Comparative effect of oncolytic adenoviruses with E1A-55 kDa or E1B-55 kDa deletions in malignant gliomas.
Replication-competent oncolytic adenoviruses hold considerable promise for treating malignant gliomas. The toxicity of the clinically tested E1B-55 kDa mutant virus is negligible; however, its full clinical potential is still being evaluated. The purpose of the present study is to compare the antiglioma activity in vitro and in vivo between Delta-24, an E1A mutant adenovirus, and RA55, an E1B-55 kDa mutant adenovirus. We selected human glioma cell lines that were tumorigenic in nude mice and express wild-type p53 (U-87 MG, D54 MG) or mutant p53 (U-251 MG, U-373 MG) protein. Our studies demonstrated that Delta-24 induced a more potent antiglioma effect in vitro than RA55. Moreover, Delta-24 replicated markedly more efficiently than RA55 in both wild-type and mutant p53 scenarios. Importantly, direct intratumoral injection of Delta-24, but not RA55, significantly suppresses tumor growth in intracranial (U-87 MG, U-251 MG) or subcutaneous (D54 MG) animal models. Staining for hexon protein detected replicating adenoviruses in xenografts infected with Delta-24, but not with RA55. Collectively, these data indicate that E1A mutant adenoviruses targeting the Rb pathway are more powerful putative agents for antiglioma therapy than E1B mutant adenoviruses, and suggest that E1A mutant adenoviruses should be tested in the clinical setting for patients with malignant gliomas.
Jiang
Hong
H
Brain Tumor Center, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Gomez-Manzano
Candelaria
C
Alemany
Ramon
R
Medrano
Diana
D
Alonso
Marta
M
Bekele
B Nebiyou
BN
Lin
E
E
Conrad
Charles C
CC
Yung
W K Alfred
WK
Fueyo
Juan
J
D000256:Adenoviridae / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000172:deficiency / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000172:deficiency / Q000235:genetics*; D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D017353:Gene Deletion; D005910:Glioma / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D016159:Tumor Suppressor Protein p53
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