Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Gene Ther. 2010 Feb;17(2):190-201. doi: 10.1038/gt.2009.142. Epub 2009 Nov 12.
The pressing challenge for contemporary gene therapy is to deliver enough therapeutic genes to enough cancer cells in vivo. With the aim of improving viral distribution and tumor penetration, we explored the use of decorin to enhance viral spreading and tumor tissue penetration. We generated decorin-expressing replication-incompetent (dl-LacZ-DCNG, dl-LacZ-DCNQ and dl-LacZ-DCNK) and replication-competent (Ad-DeltaE1B-DCNG, Ad-DeltaE1B-DCNQ and Ad-DeltaE1B-DCNK) adenoviruses (Ads). Point mutants of decorin gene (DCNG), DCNK and DCNQ, have a negative and moderate binding affinity to type-I collagen fibril, respectively. In both tumor spheroids and established solid tumors in vivo, tissue penetration potency of dl-LacZ-DCNG was greatly enhanced than those of dl-LacZ, dl-LacZ-DCNQ and dl-LacZ-DCNK, and this enhanced tissue penetration effect derived from decorin-expressing Ad was dependent on the binding affinity of decorin to collagen fibril. Expression of DCNG enhanced viral spread of replicating Ad, leading to improved tumor reduction and survival benefit. Moreover, the tumoricidal effects of Ad-DeltaE1B-DCNQ and Ad-DeltaE1B-DCNK were lessened, as the binding affinity to collagen was decreased, showing that the increased cancer cell cytotoxicity was driven by the action of decorin on extracellular matrix (ECM). Furthermore, Ad-DeltaE1B-DCNG substantially decreased ECM components within the tumor tissue. Finally, intratumoral injection of Ad-DeltaE1B-DCNG in primary tumor site greatly reduced the formation of B16BL6 melanoma cell pulmonary metastases in mice. Taken together, these data show the utility of decorin as a dispersion agent and highlight its utility and potential in improving the efficacy of replicating Ad-mediated cancer gene therapy.
当代基因治疗的紧迫挑战是在体内将足够的治疗基因递送到足够数量的癌细胞中。为了提高病毒的分布和肿瘤的穿透性，我们探索了使用decorin 来增强病毒的扩散和肿瘤组织的穿透性。我们生成了表达 decorin 的复制缺陷型（dl-LacZ-DCNG、dl-LacZ-DCNQ 和 dl-LacZ-DCNK）和复制型（Ad-DeltaE1B-DCNG、Ad-DeltaE1B-DCNQ 和 Ad-DeltaE1B-DCNK）腺病毒（Ads）。decorin 基因的点突变体（DCNG、DCNK 和 DCNQ）分别对 I 型胶原纤维具有负中和中等的结合亲和力。在肿瘤球体和体内建立的实体瘤中，dl-LacZ-DCNG 的组织穿透能力比 dl-LacZ、dl-LacZ-DCNQ 和 dl-LacZ-DCNK 都大大增强，这种增强的组织穿透效果来自于表达 decorin 的 Ad，这取决于 decorin 与胶原纤维的结合亲和力。DCNG 的表达增强了复制型 Ad 的病毒传播，导致肿瘤体积减小和生存获益的改善。此外，由于与胶原的结合亲和力降低，Ad-DeltaE1B-DCNQ 和 Ad-DeltaE1B-DCNK 的杀肿瘤效果减弱，表明细胞外基质（ECM）上 decorin 的作用驱动了癌细胞的细胞毒性增加。此外，Ad-DeltaE1B-DCNG 可大大减少肿瘤组织内的 ECM 成分。最后，在原发性肿瘤部位瘤内注射 Ad-DeltaE1B-DCNG 可大大减少 B16BL6 黑色素瘤细胞肺转移的形成。总之，这些数据表明 decorin 可作为一种分散剂，并强调其在提高复制型 Ad 介导的癌症基因治疗疗效方面的应用和潜力。
