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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3543-3549. Prepublished online as a Blood First Edition Paper on August 12, 2004; DOI 10.1182/blood-2004-03-0852. This Article Full Text (PDF) All Versions of this Article: 2004-03-0852v1 104/12/3543    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Frank, O. Articles by Baum, C. Search for Related Content PubMed PubMed Citation Articles by Frank, O. Articles by Baum, C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 8, 2004 Accepted June 2, 2004 Tumor cells escape suicide gene therapy by genetic and epigenetic instability Oliver Frank, Cornelia Rudolph, Christoph Heberlein, Nils von Neuhoff, Evelin Schroeck, Axel Schambach, Brigitte Schlegelberger, Boris Fehse, Wolfram Ostertag, Carol Stocking, and Christopher Baum* Department of Cell and Virus Genetics, Heinrich Pette Institute, Hamburg, Germany Institute for Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany Biotechnologie, Celltec GmbH, Hamburg, Germany Institute of Clinical Genetics, Medical Faculty Carl Gustav Carus, Dresden, Germany Department of Bone Marrow Transplantation, University Hospital Eppendorf, Hamburg, Germany Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Department of Hematology, Hemostaseology, Hemostaseology and Oncology, Hannover Medical School, Hannover, Germany * Corresponding author; email: baum.christopher{at}mh-hannover.de. Transfer and expression of suicide genes is one cornerstone of cancer gene therapy and is also considered as a proactive tool to enhance the safety of somatic transgenesis. Here we addressed whether retrovirus-mediated suicide gene therapy would result in a predictable anti-tumor efficiency, given that problems related to gene transfer are solved or that the suicide gene is used in a proactive approach. Using retroviral vectors encoding the thymidine kinase gene of herpes simplex virus, we transduced EL-4 lymphoma cells and induced experimental tumors in congeneic C57Bl/6 mice. Systemic administration of ganciclovir (GCV) resulted in remission of transduced clonal and polyclonal tumors in vivo. However, GCV-resistant relapses occurred and were found to be associated with postinsertional alterations of transgene structure or loss of the entire transgene. Complete loss of a retrovirally marked fusion chromosome was confirmed by spectral karyotyping. Transgene silencing occurred in another clone. We conclude that genetic as well as epigenetic instability related to biological features of the tumor, the insertion site and the vector represent relevant limitations of retroviral suicide gene therapy. Considering the mechanisms of escape identified here, the proactive use of suicide genes to prevent complications of insertional mutagenesis may still be efficient. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Kieback, J. Charo, D. Sommermeyer, T. Blankenstein, and W. Uckert A safeguard eliminates T cell receptor gene-modified autoreactive T cells after adoptive transfer PNAS, January 15, 2008; 105(2): 623 - 628. [Abstract] [Full Text] [PDF] M. Heuser, B. Argiropoulos, F. Kuchenbauer, E. Yung, J. Piper, S. Fung, R. F. Schlenk, K. Dohner, T. Hinrichsen, C. Rudolph, et al. MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML Blood, September 1, 2007; 110(5): 1639 - 1647. [Abstract] [Full Text] [PDF] D. Cross and J. K. Burmester Gene therapy for cancer treatment: past, present and future. Clin. Med. Res., September 1, 2006; 4(3): 218 - 227. [Abstract] [Full Text] [PDF] B.-J. Park, Y. S. Oh, S. Y. Park, S. J. Choi, C. Rudolph, B. Schlegelberger, and S. Kim AIMP3 Haploinsufficiency Disrupts Oncogene-Induced p53 Activation and Genomic Stability. Cancer Res., July 15, 2006; 66(14): 6913 - 6918. [Abstract] [Full Text] [PDF] T. Eschenhagen and W. H. Zimmermann Engineering Myocardial Tissue Circ. Res., December 9, 2005; 97(12): 1220 - 1231. [Abstract] [Full Text] [PDF] O. Frank, M. Giehl, C. Zheng, R. Hehlmann, C. Leib-Mosch, and W. Seifarth Human Endogenous Retrovirus Expression Profiles in Samples from Brains of Patients with Schizophrenia and Bipolar Disorders J. Virol., September 1, 2005; 79(17): 10890 - 10901. [Abstract] [Full Text] [PDF]

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