A novel E1A-E1B mutant adenovirus induces glioma regression in vivo.
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.
Gomez-Manzano
Candelaria
C
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Balague
Cristina
C
Alemany
Ramon
R
Lemoine
Michael G
MG
Mitlianga
Paraskevi
P
Jiang
Hong
H
Khan
Asadullah
A
Alonso
Marta
M
Lang
Frederick F
FF
Conrad
Charles A
CA
Liu
Ta-Jen
TJ
Bekele
B Nebiyou
BN
Yung
W K Alfred
WK
Fueyo
Juan
J
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
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D017931:DNA Primers