Comparative evaluation of preclinical in vivo models for the assessment of replicating retroviral vectors for the treatment of glioblastoma.
Despite impressive improvements in neurosurgical techniques, radiation and chemotherapy during the past few years, little progress has been made in the treatment of malignant gliomas. Recently, the efficacy of suicide gene therapy based on replication-competent retroviral (RCR) vectors as delivery vehicles for the therapeutic gene has been described in the treatment of experimental cancer, including gliomas. In this study, we have thus critically evaluated a panel of human and rodent glioma/glioblastoma cell lines (U-87MG, U-118MG, LN-18, LN-229, 8-MG-BA, 42-MG-BA, A-172, T-98G, UVW, C6, 9L, G-26, GL-261, Tu-2449, Tu-9648) with respect to RCR virus vector spread, sensitivity towards the cytosine deaminase (CD)/5-flurocytosine (5-FC)/5-flurouracil (5-FU) suicide system, and orthotopic growth characteristics in mice to identify suitable preclinical animal models for the development of a glioblastoma gene therapy. Rapid virus spread was observed in eight out of nine human cell lines tested in vitro. As expected, only CD-expressing cells became sensitive to 5-FC, due to their ability to convert the prodrug in its toxic form, 5-FU. All LD(50) values were within the range of concentrations obtained in human body fluids after conventional antifungal 5-FC administration. In addition, a significant bystander effect was observed in all human glioma cell lines tested. Injection of the RCR vector into pre-established orthotopic mouse tumor xenografts revealed substantial infection and virus spread of tumor tissue from most cell types.
Hlavaty
Juraj
J
Institute of Virology, Department of Pathobiology, University of Veterinary Medicine, 1210 Vienna, Austria.
Jandl
Gerrit
G
Liszt
Melissa
M
Petznek
Helga
H
König-Schuster
Marielle
M
Sedlak
Jenny
J
Egerbacher
Monika
M
Weissenberger
Jakob
J
Salmons
Brian
B
Günzburg
Walter H
WH
Renner
Matthias
M
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D024201:Bystander Effect; D043525:Cytosine Deaminase / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005437:Flucytosine / Q000627:therapeutic use; D005472:Fluorouracil / Q000627:therapeutic use; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005822:Genetic Vectors; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D011355:Prodrugs / Q000627:therapeutic use; D012190:Retroviridae / Q000235:genetics*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*
D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil