The therapeutic efficacy of adenoviral vectors for cancer gene therapy is limited by a low level of primary adenovirus receptors on tumour cells
The therapeutic efficacy of adenoviral vectors for cancer gene therapy is limited by a low level of primary adenovirus receptors on tumour cells
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DOI：
10.1016/s0959-8049(02)00131-4
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发表时间：
2002-09-01
影响因子：
8.4
通讯作者：
Douglas, JT
中科院分区：
文献类型：
--
作者：
Kim, M;Zinn, KR;Douglas, JT
复制缺陷型腺病毒载体目前被用作癌症基因治疗的基因递送载体。为了解决腺病毒载体的治疗效果受到其不能感染表达低水平的腺病毒的主要细胞受体（柯萨奇病毒和腺病毒受体（CAR））的肿瘤细胞的限制的假设，我们采用了一对卵巢癌细胞系，其差异仅在于表达Ad 5的主要受体。因此，这种新的系统允许直接评估腺病毒载体的功效与宿主癌细胞的初级受体水平之间的关系，而不受其他可变细胞因子的混杂影响。我们证明，肿瘤细胞上的主要细胞受体的缺陷限制了腺病毒载体在两种不同的癌症基因治疗方法，TP 53基因替代治疗和单纯疱疹病毒胸苷激酶/更昔洛韦自杀基因治疗中的疗效。此外，我们表明，肿瘤细胞上的主要受体的缺陷限制了体内腺病毒介导的基因转移的效率。由于许多研究已经报道了原代癌细胞仅表达低水平的CAR，我们的结果表明，重定向腺病毒以实现CAR非依赖性感染的策略对于实现腺病毒载体在临床环境中的全部潜力是必要的。(C)2002爱思唯尔科技有限公司版权所有。
Replication-defective adenoviral vectors are currently being employed as gene delivery vehicles for cancer gene therapy. To address the hypothesis that the therapeutic efficacy of adenoviral vectors is restricted by their inability to infect tumour cells expressing low levels of the primary cellular receptor for adenoviruses, the coxsackievirus and adenovirus receptor (CAR), we have employed a pair of ovarian cancer cell lines differing only in the expression of a primary receptor for Ad5. This novel system thus allowed the direct evaluation of the relationship between the efficacy of an adenoviral vector and the primary receptor levels of the host cancer cell, without the confounding influence of other variable cellular factors. We demonstrate that a deficiency of the primary cellular receptor on the tumour cells restricts the efficacy of adenoviral vectors in two distinct cancer gene therapy approaches, TP53 gene replacement therapy and herpes simplex virus thymidine kinase/ganciclovir suicide gene therapy. Moreover, we show that a deficiency of the primary receptor on the tumour cells limits the efficiency of adenovirus-mediated gene transfer in vivo. Since a number of studies have reported that primary cancer cells express only low levels of CAR, our results suggest that strategies to redirect adenoviruses to achieve CAR-independent infection will be necessary to realize the full potential of adenoviral vectors in the clinical setting. (C) 2002 Elsevier Science Ltd. All rights reserved.