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Inter‐patient variation in efficacy of five oncolytic adenovirus candidates for ovarian cancer therapy
Author(s) -
Lam John T.,
Kanerva Anna,
Bauerschmitz Gerd J.,
Takayama Koichi,
Suzuki Kaori,
Yamamoto Masato,
Bhoola Snehal M.,
Liu Bin,
Wang Minghui,
Barnes Mack N.,
Alvarez Ronald D.,
Siegal Gene P.,
Curiel David T.,
Hemminki Akseli
Publication year - 2004
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.635
Subject(s) - oncolytic virus , ovarian cancer , genetic enhancement , biology , cancer research , viral replication , virotherapy , cancer , viral vector , oncolytic adenovirus , virology , virus , gene , biochemistry , genetics , recombinant dna
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‐Δ24RGD, and Ad5/3‐Δ24. 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. Copyright © 2004 John Wiley & Sons, Ltd.