量的未修饰的AdCMVHSV-TK颗粒相比，携带单纯疱疹病毒胸苷激酶基因的FGF 2重定向腺病毒载体（AdCMVHSV-TK）显示出显著延长生存期。此外，与未修饰的载体相比，使用低10倍剂量的FGF 2重定向的AdCMVHSV-TK实现了相等的存活率。据我们所知，这是第一份报告表明，提高腺病毒载体的体内转导效率的策略将具有临床实用性。
A number of preclinical and human clinical gene therapy trials using adenoviral vectors have shown that the number of viral particles necessary to give adequate levels of gene transfer can be associated with significant vector-related toxicity. In an effort to reduce the number of adenoviral particles required for a given level of gene transfer, we sought to redirect adenoviral infection via a receptor that is highly expressed on the target cells. By using basic fibroblast growth factor (FGF2) as the targeting ligand, adenovirus-mediated gene transfer to the human ovarian cancer cell line SKOV3.ip1 was significantly enhanced, permitting the transduction of a greater number of target cells to be achieved by a given dose of virus. In a murine model of human ovarian carcinoma, an FGF2-redirected adenoviral vector carrying the gene for herpes simplex virus thymidine kinase (AdCMVHSV-TK) was shown to result in a significant prolongation of survival compared with the same number of particles of unmodified AdCMVHSV-TK. In addition, equivalent survival rates were achieved with a 10-fold lower dose of the FGF2-redirected AdCMVHSV-TK compared with the unmodified vector. To our knowledge, this is the first report demonstrating that strategies to enhance the efficiency of in vivo transduction of adenoviral vectors will be of clinical utility.