An advanced generation of adenoviral vectors selectively enhances gene transfer for ovarian cancer gene therapy approaches
An advanced generation of adenoviral vectors selectively enhances gene transfer for ovarian cancer gene therapy approaches
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DOI：
10.1006/gyno.1999.5432
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发表时间：
1999-08-01
影响因子：
4.7
通讯作者：
Curiel, DT
中科院分区：
文献类型：
--
作者：
Vanderkwaak, TJ;Wang, MH;Curiel, DT
目标。我们推测，在卵巢癌中，将整合素结合Arg-Gly-Asp(RGD)的多肽整合到腺病毒纤维旋钮的HI环上，可以通过修饰的Ad载体实现增强的、柯萨奇-腺病毒受体非依赖性的基因转移。将荧光素酶编码腺病毒(AdCMVLuc)或在旋钮HI环内含有RGD基序的转基因腺病毒(Ad5LucRGD)分别导入卵巢癌细胞系、卵巢癌细胞、原代肿瘤组织和间皮组织。检测荧光素酶活性，比较两种病毒的转导效率。在所有已建立的卵巢细胞系和原代肿瘤细胞样本中，与AdCMVLuc相比，Ad5LucRGD显著增强了基因转移。卵巢癌细胞株的基因转移增强了2.5%至471.6倍，腹水样本的基因转移增强了26.1%至64.0倍，肿瘤外植体的基因转移增强了1.6%至11.1倍。RGD重定向对正常间皮组织的基因转移量虽略有增加，但远低于卵巢癌细胞。这项研究表明，在卵巢癌的情况下，具有改良嗜性的基因改变的腺病毒能够更有效地进行基因转移。相对于腹膜间皮细胞的较高水平的转移可以被利用来提高使用腺病毒载体进行干预的治疗指数。因此，有必要进行研究，以确定这种靶向载体方法在卵巢癌基因治疗策略中的体内实用性。(C)1999年学术出版社。
Objective. We hypothesized that incorporation of an integrin binding Arg-Gly-Asp (RGD)-containing peptide to the HI loop of the adenovirus fiber knob would allow enhanced, coxsackie-adenovirus receptor-independent gene transfer by modified Ad vector in the context of ovarian cancer.Methods. Ovarian cancer cell lines, primary ovarian cancer cells, primary tumor explants, and mesothelial tissue were transfected with luciferase encoding adenovirus (AdCMVLuc) or a genetically modified adenovirus (Ad5lucRGD) which contained an RGD motif within the HI loop of the knob. The luciferase activity was measured and the transduction efficiencies of both viruses were compared.Results. In all established ovarian cell lines and primary tumor cell samples there was dramatically augmented gene transfer observed with the Ad5lucRGD compared to AdCMVLuc. The enhanced gene transfer in ovarian cancer cell lines ranged from 2.5- to 471.6-fold, in ascites samples from 26.1- to 64.0-fold, and in tumor explants from 1.6- to 11.1-fold. Although gene transfer to normal mesothelial tissue was slightly augmented by RGD retargeting, the level of gene transfer was much lower than that seen in ovarian cancer cells.Conclusion. This study demonstrates that genetically altered adenoviruses with modified tropism are capable of more efficient gene transfer in the context of ovarian cancer. The higher level of transfer with respect to peritoneal mesothelium can be exploited to enhance the therapeutic index of interventions using adenoviral vectors. Studies are warranted, therefore, to determine the in vivo utility of this targeted vector approach in the context of gene therapeutic strategies for cancer of the ovary. (C) 1999 Academic Press.