Gao Y, Ng S S M, Chau D H W, Yao H, Yang C, Man K, Huang P T, Huang C, Huang J J, Kung H-F, Lin M C
Department of Chemistry, Institute of Molecular Biology, The University of Hong Kong, Pokfulam, Hong Kong, China.
Cancer Gene Ther. 2008 Nov;15(11):723-32. doi: 10.1038/cgt.2008.33. Epub 2008 Jun 6.
The low in vivo transduction efficiency of recombinant adeno-associated virus (rAAV) and the undesirably strong immunogenicity of adenovirus (rAdv) have limited their clinical utilization in cancer gene therapy. We have previously demonstrated that intratumoral injection of rAAV expressing a C-terminal polypeptide of human telomerase reverse transcriptase (rAAV-hTERTC27) effectively inhibits the growth of glioblastoma xenografts in nude mice. To further improve its efficacy, we combined rAAV-hTERTC27 with rAdv and investigated the efficiency of the cocktail vectors in vivo. At a nontherapeutic dose (1 x 10(8) plaque-forming units (PFUs)), rAdv-null and rAdv-hTERTC27 were equipotent in enhancing the therapeutic efficacy of rAAV-hTERTC27 (1.5 x 10(11) v.g.), and complete tumor regression was achieved in 25% of the treated animals. Importantly, the combination of rAAV-hTERTC27 and a therapeutic dose (2.5 x 10(9) PFU) of rAdv-hTERTC27 significantly augmented the therapeutic effects and led to a 38% complete tumor regression rate. In vivo optical imaging also showed that rAAV-luc/rAdv-luc cocktail vectors could synergistically enhance the early transient and latent sustained expression of luciferase, as compared to rAdv-luc and rAAV-luc alone. These findings suggest that the combination of rAAV-hTERTC27 and a therapeutic dose of rAdv-hTERTC27 is potentially a promising treatment for glioblastoma, and the rAAV/rAdv cocktail vector system warrants further development for cancer gene therapy.
重组腺相关病毒（rAAV）在体内的转导效率较低，腺病毒（rAdv）的免疫原性过强，这些都限制了它们在癌症基因治疗中的临床应用。我们之前已经证明，瘤内注射表达人端粒酶逆转录酶C末端多肽的rAAV（rAAV-hTERTC27）可有效抑制裸鼠体内胶质母细胞瘤异种移植物的生长。为了进一步提高其疗效，我们将rAAV-hTERTC27与rAdv联合使用，并研究了这种混合载体在体内的效率。在非治疗剂量（1×10⁸ 噬斑形成单位（PFU））下，rAdv-null和rAdv-hTERTC27在增强rAAV-hTERTC27（1.5×10¹¹ 病毒基因组（v.g.））的治疗效果方面具有同等效力，25%的治疗动物实现了肿瘤完全消退。重要的是，rAAV-hTERTC27与治疗剂量（2.5×10⁹ PFU）的rAdv-hTERTC27联合使用显著增强了治疗效果，导致肿瘤完全消退率达到38%。体内光学成像还显示，与单独的rAdv-luc和rAAV-luc相比，rAAV-luc/rAdv-luc混合载体可协同增强荧光素酶的早期瞬时和潜伏持续表达。这些发现表明，rAAV-hTERTC27与治疗剂量的rAdv-hTERTC27联合使用可能是胶质母细胞瘤的一种有前景的治疗方法，并且rAAV/rAdv混合载体系统值得在癌症基因治疗中进一步开发。
