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

Ennio Tasciotti, Monica Zoppè, Mauro Giacca

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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 TKgene 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.

Original languageEnglish (US)
Pages (from-to)64-74
Number of pages11
JournalCancer Gene Therapy
Issue number1
StatePublished - Jan 1 2003


  • Acyclovir
  • Bystander effect
  • Cancer gene therapy
  • Ganciclovir
  • HIV-1 Tat
  • Intercellular translocation
  • Protein transduction
  • Thymidine kinase

ASJC Scopus subject areas

  • Cancer Research
  • Genetics


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