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; Christopher Baum

doi:10.1182/blood-2004-03-0852

Tumor cells escape suicide gene therapy by genetic and epigenetic instability

Standard

Tumor cells escape suicide gene therapy by genetic and epigenetic instability. / Frank, Oliver; Rudolph, Cornelia; Heberlein, Christoph; von Neuhoff, Nils; Schröck, Evelin; Schambach, Axel; Schlegelberger, Brigitte; Fehse, Boris; Ostertag, Wolfram; Stocking, Carol; Baum, Christopher.

In: BLOOD, Vol. 104, No. 12, 01.12.2004, p. 3543-9.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Frank, O, Rudolph, C, Heberlein, C, von Neuhoff, N, Schröck, E, Schambach, A, Schlegelberger, B, Fehse, B, Ostertag, W, Stocking, C & Baum, C 2004, 'Tumor cells escape suicide gene therapy by genetic and epigenetic instability', BLOOD, vol. 104, no. 12, pp. 3543-9. https://doi.org/10.1182/blood-2004-03-0852

APA

Frank, O., Rudolph, C., Heberlein, C., von Neuhoff, N., Schröck, E., Schambach, A., Schlegelberger, B., Fehse, B., Ostertag, W., Stocking, C., & Baum, C. (2004). Tumor cells escape suicide gene therapy by genetic and epigenetic instability. BLOOD, 104(12), 3543-9. https://doi.org/10.1182/blood-2004-03-0852

Vancouver

Frank O, Rudolph C, Heberlein C, von Neuhoff N, Schröck E, Schambach A et al. Tumor cells escape suicide gene therapy by genetic and epigenetic instability. BLOOD. 2004 Dec 1;104(12):3543-9. https://doi.org/10.1182/blood-2004-03-0852

Bibtex

@article{0721b8daf2c94fa895791b5b050a7a0d,

title = "Tumor cells escape suicide gene therapy by genetic and epigenetic instability",

abstract = "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.",

keywords = "Animals, Cell Line, Tumor, Chromosome Deletion, Drug Resistance, Neoplasm/genetics, Ganciclovir/administration & dosage, Gene Silencing, Genes, Transgenic, Suicide, Genetic Therapy/methods, Genomic Instability, Lymphoma/genetics, Mice, Neoplasm Transplantation, Recombination, Genetic, Recurrence, Thymidine Kinase/administration & dosage",

author = "Oliver Frank and Cornelia Rudolph and Christoph Heberlein and {von Neuhoff}, Nils and Evelin Schr{\"o}ck and Axel Schambach and Brigitte Schlegelberger and Boris Fehse and Wolfram Ostertag and Carol Stocking and Christopher Baum",

year = "2004",

month = dec,

day = "1",

doi = "10.1182/blood-2004-03-0852",

language = "English",

volume = "104",

pages = "3543--9",

journal = "BLOOD",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "12",

}

RIS

TY - JOUR

T1 - Tumor cells escape suicide gene therapy by genetic and epigenetic instability

AU - Frank, Oliver

AU - Rudolph, Cornelia

AU - Heberlein, Christoph

AU - von Neuhoff, Nils

AU - Schröck, Evelin

AU - Schambach, Axel

AU - Schlegelberger, Brigitte

AU - Fehse, Boris

AU - Ostertag, Wolfram

AU - Stocking, Carol

AU - Baum, Christopher

PY - 2004/12/1

Y1 - 2004/12/1

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Line, Tumor

KW - Chromosome Deletion

KW - Drug Resistance, Neoplasm/genetics

KW - Ganciclovir/administration & dosage

KW - Gene Silencing

KW - Genes, Transgenic, Suicide

KW - Genetic Therapy/methods

KW - Genomic Instability

KW - Lymphoma/genetics

KW - Mice

KW - Neoplasm Transplantation

KW - Recombination, Genetic

KW - Recurrence

KW - Thymidine Kinase/administration & dosage

U2 - 10.1182/blood-2004-03-0852

DO - 10.1182/blood-2004-03-0852

M3 - SCORING: Journal article

C2 - 15308565

VL - 104

SP - 3543

EP - 3549

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 12

ER -