RRC ID 3802
Author Fukuda K, Abei M, Ugai H, Kawashima R, Seo E, Wakayama M, Murata T, Endo S, Hamada H, Hyodo I, Yokoyama KK.
Title E1A, E1B double-restricted replicative adenovirus at low dose greatly augments tumor-specific suicide gene therapy for gallbladder cancer.
Journal Cancer Gene Ther.
Abstract Combination therapy with replicative oncolytic viruses is a recent topic in innovative cancer therapy, but few studies have examined the efficacy of oncolytic adenovirus plus replication-deficient adenovirus carrying a suicide gene. We aim to evaluate whether an E1A, E1B double-restricted oncolytic adenovirus, AxdAdB-3, can improve the efficacy for gallbladder cancers (GBCs) of the replication-deficient adenovirus-based herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) therapy directed by the carcinoembryonic antigen (CEA) promoter. Cytopathic effects of AxdAdB-3 plus AxCEAprTK (an adenovirus expressing HSVtk directed by CEA promoter) or AxCAHSVtk (an adenovirus expressing HSVtk directed by a nonspecific CAG promoter) with GCV administration were examined in several GBC lines and normal cells. Efficacy in vivo was tested in severe combined immunodeficiency disease mice with GBC xenografts. Addition of AxdAdB-3 (1 multiplicity of infection, MOI) significantly enhanced the cytopathic effects of AxCEAprTK (10 MOI)/GCV on GBC cells. The augmented effect was attributable to the replication of the AxCEAprTK and also to the enhanced CEA promoter activity, which was presumably transactivated by E1A. In normal cells, AxdAdB-3 (20 MOI) plus AxCEAprTK (200 MOI)/GCV was not cytopathic, whereas AxdAdB-3 (1 MOI) plus AxCAHSVtk (10 MOI)/GCV was significantly toxic. Low-dose AxdAdB-3 (2 x 10(7) PFU, plaque-forming unit) plus AxCEAprTK (2 x 10(8) PFU)/GCV significantly suppressed the growth of GBC xenografts as compared with either AxdAdB-3 (2 x 10(7) PFU)/GCV or AxCEAprTK (2 x 10(9) PFU)/GCV alone. E1A, E1B double-restricted replicating adenovirus at low dose significantly augmented the efficacy of CEA promoter-directed HSVtk/GCV therapy without obvious toxicity to normal cells, suggesting a potential use of this combination for treating GBC and other CEA-producing malignancies.
Volume 16(2)
Pages 126-36
Published 2009-2
DOI 10.1038/cgt.2008.67
PII cgt200867
PMID 18818710
MeSH Adenoviridae / genetics Adenoviridae / metabolism* Adenovirus E1A Proteins / genetics Adenovirus E1A Proteins / metabolism* Adenovirus E1B Proteins / genetics Adenovirus E1B Proteins / metabolism* Animals Carcinoembryonic Antigen / genetics Carcinoembryonic Antigen / metabolism Cell Line, Tumor Female Gallbladder Neoplasms / genetics Gallbladder Neoplasms / therapy* Gallbladder Neoplasms / virology Genetic Therapy / methods* HeLa Cells Humans Mice Mice, SCID Oncolytic Virotherapy* Virus Replication*
IF 4.044
Times Cited 13
WOS Category MEDICINE, RESEARCH & EXPERIMENTAL BIOTECHNOLOGY & APPLIED MICROBIOLOGY GENETICS & HEREDITY ONCOLOGY
Resource
DNA material AxCAHSVtk (RDB01429) AxCALacZ (RDB01745) Ax1w1 (RDB01746)