Chen Lin, Chen Dongfeng, Gong Mouchun, Na Manli, Li Linfang, Wu Hongping, Jiang Lihua, Qian Yanzhen, Fang Guoen, Xue Xuchao
Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Cancer Lett. 2009 Nov 1;284(2):141-8. doi: 10.1016/j.canlet.2009.04.026. Epub 2009 May 17.
Chimeric adenoviral vectors possessing fiber derived from human adenovirus subgroup B (Ad35) have been developed for their high infection efficiency in cell types which are refractory to adenovirus serotype 5 (Subgroup C). The present study constructed an E1B-deleted chimeric oncolytic adenovirus, SG235-TRAIL, which carries a human TRAIL gene expression cassette and whose fiber shaft and knob domains are from serotype Ad35. It was found that SG235-TRAIL preferentially replicated in gastric cancer cell lines, SGC-7901 and BGC-823 compared to in normal human fibroblast BJ cells. Also, when compared with a replication-deficient chimeric vector Ad5/35-TRAIL, SG235-TRAIL mediated a higher level of the transgene expression via viral replication in the cancer cells. Further, because of the more efficient cell-entry and infection, SG235-TRAIL induced stronger cell apoptosis than the Ad5 CRAD vector, ZD55-TRAIL. In addition, SG235-TRAIL in combination with the chemotherapeutic drug, taxol, produced a synergistic cytotoxic effect in cancer cells in vitro without causing significant toxicity to normal cells. In the gastric tumor xenograft mouse model, intratumoral SG235-TRAIL injection produced a significant antitumor effect 14 days after treatment. Pathological examination demonstrated TRAIL expression and associated apoptosis in majority of SG235-TRAIL-treated tumor cells. These results suggest that SG235-TRAIL is a potential novel, efficient anti-cancer agent, and in combination with taxol, it would be even more useful with considerably low toxic side effects.
具有源自人B亚组腺病毒（Ad35）纤维的嵌合腺病毒载体，因其在对5型腺病毒（C亚组）难治的细胞类型中具有高感染效率而被开发出来。本研究构建了一种E1B缺失的嵌合溶瘤腺病毒SG235-TRAIL，其携带人TRAIL基因表达盒，且其纤维杆和纤维结结构域来自Ad35血清型。研究发现，与正常人成纤维细胞BJ细胞相比，SG235-TRAIL在胃癌细胞系SGC-7901和BGC-823中优先复制。此外，与复制缺陷型嵌合载体Ad5/35-TRAIL相比，SG235-TRAIL通过癌细胞中的病毒复制介导了更高水平的转基因表达。此外，由于更有效的细胞进入和感染，SG235-TRAIL比Ad5 CRAD载体ZD55-TRAIL诱导更强的细胞凋亡。另外，SG235-TRAIL与化疗药物紫杉醇联合使用，在体外对癌细胞产生协同细胞毒性作用，而对正常细胞无明显毒性。在胃肿瘤异种移植小鼠模型中，瘤内注射SG235-TRAIL在治疗14天后产生了显著的抗肿瘤作用。病理检查显示，大多数经SG235-TRAIL处理的肿瘤细胞中存在TRAIL表达及相关凋亡。这些结果表明，SG235-TRAIL是一种潜在的新型高效抗癌药物，与紫杉醇联合使用时，其毒性副作用更低，将更有用。
