دورية
Intratumoral Spread and Increased Efficacy of a p53-VP22 Fusion Protein Expressed by a Recombinant Adenovirus
| العنوان: | Intratumoral Spread and Increased Efficacy of a p53-VP22 Fusion Protein Expressed by a Recombinant Adenovirus |
|---|---|
| المؤلفون: | Wills, Ken N., Atencio, Isabella A., Avanzini, Jenny B., Neuteboom, Saskia, Phelan, Anne, Philopena, Jennifer, Sutjipto, Suganto, Vaillancourt, Mei T., Wen, Shu Fen, Ralston, Robert O., Johnson, Duane E. |
| المصدر: | The Journal of Virology; September 2001, Vol. 75 Issue: 18 p8733-8741, 9p |
| مستخلص: | ABSTRACTIn 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. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 0022538X 10985514 |
|---|---|
| DOI: | 10.1128/JVI.75.18.8733-8741.2001 |