Inter-patient variation in efficacy of five oncolytic adenovirus candidates for ovarian cancer therapy.
BACKGROUND
Gene therapy offers a new strategy for cancer treatment. Adenoviruses represent the most widely used gene therapy vector and feature an excellent safety record. Conditionally replicative adenoviruses (CRAds) effect solid tumor penetration and tumor selective oncolysis and consequently offer potential efficacy for metastatic disease treatment. We evaluated five CRAds as candidate clinical agents for ovarian cancer therapy: RGDCRADcox-2R, Ad5VEGFE1, Ad5/3VEGFE1, Ad5-Delta24RGD, and Ad5/3-Delta24.


METHODS
DNA replication by these five CRAds, wild-type adenovirus, and an E1-deleted control was measured in purified primary ovarian cancer cell spheroids by quantitative PCR. CRAd-mediated oncolysis was quantified in ovarian cancer cell monolayers and three-dimensional spheroids by cellular viability assays. The therapeutic efficacy of each CRAd was tested by intraperitoneal administration in mice with peritoneally disseminated human ovarian cancer.


RESULTS
An increase in viral DNA was noted in primary tumor cell spheroids for all replicative viruses tested. Variation was noted in viral DNA replication between patient samples. All five CRAds induced remarkable oncolysis. They also prolonged survival in vivo compared with the wild-type control group.


CONCLUSIONS
All five CRAds tested showed robust DNA replication, oncolysis, and in vivo therapeutic efficacy. Each virus has potential for clinical testing, and such further testing will ultimately determine its safety and relative usefulness. Variation of CRAd DNA replication between different patient samples suggests that target tissue features, such as surface receptors and endogenous transcription factors, may affect CRAd infectivity and replicativity. Evaluation of such factors may become important to optimize cancer therapy for individual patients.
Lam
John T
JT
Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Kanerva
Anna
A
Bauerschmitz
Gerd J
GJ
Takayama
Koichi
K
Suzuki
Kaori
K
Yamamoto
Masato
M
Bhoola
Snehal M
SM
Liu
Bin
B
Wang
Minghui
M
Barnes
Mack N
MN
Alvarez
Ronald D
RD
Siegal
Gene P
GP
Curiel
David T
DT
Hemminki
Akseli
A
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016923:Cell Death; D004279:DNA, Viral / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D018874:Spheroids, Cellular; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000494:pharmacology*; D014779:Virus Replication
D004279:DNA, Viral; D042461:Vascular Endothelial Growth Factor A