Selective gene delivery to head and neck cancer cells via an integrin targeted adenoviral vector.
Selective gene delivery to head and neck cancer cells via an integrin targeted adenoviral vector.
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发表时间：
1999-09
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通讯作者：
K. Kasono;J. Blackwell;J. T. Douglas;I. Dmitriev;T. Strong;Paul R. Reynolds;David A Kropf;W. Carroll;G. Peters;R. P. Bucy;D. Curiel;Gene Therapy Program;Clinical Pathology
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作者：
K. Kasono;J. Blackwell;J. T. Douglas;I. Dmitriev;T. Strong;Paul R. Reynolds;David A Kropf;W. Carroll;G. Peters;R. P. Bucy;D. Curiel;Gene Therapy Program;Clinical Pathology
基于腺病毒载体介导的基因递送的头颈部鳞状细胞癌（SCCHN）的体内癌症基因治疗方法受到基因转移至肿瘤细胞的次优功效的限制。我们假设，这个问题是由于缺乏主要的腺病毒受体，柯萨奇-腺病毒受体（CAR），对肿瘤的目标。对SCCHN细胞系的CAR水平的研究证实，它们对腺病毒载体的相对不应性是基于这种缺陷。为了避免这种缺陷，我们应用了一种靶向SCCHN肿瘤细胞标志物的腺病毒载体。在这方面，α 2 β 1和α 3 β 1类整联蛋白在SCCHN中经常过表达。此外，这些整联蛋白识别RGD肽基序。在此基础上，我们应用经遗传修饰以在纤维蛋白的HI环内含有此类肽的腺病毒载体作为改变病毒嗜性的手段。研究证实，通过这种策略实现的CAR非依赖性基因递送允许增强基因转移到SCCHN肿瘤细胞的效率。重要的是，与正常细胞相比，这种策略可以实现肿瘤细胞中基因转移的优先增强。通过腺病毒载体实现增强的和特异性的基因转移到肿瘤细胞的能力对于SCCHN和其他肿瘤的基因治疗策略具有重要意义。
In vivo cancer gene therapy approaches for squamous cell carcinoma of the head and neck (SCCHN) based on adenoviral vector-mediated gene delivery have been limited by the suboptimal efficacy of gene transfer to tumor cells. We hypothesized that this issue was due to deficiency of the primary adenoviral receptor, the coxsackie-adenovirus receptor (CAR), on the tumor targets. Studies of CAR levels on SCCHN cell lines confirmed that their relative refractoriness to the adenoviral vector was based on this deficiency. To circumvent this deficiency, we applied an adenoviral vector targeted to a tumor cell marker characteristic of SCCHN. In this regard, integrins of the alpha2beta1 and alpha3beta1 class are frequently overexpressed in SCCHN. Furthermore, these integrins recognize the RGD peptide motif. On this basis, we applied an adenoviral vector genetically modified to contain such a peptide within the HI loop of the fiber protein as a means to alter viral tropism. Studies confirmed that the CAR-independent gene delivery achieved via this strategy allowed enhanced gene transfer efficiencies to SCCHN tumor cells. Importantly, this strategy could achieve preferential augmentation of gene transfer in tumor cells compared with normal cells. The ability to achieve enhanced and specific gene transfer to tumor cells via adenoviral vectors has important implications for gene therapy strategies for SCCHN and for other neoplasms in general.