title: Adenovirus-mediated expression of HSV1-TK or Fas ligand induces cell death in primary human glioma-derived cell cultures that are resistant to the chemotherapeutic agent CCNU.
abstract: Due to minimal treatment success with surgery, radiotherapy, and chemotherapy, the aim of this study was to test the therapeutic potential of gene therapy for the treatment of glioblastoma multiforme (GBM). We have quantitatively analyzed two gene therapy approaches using short-term human glioma cell cultures derived from surgical biopsies (designated IN859, IN1612, IN2045, IN1760, and IN1265) and compared the results of gene therapy with the chemosensitivity of the same cells. All of the glioma cell cultures tested were susceptible to recombinant adenovirus (RAd)-mediated infection. Expression of herpes simplex virus type 1-thymidine kinase (RAd128), followed by ganciclovir treatment, induced apoptosis in all of the glioma cell cultures studied, including three that are resistant to the chemotherapeutic drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Expression of murine Fas ligand (RAdhCMV-mFasL) also induced cell death in four of the five cell cultures studied. One cell culture that was resistant to CCNU was also resistant to apoptosis induced by mFasL expression. These results suggest that sensitivity to chemotherapeutic agents does not necessarily correlate with the sensitivity to gene therapy treatments. RAds expressing therapeutic gene products in human glioma cell cultures are able to induce apoptosis even in some cells that are resistant to a commonly used chemotherapeutic agent. Therefore, RAd-mediated gene transfer could be a good candidate to further develop gene therapy for the treatment of GBM.
authors.affiliation: Molecular Medicine and Gene Therapy Unit, School of Medicine, University of Manchester, Manchester M13 9PT, UK.
authors.forename: T C
authors.initials: TC
authors.lastname: Maleniak
authors.forename: J L
authors.initials: JL
authors.lastname: Darling
authors.forename: P R
authors.initials: PR
authors.lastname: Lowenstein
authors.forename: M G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D004274:DNA, Recombinant; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein; D005697:Galactosides / Q000378:metabolism; D015774:Ganciclovir / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D005909:Glioblastoma / Q000378:metabolism / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D006801:Humans; D007211:Indoles / Q000378:metabolism; D008130:Lomustine / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004274:DNA, Recombinant; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005697:Galactosides; D007211:Indoles; D008562:Membrane Glycoproteins; D008130:Lomustine; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside