A cyclooxygenase-2 promoter-based conditionally replicating adenovirus with enhanced infectivity for treatment of ovarian adenocarcinoma.
Conditionally replicating adenoviruses (CRADs) take advantage of tumor-specific characteristics for preferential replication and subsequent oncolysis of cancer cells. The antitumor effect is determined by the capability to infect tumor cells. Here, we used RGDCRADcox-2R, which features the cyclooxygenase-2 promoter for replication control and an integrin binding RGD-4C motif for enhanced infectivity of ovarian cancer cells. RGDCRADcox-2R replicated in and killed human ovarian cancer cells effectively, while the replication in nonmalignant cells was low. Importantly, the therapeutic efficacy, as evaluated in an orthotopic model of peritoneally disseminated ovarian cancer, was significantly improved and toxicity was lower than with a wild-type virus. Thus, this CRAD could be tested for treatment of ovarian cancer in humans.
Rational Drug Design, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
A
A
Kanerva
G J
GJ
Bauerschmitz
M
M
Yamamoto
J T
JT
Lam
R D
RD
Alvarez
G P
GP
Siegal
D T
DT
Curiel
A
A
Hemminki
D000230:Adenocarcinoma / Q000628:therapy*; D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D010051:Ovarian Neoplasms / Q000628:therapy*; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D014779:Virus Replication
D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases