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Specific tumor-cell killing with adenovirus vectors containing the apoptin gene

Gene Therapy volume 6, pages 882–892 (1999)Cite this article

Abstract

Specificity is an essential prerequisite for cancer gene therapy. Recently we described that apoptin, a protein of 121 amino acids which is derived from the chicken anemia virus, induces programmed cell death or apoptosis in transformed and malignant cells, but not in normal, diploid cells (Danen-van Oorschot AAAM et al, Proc Natl Acad Sci USA 1997; 94: 5843–5847). This protein has an intrinsic specificity that allows it to selectively kill tumor cells, irrespective of the p53 or Bcl-2 status of these cells. Hence, it is attractive to explore the use of the apoptin gene for therapeutic applications, viz cancer gene therapy. In this paper, we describe the generation and characterization of an adenovirus vector, AdMLPvp3, for the expression of apoptin. Despite the fact that apoptin ultimately induces apoptosis in the helper cells, which are transformed by the adenovirus type 5 early region 1 (E1), the propagation kinetics and yields of AdMLPvp3 are similar to those of control vec- tors. Infection with AdMLPvp3 of normal rat hepatocytes in cell culture did not increase the frequency of apoptosis. In contrast, in the hepatoma cell lines HepG2 and Hep3b, infection with AdMLPvp3, but not with control vectors, led to a rapid induction of programmed cell death. Experiments in rats demonstrated that AdMLPvp3 could be safely administered by intraperitoneal, subcutaneous or intravenous injection. Repeated intravenous doses of AdMLPvp3 were also well tolerated, indicating that the apoptin-expressing virus can be administered without severe adverse effects. In a preliminary experiment, a single intratumoral injection of AdMLPvp3 into a xenogeneic tumor (HepG2 cells in Balb/Cnu/nu mice) resulted in a significant reduction of tumor growth. Taken together, our data demonstrate that adenovirus vectors for the expression of the apoptin gene may constitute a powerful tool for the treatment of solid tumors.

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Author notes

  1. A M Pietersen and M M van der Eb: The first two authors contributed equally to the data presented in this manuscript and should both be regarded ‘first author’

Authors and Affiliations

  1. Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands

    A M Pietersen, M M van der Eb, H J Rademaker, D J M van den Wollenberg, M J W E Rabelink, H van Ormondt, A J van der Eb, R C Hoeben & M H M Noteborn

  2. Leadd BV, Leiden, The Netherlands

    A M Pietersen, D Masman & M H M Noteborn

  3. Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands

    M M van der Eb, P J K Kuppen, J H van Dierendonck & C J H van de Velde

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  1. A M Pietersen
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  2. M M van der Eb
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Pietersen, A., van der Eb, M., Rademaker, H. et al. Specific tumor-cell killing with adenovirus vectors containing the apoptin gene. Gene Ther 6, 882–892 (1999). https://doi.org/10.1038/sj.gt.3300876

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