Adenoviral gene therapy for renal cancer requires retargeting to alternative cellular receptors.
Adenoviral gene therapy for renal cancer requires retargeting to alternative cellular receptors.
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DOI：
10.1016/s1525-0016(16)44194-8
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发表时间：
2002-08
期刊：
影响因子：
11.2
通讯作者：
Y. Haviv;J. Blackwell;A. Kanerva;Peter A. Nagi;V. Krasnykh;I. Dmitriev;Minghui Wang;S. Naito;Xiaosheng Lei;A. Hemminki;D. Carey;D. Curiel
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文献类型：
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作者：
Y. Haviv;J. Blackwell;A. Kanerva;Peter A. Nagi;V. Krasnykh;I. Dmitriev;Minghui Wang;S. Naito;Xiaosheng Lei;A. Hemminki;D. Carey;D. Curiel
转移性肾细胞癌是人类最难治疗的恶性肿瘤之一。因此，鉴定具有更好抗肿瘤活性的新药物在晚期RCC的治疗中值得优先考虑。在这方面，腺病毒（Ad）载体的基因治疗是一个有前途的新模式的癌症。然而，使用Ad载体进行癌症基因治疗的主要限制因素是它们对主要Ad受体（科萨基和腺病毒受体（CAR））的细胞表达的关键依赖性，已知该受体在许多癌症类型中下调。在RCC系中鉴定CAR缺陷后，我们发现αvβ3和αvβ5整联蛋白以及Ad血清型3（Ad 3）的推定受体的丰富膜表达。作为避免CAR缺陷的RCC的替代基因治疗方法，我们采用了将无复制能力的Ad载体和有复制能力的Ad病毒重靶向αvβ3和αvβ5整联蛋白以及推定的Ad 3受体。这些遗传改变Ad嗜性的策略是基于将半胱氨酸-天冬氨酸-半胱氨酸-精氨酸-甘氨酸-天冬氨酸-半胱氨酸-苯丙氨酸-半胱氨酸（RGD）基序插入Ad纤维节结构域的HI环或基于产生由腺病毒血清型5轴/Ad 3节组成的嵌合Ad纤维。这两种策略都被证明可以高效地规避CAR缺陷并增强基因递送到RCC细胞中。此外，在有复制能力的Ad的背景下，嗜性改变导致重定向病毒在体外和体内感染、复制和裂解RCC模型的不同能力。重定向策略在复制能力的Ad的情况下特别有益。这些发现强调了RCC中CAR非依赖性细胞进入机制的重要性，并且对于RCC和其他CAR阴性肿瘤的病毒抗肿瘤药物的开发具有重要意义。
Metastatic renal cell carcinoma (RCC) is one of the most treatment-resistantmalignancies in humans. Therefore, the identification of new agents with better antitumor activity merits a high priority in the treatment of advanced RCC. In this regard, gene therapy with adenoviral (Ad) vectors is a promising new modality for cancer. However, a primary limiting factor for the use of Ad vectors for cancer gene therapy is their critical dependence on cellular expression of the primary Ad receptor, the coxsackie and adenovirus receptor (CAR), known to be down-regulated in many cancer types. Following the identification of CAR deficiency in RCC lines, we have found abundant membrane expression of αvβ3 and αvβ5 integrins and of the putative receptor to Ad serotype 3 (Ad3). As an alternative gene therapy approach for RCC that would circumvent CAR deficiency, we employed retargeting of replication-incompetent Ad vectors and replication-competent Ad viruses to αvβ3 and αvβ5 integrins and to the putative Ad3 receptor. These strategies to genetically alter Ad tropism were based on either the insertion of a cysteine-aspartate-cysteine-arginine-glycine-aspartate-cysteine-phenylalanine-cysteine (RGD) motif into the HI loop of the Ad fiber knob domain or on generation of a chimeric Ad fiber composed of adenovirus serotype 5 shaft/Ad3 knob. Both strategies proved highly efficient to circumvent CAR deficiency and enhance gene delivery into RCC cells. Furthermore, in the context of replication-competent Ad, tropism alteration resulted in distinct capacity of the retargeted viruses to infect, replicate, and lyse RCC modelsin vitroandin vivo. The retargeting strategies were particularly beneficial in the context of replication-competent Ad. These findings underscore the importance of CAR-independent cellular entry mechanisms in RCC and are highly consequential for the development of viral antitumor agents for RCC and other CAR-negative tumors.