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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.
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GENE THERAPY
Tumor cells escape suicide gene therapy by genetic and epigenetic instability
Oliver Frank,
Cornelia Rudolph,
Christoph Heberlein,
Nils von Neuhoff,
Evelin Schröck,
Axel Schambach,
Brigitte Schlegelberger,
Boris Fehse,
Wolfram Ostertag,
Carol Stocking, and
Christopher Baum
From the Department of Cell & Virus Genetics, Heinrich-Pette-Institute, Hamburg, Germany; Medical Clinic III, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany; Institute for Cellular and Molecular Pathology, Hannover Medical School, Hannover, Germany; Celltec Biotechnology GmbH, Hamburg, Germany; Institute of Clinical Genetics, Medical Faculty Carl Gustav Carus, Dresden, Germany; Department of Hematology, Hemostaseology and Oncology, Hannover Medical School, Hannover, Germany; Bone Marrow Transplantation, University Hospital Eppendorf, Hamburg, Germany; and Div of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
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 antitumor 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 biologic 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.
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