title: Complete eradication of xenograft hepatoma by oncolytic adenovirus ZD55 harboring TRAIL-IETD-Smac gene with broad antitumor effect.
abstract: Cancer-targeting dual-gene virotherapy (CTGVT-DG) is an important modification of CTGVT, in which two suitable genes are used to obtain an excellent antitumor effect. A key problem is to join the two genes to form one fused gene, and then to clone it into the oncolytic viral vector so that only one investigational new drug application, instead of two, is required for clinical use. Many linkers (e.g., internal ribosome entry site) are used to join two genes together, but they are not all equally efficacious. Here, we describe finding the best linker, that is, sequence encoding the four amino acids IETD, to join the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene and the second mitochondria-derived activator of caspase (Smac) gene to form TRAIL-IETD-Smac and inserting it into oncolytic viral vector ZD55 to construct ZD55-TRAIL-IETD-Smac, which matched ZD55-TRAIL plus ZD55-Smac in completely eliminating xenograft hepatoma. ZD55-TRAIL-IETD-Smac works by quantitative cleavage at IETD↓by inducing caspase-8; activation or inhibition of caspase-8 could up- or downregulate cleavage, respectively. The cleaved product, TRAIL-IETD, does not affect the function of TRAIL. Numerous experiments have shown that the combined use of ZD55-TRAIL plus ZD55-X could completely eradicate many xenograft tumors, and therefore the IETD is potentially a useful linker to construct many antitumor drugs, for example, ZD55-TRAIL-IETD-X, where X has a compensative or synergetic effect on TRAIL. We found that the antitumor effect of ZD55-IL-24-IETD-TRAIL also has an equivalent antitumor effect compared with the combined use of ZD55-IL-24 plus ZD55-TRAIL, because ZD55-IL-24 could also induce caspase-8. This means that IETD, as a two-gene linker, may have broad use.
authors.affiliation: Xinyuan Institute of Medicine and Biotechnology, School of Life Science, Zhejiang Sci-Tech University, Hangzhou, China.
authors.forename: Shi-Bing
authors.initials: SB
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tan
authors.forename: Wen
authors.initials: W
authors.lastname: Lei
authors.forename: Yi-Gang
authors.initials: YG
authors.lastname: Wang
authors.forename: Xiu-Mei
authors.initials: XM
authors.lastname: Zhou
authors.forename: Xiao-Yuan
authors.initials: XY
authors.lastname: Jia
authors.forename: Kang-Jian
authors.initials: KJ
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Chu
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Liu
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Qian
mesh_terms: D000256:Adenoviridae; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D053181:Caspase 8