Normal brain cells contribute to the bystander effect in suicide gene therapy of malignant glioma.
OBJECTIVE
Lentiviral vectors pseudotyped with glycoproteins of the lymphocytic choriomeningitis virus (LCMV-GP) are promising candidates for gene therapy of malignant glioma, as they specifically and efficiently transduce glioma cells in vitro and in vivo. Here, we evaluated the therapeutic efficacy of LCMV-GP and vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped vectors.


METHODS
Therapeutic efficacy was tested for unmodified (9L) and DsRed-modified (9LDsRed) gliomas using the suicide gene thymidine kinase of the herpes simplex virus type 1 (HSV-1-tk). Positron emission tomography (PET) and magnetic resonance imaging were done to analyze transduction of tumors and monitor therapeutic outcome.


RESULTS
LCMV-GP pseudotypes mediated a successful eradication of 9LDsRed tumors with 100% of long-term survivors. Before initiation of ganciclovir treatment, a strong HSV-1-tk expression within the tumor was detected by noninvasive PET using the tracer 9-[4-[(18)F]fluoro-3-(hydroxymethyl)butyl]guanine. Therapeutic outcome was successfully monitored by magnetic resonance imaging and PET imaging and correlated with the histopathologic data. In the 9L model, LCMV-GP and VSV-G pseudotyped lentiviral vectors displayed similar therapeutic efficacy. Further studies revealed that normal brain cells transduced with VSV-G pseudotypes were not eliminated by ganciclovir treatment and contributed significantly to the bystander killing of tumor cells.


CONCLUSIONS
Suicide gene transfer using pseudotyped lentiviral vectors was very effective in the treatment of rat glioma and therefore is an attractive therapeutic strategy also in human glioblastoma especially in conjunction with an imaging-guided approach. In addition, high selectivity of gene transfer to tumor cells may not always be desirable for therapeutic genes that exert a clear bystander effect.
Miletic
Hrvoje
H
Department of Biomedicine, University of Bergen, Jonas Liesvei 91, Bergen, Norway. Hrvoje.Miletic@biomed.uib.no
Fischer
Yvonne Heidemarie
YH
Giroglou
Tsanan
T
Rueger
Maria Adele
MA
Winkeler
Alexandra
A
Li
Huongfeng
H
Himmelreich
Uwe
U
Stenzel
Werner
W
Jacobs
Andreas H
AH
von Laer
Dorothee
D
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D001932:Brain Neoplasms / Q000628:therapy*; D015774:Ganciclovir / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D005910:Glioma / Q000628:therapy*; D006023:Glycoproteins / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics; D008279:Magnetic Resonance Imaging; D049268:Positron-Emission Tomography; D051381:Rats; D013937:Thymidine Kinase / Q000235:genetics; D018116:Vesiculovirus / Q000235:genetics
D000998:Antiviral Agents; D006023:Glycoproteins; D013937:Thymidine Kinase; D015774:Ganciclovir