title: HCCS1-armed, quadruple-regulated oncolytic adenovirus specific for liver cancer as a cancer targeting gene-viro-therapy strategy.
abstract: BACKGROUND
  In previously published studies, oncolytic adenovirus-mediated gene therapy has produced good results in targeting cancer cells. However, safety and efficacy, the two most important aspects in cancer therapy, remain serious challenges. The specific expression or deletion of replication related genes in an adenovirus has been frequently utilized to regulate the cancer cell specificity of a virus. Accordingly, in this study, we deleted 24 bp in E1A (bp924-bp947) and the entirety of E1B, including those genes encoding E1B 55kDa and E1B19kDa. We used the survivin promoter (SP) to control E1A in order to construct a new adenovirus vector named Ad.SP.E1A(Δ24).ΔE1B (briefly Ad.SPDD). HCCS1 (hepatocellular carcinoma suppressor 1) is a novel tumor suppressor gene that is able to specifically induce apoptosis in cancer cells. The expression cassette AFP-HCCS1-WPRE-SV40 was inserted into Ad.SPDD to form Ad.SPDD-HCCS1, enabling us to improve the safety and efficacy of oncolytic-mediated gene therapy for liver cancer.
  
  
  RESULTS
  Ad.SPDD showed a decreased viral yield and less toxicity in normal cells but enhanced toxicity in liver cancer cells, compared with the cancer-specific adenovirus ZD55 (E1B55K deletion). Ad.SPDD-HCCS1 exhibited a potent anti-liver-cancer ability and decreased toxicity in vitro. Ad.SPDD-HCCS1 also showed a measurable capacity to inhibit Huh-7 xenograft tumor growth on nude mice. The underlying mechanism of Ad.SPDD-HCCS1-induced liver cancer cell death was found to be via the mitochondrial apoptosis pathway.
  
  
  CONCLUSIONS
  These results demonstrate that Ad.SPDD-HCCS1 was able to elicit reduced toxicity and enhanced efficacy both in vitro and in vivo compared to a previously constructed oncolytic adenovirus. Ad.SPDD-HCCS1 could be a promising candidate for liver cancer therapy.
authors: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Hai-Neng
authors: HN
authors: Xu
authors: Wei-Dan
authors: WD
authors: Huang
authors: Ying
authors: Y
authors: Cai
authors: Miao
authors: M
authors: Ding
authors: Jin-Fa
authors: JF
authors: Gu
authors: Na
authors: N
authors: Wei
authors: Lan-Ying
authors: LY
authors: Sun
authors: Xin
authors: X
authors: Cao
authors: Hua-Guang
authors: HG
authors: Li
authors: Kang-Jian
authors: KJ
authors: Zhang
authors: Xin-Ran
authors: XR
authors: Liu
authors: Xin-Yuan
authors: XY
authors: Liu
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; C503307:VPS53 protein, human; D033921:Vesicular Transport Proteins