An advanced generation of adenoviral vectors selectively enhances gene transfer for ovarian cancer gene therapy approaches.
OBJECTIVE
We hypothesized that incorporation of an integrin binding Arg-Gly-Asp (RGD)-containing peptide to the HI loop of the adenovirus fiber knob would allow enhanced, coxsackie-adenovirus receptor-independent gene transfer by modified Ad vector in the context of ovarian cancer.


METHODS
Ovarian cancer cell lines, primary ovarian cancer cells, primary tumor explants, and mesothelial tissue were transfected with luciferase encoding adenovirus (AdCMVLuc) or a genetically modified adenovirus (Ad5lucRGD) which contained an RGD motif within the HI loop of the knob. The luciferase activity was measured and the transduction efficiencies of both viruses were compared.


RESULTS
In all established ovarian cell lines and primary tumor cell samples there was dramatically augmented gene transfer observed with the Ad5lucRGD compared to AdCMVLuc. The enhanced gene transfer in ovarian cancer cell lines ranged from 2.5- to 471.6-fold, in ascites samples from 26.1- to 64.0-fold, and in tumor explants from 1.6- to 11.1-fold. Although gene transfer to normal mesothelial tissue was slightly augmented by RGD retargeting, the level of gene transfer was much lower than that seen in ovarian cancer cells.


CONCLUSIONS
This study demonstrates that genetically altered adenoviruses with modified tropism are capable of more efficient gene transfer in the context of ovarian cancer. The higher level of transfer with respect to peritoneal mesothelium can be exploited to enhance the therapeutic index of interventions using adenoviral vectors. Studies are warranted, therefore, to determine the in vivo utility of this targeted vector approach in the context of gene therapeutic strategies for cancer of the ovary.
Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.
T J
TJ
Vanderkwaak
M
M
Wang
J
J
Gómez-Navarro
C
C
Rancourt
I
I
Dmitriev
V
V
Krasnykh
M
M
Barnes
G P
GP
Siegal
R
R
Alvarez
D T
DT
Curiel
D000256:Adenoviridae / Q000235:genetics*; D000595:Amino Acid Sequence / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D009842:Oligopeptides / Q000235:genetics; D010051:Ovarian Neoplasms / Q000628:therapy*; D014407:Tumor Cells, Cultured
D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D008156:Luciferases