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Study on Targeting Oncolytic Adenovirus with E1B Gene Deletion and Mda-7/IL-24 for Hepatocellular Carcinoma Therapy

Author: ZhangJing
Tutor: LiuXinYuan
School: Zhejiang University of Technology
Course: Biochemistry and Molecular Biology
Keywords: Targeted gene - viral treatment E1B wholly deleted mda-7/IL-24 AFP
CLC: R735.7
Type: Master's thesis
Year: 2010
Downloads: 29
Quote: 0
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Abstract


The malignancy serious threat to human life and health, including liver cancer is one of the world's most common malignancy. Many patients with hepatitis B in China, is the world's countries with the highest incidence of liver cancer. Liver cancer because of its high incidence and high mortality, is difficult to diagnose, easy to relapse, cancer of the King \The latest statistics show that the incidence of liver cancer in China accounted for 55% of global deaths accounted for 45% of the world, and therefore the treatment of liver cancer imminent. Tumors, including liver cancer is due to a genetic disorder caused by the disease, gene therapy is generally considered to be the hope of mankind overcome cancer. Especially targeted gene therapy research is more important. In gene therapy, choice of the vector is the key. Viral vectors because of its high transfection continued, gene expression in a long time, etc. become the preferred carrier for cancer gene therapy. Tumor-specific proliferation of adenovirus the (Instant tumor adenovirus), is currently the most promising targeted one of the gene therapy vector. Copy the most important element of the adenovirus E1 region, and we start the sub-alpha-fetoprotein levels with the hepatoma-specific promoter to (AFP) instead of the promoter of the E1A itself, constitute the Ad-enAFP-E1A. The E1B District by 55kDa and 19kDa. 55 kDa absence of p53 mutations in tumor cells can be targeted to, and can selectively inhibit viral mRNA out of the nucleus. 19 kDa Bcl-2 homologue E1B 19 kDa absence in recent research reports through multi-channels to induce tumor cell apoptosis, and enhance the ability of the spread of the virus may have, therefore, also delete E1B 55kDa and 19kDa can not only enhance the targeting of the virus, and the virus can greatly improve the ability to pro-apoptotic, is a new method of transformation of oncolytic adenovirus. Said construct abbreviated Ad.enAFP-E1A-△ E1B is having hepatoma specific three targeted oncolytic adenovirus vector, this adenovirus can only be targeted hepatoma cells and having a high safety and destruction. Academician Liu Xinyuan cancer targeted gene - the concept of viral therapy (Targeting Gene-Virotherapy) 2001, after the proposed dual-targeted gene - viral therapy (Dual Targeting Gene-Virotherapy) strategy. This strategy, a targeting of a viral vector carrying a good tumor therapeutic genes, using the the oncolytic virus specific lysis in tumor cells, proliferation and tumor therapeutic gene strongly induce apoptosis of cancer cells or inhibition \coordinated operations, and thus achieve the dual role of the virus in the tumor-specific proliferation and therapeutic gene synergistic anti-tumor. In this research, select melanoma differentiation associated gene of -7 / white interleukin -24 (mda-7/IL-24) gene as a new build viral vector carrying tumor therapeutic gene. IL-24 is a multifunctional regulating cytokine-induced apoptosis of cancer cells, due to its tumor-killing effect is significant, and has a high selectivity, non-toxic to normal cells, IL-24 gene in cancer gene therapy the \In this study of IL-24 insert hepatoma-specific dual-targeted oncolytic adenovirus vector Ad.enAFP-E1A-_ △ E1B we build, re-composition of the gene - the virus Ad.enAFP-E1A-_ △ E1B-IL- 24. Vitro experiments showed that E1A-_ △ Ad.enAFP-E1B-IL-24 can induce the death of liver tumor cells, strong performance tumor killing ability, and almost no killing effect on normal liver cells prove effective security. Hepatoma cell line in Huh-7 tumor-bearing nude mice animal experiments proved Ad.enAFP-E1A-_ △ E1B-IL-24 can completely inhibit the further deterioration of the tumor, and has the potential transmission capacity can be anti-hepatoma cells and improve the tumor-bearing the survival rate of nude mice. Found Ad.enAFP-E1A-_ △ E1B-IL-24 induce tumor cell apoptosis mechanism is mainly related to the death receptor-mediated apoptosis pathway and mitochondrial / cytochrome C-mediated apoptosis pathway. The subject preliminary practice tumor targeting gene - viral treatment strategies, hepatoma-specific oncolytic adenovirus vector was constructed successfully, and to provide a safer and more effective targeted cancer gene - viral treatment for liver cancer clinical research program, has laid a solid foundation for the successful realization of the specific treatment of liver cancer. In addition, in the study of the transformation of the adenovirus E1B 19 kDa delete not only promote apoptosis of tumor cells, and can enhance the ability of the virus to spread these findings for future tumor targeting gene viral vectors - viral treatment rehabilitation and research applications have important significance for new ideas and direction.

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CLC: > Medicine, health > Oncology > Gastrointestinal Cancer > Liver tumors
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