title: Comparative evaluation of preclinical in vivo models for the assessment of replicating retroviral vectors for the treatment of glioblastoma.
abstract: 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.
authors.affiliation: Institute of Virology, Department of Pathobiology, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Juraj
authors.initials: J
authors.lastname: Hlavaty
authors.forename: Gerrit
authors.initials: G
authors.lastname: Jandl
authors.forename: Melissa
authors.initials: M
authors.lastname: Liszt
authors.forename: Helga
authors.initials: H
authors.lastname: Petznek
authors.forename: Marielle
authors.initials: M
authors.lastname: König-Schuster
authors.forename: Jenny
authors.initials: J
authors.lastname: Sedlak
authors.forename: Monika
authors.initials: M
authors.lastname: Egerbacher
authors.forename: Jakob
authors.initials: J
authors.lastname: Weissenberger
authors.forename: Brian
authors.initials: B
authors.lastname: Salmons
authors.forename: Walter H
authors.initials: WH
authors.lastname: Günzburg
authors.forename: Matthias
authors.initials: M
authors.lastname: Renner
mesh_terms: 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*
chemical_list: D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil