HDACi phenylbutyrate increases bystander killing of HSV-tk transfected glioma cells.
Malignant glioma patients have a dismal prognosis with an urgent need of new treatment modalities. Previously developed gene therapies for brain tumors showed promising results in experimental animal models, but failed in clinical trials due to low transfection rates and insufficient expression of the transgene in tumor cells, as well as low bystander killing effects. We have previously shown that the histone deacetylase inhibitor 4-phenylbutyrate (4-PB) enhances gap junction communication between glioma cells in culture. In this study, we demonstrate an activation of recombinant HSV-tk gene expression, and a dramatic enhancement of gap junction-mediated bystander killing effect by administration of the HSV-tk prodrug ganciclovir together with 4-PB. These findings that 4-PB potentiates "suicide gene" expression as well as enhances gap junctional communication and bystander killing of tumor cells justify further testing of this paradigm as an adjunct to suicide gene therapy of malignant gliomas.
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Ole
O
Ammerpohl
Dorit
D
Thormeyer
Zahidul
Z
Khan
Ioulia B
IB
Appelskog
Zoran
Z
Gojkovic
Per M
PM
Almqvist
Tomas J
TJ
Ekström
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000378:metabolism / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D024201:Bystander Effect / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018031:Connexin 43 / Q000378:metabolism; D015774:Ganciclovir / Q000378:metabolism / Q000627:therapeutic use; D017629:Gap Junctions / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D006034:Glycyrrhetinic Acid / Q000378:metabolism / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D010654:Phenylbutyrates / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D018031:Connexin 43; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; D011993:Recombinant Fusion Proteins; D013937:Thymidine Kinase; D006655:Histone Deacetylases; D006034:Glycyrrhetinic Acid; D015774:Ganciclovir