Stoff-Khalili M A, Rivera A A, Glasgow J N, Le L P, Stoff A, Everts M, Tsuruta Y, Kawakami Y, Bauerschmitz G J, Mathis J M, Pereboeva L, Seigal G P, Dall P, Curiel D T
Department of Medicine, Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Gene Ther. 2005 Dec;12(23):1696-706. doi: 10.1038/sj.gt.3302588.
The development of novel therapeutic strategies is imperative for the treatment of advanced cancers like ovarian cancer and glioma, which are resistant to most traditional treatment modalities. In this regard, adenoviral (Ad) cancer gene therapy is a promising approach. However, the gene delivery efficiency of human serotype 5 recombinant adenoviruses (Ad5) in cancer gene therapy clinical trials to date has been limited, mainly due to the paucity of the primary Ad5 receptor, the coxsackie and adenovirus receptor (CAR), on human cancer cells. To circumvent CAR deficiency, Ad5 vectors have been retargeted by creating chimeric fibers possessing the knob domains of alternate human Ad serotypes. Recently, more radical modifications based on 'xenotype' knob switching with non-human adenovirus have been exploited. Herein, we present the characterization of a novel vector derived from a recombinant Ad5 vector containing the canine adenovirus serotype 1 (CAV-1) knob (Ad5Luc1-CK1), the tropism of which has not been previously described. We compared the function of this vector with our other chimeric viruses displaying the CAV-2 knob (Ad5Luc1-CK2) and Ad3 knob (Ad5/3Luc1). Our data demonstrate that the CAV-1 knob can alter Ad5 tropism through the use of a CAR-independent entry pathway distinct from that of both Ad5Luc1-CK2 and Ad5/3-Luc1. In fact, the gene transfer efficiency of this novel vector in ovarian cancer cell lines, and more importantly in patient ovarian cancer primary tissue slice samples, was superior relative to all other vectors applied in this study. Thus, CAV-1 knob xenotype gene transfer represents a viable means to achieve enhanced transduction of low-CAR tumors.
对于卵巢癌和神经胶质瘤等晚期癌症的治疗而言，开发新的治疗策略势在必行，因为这些癌症对大多数传统治疗方式均具有抗性。在这方面，腺病毒（Ad）癌症基因治疗是一种很有前景的方法。然而，迄今为止，人血清型5重组腺病毒（Ad5）在癌症基因治疗临床试验中的基因递送效率一直有限，这主要是由于人类癌细胞上主要的Ad5受体——柯萨奇病毒和腺病毒受体（CAR）数量稀少。为了克服CAR缺陷，人们通过构建具有替代人Ad血清型的球状结构域的嵌合纤维，对Ad5载体进行了重新靶向。最近，基于与非人类腺病毒进行“异种型”球状结构域切换的更彻底修饰也已得到应用。在此，我们展示了一种源自重组Ad5载体的新型载体的特性，该载体含有犬腺病毒血清型1（CAV-1）的球状结构域（Ad5Luc1-CK1），其嗜性此前尚未见报道。我们将该载体的功能与我们其他展示CAV-2球状结构域的嵌合病毒（Ad5Luc1-CK2）和Ad3球状结构域（Ad5/3Luc1）进行了比较。我们的数据表明，CAV-1球状结构域可通过使用一种独立于CAR的进入途径来改变Ad5嗜性，该途径不同于Ad5Luc1-CK2和Ad5/3-Luc1的途径。事实上，这种新型载体在卵巢癌细胞系中，更重要的是在患者卵巢癌原发组织切片样本中的基因转移效率，相对于本研究中应用的所有其他载体均更优。因此，CAV-1球状结构域异种型基因转移是实现低CAR肿瘤增强转导的一种可行手段。
