Intratumoral Spread and Increased Efficacy of a p53-VP22 Fusion Protein Expressed by a Recombinant Adenovirus
| Autor: | Jenny Avanzini, Shu Fen Wen, Mei Vaillancourt, Isabella A. Atencio, Duane E. Johnson, Robert O. Ralston, Wills Ken N, Saskia Neuteboom, Jennifer Philopena, Suganto Sutjipto, Anne Phelan |
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| Rok vydání: | 2001 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Recombinant Fusion Proteins Genetic enhancement Genetic Vectors Immunology Gene Expression Apoptosis Herpesvirus 1 Human Biology Microbiology In vivo Cyclins Virology Chlorocebus aethiops Tumor Cells Cultured Animals Humans Cytotoxic T cell Viral Structural Proteins Adenoviruses Human Intercellular transport Neoplasms Experimental Gene Therapy Transfection Molecular biology Fusion protein Caspase 9 In vitro Enzyme Activation Caspases Insect Science COS Cells Cancer research Tumor Suppressor Protein p53 |
| Zdroj: | Journal of Virology. 75:8733-8741 |
| ISSN: | 1098-5514 0022-538X |
| Popis: | In vitro experiments have demonstrated intercellular trafficking of the VP22 tegument protein of herpes simplex virus type 1 from infected cells to neighboring cells, which internalize VP22 and transport it to the nucleus. VP22 also can mediate intercellular transport of fusion proteins, providing a strategy for increasing the distribution of therapeutic proteins in gene therapy. Intercellular trafficking of the p53 tumor suppressor protein was demonstrated in vitro using a plasmid expressing full-length p53 fused in-frame to full-length VP22. The p53-VP22 chimeric protein induced apoptosis both in transfected tumor cells and in neighboring cells, resulting in a widespread cytotoxic effect. To evaluate the anti-tumor activity of p53-VP22 in vivo, we constructed recombinant adenoviruses expressing either wild-type p53 (FTCB) or a p53-VP22 fusion protein (FVCB) and compared their effects in p53-resistant tumor cells. In vitro, treatment of tumor cells with FVCB resulted in enhanced p53-specific apoptosis compared to treatment with equivalent doses of FTCB. However, in normal cells there was no difference in the dose-related cytotoxicity of FVCB compared to that of FTCB. In vivo, treatment of established tumors with FVCB was more effective than equivalent doses of FTCB. The dose-response curve to FVCB was flatter than that to FTCB; maximal antitumor responses could be achieved using FVCB at doses 1 log lower than those obtained with FTCB. Increased antitumor efficacy was correlated with increased distribution of p53 protein in FVCB-treated tumors. This study is the first demonstration that VP22 can enhance the in vivo distribution of therapeutic proteins and improve efficacy in gene therapy. |
| Databáze: | OpenAIRE |
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