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Transcellular transfer of active HSV-1 thymidine kinase mediated by an 11-amino-acid peptide from HIV-1 Tat.

Abstract：

:Suicide gene therapy using herpes simplex virus type-1 (HSV-1) thymidine kinase (TK) is a widely exploited approach for gene therapy of cancer and other hyperproliferative disorders. Despite its popularity, clinical success has been so far hampered mostly by the relative inefficiency of TK gene transfer and its limited bystander effect. Here we report that fusion of TK to an 11-amino-acid peptide from the basic domain of the HIV-1 Tat protein (Tat11) imparts cell membrane translocating ability to the enzyme and significantly increases its cytotoxic efficacy. In cells expressing Tat11-TK, this protein is found extracellularly, associated with cell surface heparan sulfate proteoglycans, and is released into the cell culture medium. Based on its interaction with HSPGs, the protein is then internalized by neighboring, nonexpressing cells, which become susceptible to cell death when treated with the nucleoside analogue acyclovir. As a consequence, co-cultures of wild-type cells with cells expressing Tat11-TK show increased sensitivity to ACV through a mechanism involving apoptosis. Modification of TK by fusion with Tat11 might constitute an important step for the optimization of TK suicide gene strategy for gene therapy of cellular proliferation.

journal_name

Cancer Gene Ther

journal_title

Cancer gene therapy

authors

Tasciotti E,Zoppè M,Giacca M

doi

10.1038/sj.cgt.7700526

subject

Has Abstract

pub_date

2003-01-01 00:00:00

pages

64-74

issue

1

eissn

0929-1903

issn

1476-5500

pii

7700526

journal_volume

10

pub_type

杂志文章

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