Abstract
BackgroundGene therapy and viral therapy are used for cancer therapy for many years, but the results are less than satisfactory. Our aim was to construct a new recombinant adenovirus which is more efficient to kill hepatocarcinoma cells but more safe to normal cells.MethodsBy using the Cancer Targeting Gene-Viro-Therapy strategy, Apoptin, a promising cancer therapeutic gene was inserted into the double-regulated oncolytic adenovirus AD55 in which E1A gene was driven by alpha fetoprotein promoter along with a 55 kDa deletion in E1B gene to form AD55-Apoptin. The anti-tumor effects and safety were examined by western blotting, virus yield assay, real time polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, Hoechst33342 staining, Fluorescence-activated cell sorting, xenograft tumor model, Immunohistochemical assay, liver function analysis and Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay.ResultsThe recombinant virus AD55-Apoptin has more significant antitumor effect for hepatocelluar carcinoma cell lines (in vitro) than that of AD55 and even ONYX-015 but no or little impair on normal cell lines. Furthermore, it also shows an obvious in vivo antitumor effect on the Huh-7 liver carcinoma xenograft in nude mice with bigger beginning tumor volume till about 425 mm3 but has no any damage on the function of liver. The induction of apoptosis is involved in AD55-Apoptin induced antitumor effects.ConclusionThe AD55-Apoptin can be a potential anti-hepatoma agent with remarkable antitumor efficacy as well as higher safety in cancer targeting gene-viro-therapy system.
Highlights
Gene therapy and viral therapy are used for cancer therapy for many years, but the results are less than satisfactory
Due to the specific expression spectrum of AFP, AFP promoter was extensively used as hepatocarcinoma targetting promoter to drive the adenovirus E1A gene [8,10] or directly drive suicide genes such as herpes simplex virus thymidine kinase (HSV-tk) [11,12]
Construction and characterization of the recombinant AD55-Apoptin The dual regulated oncolytic adenovirus AD55 based on oncolytic adenovirus ZD55 with E1B 55KD deletion was constructed by using Hepatocellular carcinoma (HCC)-specific eAFP promoter to control E1A gene
Summary
Gene therapy and viral therapy are used for cancer therapy for many years, but the results are less than satisfactory. Hepatocellular carcinoma (HCC) is the third most common cause of cancer death in china and the fifth most prevalent male cancer worldwide Routine curative therapies such as liver transplantation and surgical resection are offered to only limited patients. Gene therapy exhibits a promising advantage for many diseases such as Leber’s congenital amaurosis, X-linked adrenoleukodystrophy and"Bubble boy” disease, which was selected as the one of top ten news in the journal of “sicence”[2]. It is not efficient for cancer therapy by delivering a single therapeutic gene because of polygenes related disregulated pathways in cancer cells. Due to the specific expression spectrum of AFP, AFP promoter was extensively used as hepatocarcinoma targetting promoter to drive the adenovirus E1A gene [8,10] or directly drive suicide genes such as herpes simplex virus thymidine kinase (HSV-tk) [11,12]
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