title: A novel E1A-E1B mutant adenovirus induces glioma regression in vivo.
abstract: Malignant gliomas are the most frequently occurring primary brain tumors and are resistant to conventional therapy. Conditionally replicating adenoviruses are a novel strategy in glioma treatment. Clinical trials using E1B mutant adenoviruses have been reported recently and E1A mutant replication-competent adenoviruses are in advanced preclinical testing. Here we constructed a novel replication-selective adenovirus (CB1) incorporating a double deletion of a 24 bp Rb-binding region in the E1a gene, and a 903 bp deleted region in the E1b gene that abrogates the expression of a p53-binding E1B-55 kDa protein. CB1 exerted a potent anticancer effect in vitro in U-251 MG, U-373 MG, and D-54 MG human glioma cell lines, as assessed by qualitative and quantitative viability assays. Replication analyses demonstrated that CB1 replicates in vitro in human glioma cells. Importantly, CB1 acquired a highly attenuated replicative phenotype in both serum-starved and proliferating normal human astrocytes. In vivo experiments using intracranially implanted D-54 MG glioma xenografts in nude mice showed that a single dose of CB1 (1.5 x 10(8) PFU/tumor) significantly improved survival. Immunohistochemical analyses of expressed adenoviral proteins confirmed adenoviral replication within the tumors. The CB1 oncolytic adenovirus induces a potent antiglioma effect and could ultimately demonstrate clinical relevance and therapeutic utility.
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Candelaria
authors.initials: C
authors.lastname: Gomez-Manzano
authors.forename: Cristina
authors.initials: C
authors.lastname: Balague
authors.forename: Ramon
authors.initials: R
authors.lastname: Alemany
authors.forename: Michael G
authors.initials: MG
authors.lastname: Lemoine
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Mitlianga
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Asadullah
authors.initials: A
authors.lastname: Khan
authors.forename: Marta
authors.initials: M
authors.lastname: Alonso
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: Charles A
authors.initials: CA
authors.lastname: Conrad
authors.forename: Ta-Jen
authors.initials: TJ
authors.lastname: Liu
authors.forename: B Nebiyou
authors.initials: BN
authors.lastname: Bekele
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
authors.forename: Juan
authors.initials: J
authors.lastname: Fueyo
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D017353:Gene Deletion; D005910:Glioma / Q000473:pathology* / Q000821:virology*; D006801:Humans; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping; D014183:Transplantation, Heterologous
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D017931:DNA Primers