Adenovirus-mediated expression of truncated E2F-1 suppresses tumor growth in vitro and in vivo.
BACKGROUND
Adenovirus (Ad)-mediated E2F-1 gene transfer induces apoptosis in cancer cells in vitro and in vivo, but clinical application of E2F-1 in cancer gene therapy remains controversial because of the oncogenic potential of E2F-1. This barrier can be circumvented by using the truncated form of the E2F-1 gene (E2Ftr) (amino acids 1 through 375), which lacks the E2F-1 transactivation domain and cell cycle-promoting effects.


METHODS
The authors constructed 3 adenoviral vectors that expressed E2Ftr under regulation of the tetracycline (Tet)-off system (AdTet-E2Ftr1, AdTet-E2Ftr2, and AdTet-E2Ftr3). These vectors were compared for E2Ftr expression and apoptosis induction in cancer cells and normal cells. E2Ftr antitumor activity in vivo also was assessed in a melanoma xenograft model.


RESULTS
One of the 3 vectors, AdTet-E2Ftr3, had the highest E2Ftr protein expression levels, which were correlated with the greatest induction of apoptosis and inhibition of cancer cell growth. E2Ftr induced apoptosis in a variety of cancer cell lines independent of p53 status with little cytotoxicity in normal cell lines. In a mouse melanoma xenograft model, AdTet-E2Ftr3 exhibited an approximately 80% decrease in tumor size compared with controls in vivo.


CONCLUSIONS
The current results indicated that AdTet-E2Ftr3 is a novel anticancer agent that has significant therapeutic activity in vitro and in vivo.
Gomez-Gutierrez
Jorge G
JG
Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA.
Garcia-Garcia
Aracely
A
Hao
Hongying
H
Rao
Xiao-Mei
XM
Montes de Oca-Luna
Roberto
R
Zhou
Heshan S
HS
McMasters
Kelly M
KM
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000737:chemistry / Q000235:genetics*; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000628:therapy*; D017384:Sequence Deletion; D023041:Xenograft Model Antitumor Assays
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human