gms | German Medical Science

55. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e. V. (DGNC)
1. Joint Meeting mit der Ungarischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

25. bis 28.04.2004, Köln

Limitations of suicide gene therapy in the human CNS

Limitierungen der Suicide-Gentherapie im menschlichen ZNS

Meeting Abstract

Suche in Medline nach

  • corresponding author Peter-Christian Warnke - Department of Neurosurgery, The University of Liverpool, Liverpool /UK; Abt. Stereotaktische Neurochirurgie, Universitätsklinikum Freiburg, Freiburg
  • K. Kopitzki - Department of Neurosurgery, The University of Liverpool, Liverpool /UK; Abt. Stereotaktische Neurochirurgie, Universitätsklinikum Freiburg, Freiburg
  • T. Smith - Department of Neurosurgery, The University of Liverpool, Liverpool /UK; Abt. Stereotaktische Neurochirurgie, Universitätsklinikum Freiburg, Freiburg
  • C. Ostertag - Department of Neurosurgery, The University of Liverpool, Liverpool /UK; Abt. Stereotaktische Neurochirurgie, Universitätsklinikum Freiburg, Freiburg

Deutsche Gesellschaft für Neurochirurgie. Ungarische Gesellschaft für Neurochirurgie. 55. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 1. Joint Meeting mit der Ungarischen Gesellschaft für Neurochirurgie. Köln, 25.-28.04.2004. Düsseldorf, Köln: German Medical Science; 2004. DocDI.01.09

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgnc2004/04dgnc0151.shtml

Veröffentlicht: 23. April 2004

© 2004 Warnke et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Objective

Though being very successful in rodent models of experimental brain tumours suicide gene therapy using different systems like HSV-tk have so far failed in the human setting. Coming to all these approaches is after transfection of tumour cells with the gene or drug conversion the delivery of water-soluble compound to be converted by genetically engineered cells to the cytotoxic agent. Major problems affecting the efficacy of gene therapy using varivectors and water-soluble compounds is the giant size of the extracellular space in human tumours compared to rodent models the limited permeability of the blood-brain barrier for water-soluble drugs and the high rate of intratumoural convection resulting in efflux of the cytotoxic agents into the surrounding white matter. We have therefore performed a meta analysis of gene therapy studies using suicide gene therapy in brain tumours and also performed a pharmacokinetic pilot study using VHSVTK- gancyclovir model to elucidate the impact of tumour physiology on the efficacy of gene therapy in human brain tumours.

Methods

Eleven patients harbouring glioblastoma multiforme were studied. All patients underwent measurements of bi-directional capillary permeability, size of the extracellular space and tumoural blood-flow before and after HSVTK- gancyclovir gene therapy. Patients were re-biopsied after gene therapy to quantitatively assess the extent of apoptotic cell death within the treated tumours. Also a meta analysis of published gene therapy trials using the suicide gene approaches was performed and data was stratified for tumour histology, physical chemical characteristics (log optimal/water partition co-efficient and molecular weight) of the compounds used and related to measurements of tumour physiology in tumours of the particular histological sub type.

Results

Tumours showing apoptotic response to gene therapy had a significantly smaller extracellular space ( .28 ± 1.2ml/g) compared to those not responding with increased apoptosis (.52 ± .18ml/g) p<.005. These results correlated with thallium SPECT changes before and after gene therapy (p.0027 r = 0.78). There is also a significant correlation between apoptotic rate and bi-directional capillary permeability for water-soluble compounds in these tumours (p<001). All literature studies looking at the treatment of malignant gliomas with suicide gene therapy in the majority have been dealing with glioblastoma multiforme which has an extremely low capillary permeability compared to other intracranial tumours (11.2 ± 5.4 μl/gm/min) but a huge extracellular space with a mean of .47 ± .11 μl/gm resulting in a major sink effect for small water soluble suicide drugs. Anaplastic astrocytomas also had a capillary permeability with a mean of 12.2 ± 7.8 μl/gm/min and an even larger extracellular space with a mean of .59 ± 23 μl/gm.

Conclusions

Our own experiments and the meta analysis from the literature clearly shows that gene therapy with water-soluble suicide drugs is most severely hampered by the individual tumour physiology. Whereas previous studies have entirely focussed on the low rates of transduction and ways to overcome this by monitoring in vivo gene expression usihng PET and lately MRI this entirely neglects the delivery problem which is fundamental and cannot be overcome easily as it is inherent to the tumour biology of gliomas. Therefore future gene therapy trials using suicide drugs either need to select tumours according to the physiology or incorporate new ways of delivery of the suicide drugs for example by intratumoural convection.