Ovarian cancer targeted adenoviral-mediated mda-7/IL-24 gene therapy.
OBJECTIVE
We have previously shown that adenoviral-mediated melanoma differentiation-associated gene-7 (Ad.mda-7) therapy induces apoptosis in ovarian cancer cells. However, the apoptosis induction was low and directly correlated with infectivity of Ad.mda-7. The objective of this study was to derive ovarian cancer targeted infectivity-enhanced adenoviral vectors encoding mda-7 and evaluate their enhancement in therapeutic efficacy for ovarian carcinoma.


METHODS
Infectivity-enhanced adenoviral vectors encoding mda-7 Ad.RGD.mda-7 and Ad.RGD.pK7.mda-7 were derived by incorporation of RGD and or RGD and Pk7 motifs in the fiber knobs by genetic modification. Viruses were validated by PCR for presence of mda-7 and by Western blot for expression of MDA-7 protein. To test the enhancement of therapeutic efficacy of these viruses, a panel of human ovarian carcinoma cells, OV-4, HEY, SKOV3, SKOV3.ip1, were infected by either Ad.mda-7 or Ad.RGD.mda-7 and Ad.RGD.pK7.mda-7 or their respective control viruses and the cell killing was evaluated by crystal violet staining in vitro. Further, therapeutic efficacy was evaluated in vivo using human ovarian cancer xenograft mouse models.


RESULTS
Both Ad.RGD.pK7.mda-7 and Ad.RGD.mda-7 showed significant increase in cell killing in vitro compared to unmodified Ad.mda-7 with Ad.RGD.pK7.mda-7 showing highest cell killing. Further, Ad.RGD.pK7.mda-7 showed a significant increase in survival of mice bearing human ovarian cancer xenografts compared to Ad.mda-7 and other control groups.


CONCLUSIONS
Infectivity-enhanced Ad.RGD.mda-7 and Ad.RGD.pK7.mda-7 viruses significantly enhanced ovarian cancer tumor cell killing in vitro. Significant prolongation of survival by Ad.RGD.pK7.mda-7 in murine ovarian cancer models demonstrates the high clinical translational potential of these viruses for ovarian cancer therapy.
Mahasreshti
Parameshwar J
PJ
Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, AL 35294, USA. param@uab.edu
Kataram
Manjula
M
Wu
Hongju
H
Yalavarthy
Laxmi Priya
LP
Carey
Delicia
D
Fisher
Paul B
PB
Chada
Sunil
S
Alvarez
Ronald D
RD
Haisma
Hidde J
HJ
Dent
Paul
P
Curiel
David T
DT
D000230:Adenocarcinoma / Q000235:genetics / Q000628:therapy* / Q000821:virology; D000256:Adenoviridae / Q000235:genetics / Q000472:pathogenicity; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D009842:Oligopeptides / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D016133:Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
D007378:Interleukins; D009842:Oligopeptides; D000099180:Interleukin-24; C047981:arginyl-glycyl-aspartic acid