Infectivity enhanced, cyclooxygenase-2 promoter-based conditionally replicative adenovirus for pancreatic cancer.
OBJECTIVE
Pancreatic cancer is one of the most aggressive human malignancies. Conditionally replicative adenoviruses (CRAds) have shown some promise in the treatment of cancers. However, to date, their application for pancreatic cancer has met several obstacles: one is lack of a good control element to regulate replication, and the other is relatively low adenoviral infectivity. Thus, we constructed infectivity enhanced cyclooxygenase (COX)-2 promoter-based CRAds to develop a safe and effective therapeutic modality.


METHODS
The CRAds were designed to achieve COX-2 promoter-controlled E1 expression for regulated replication (COX-2 CRAds). The infectivity-enhanced CRAds also have an RGD-4C motif in the adenoviral fiber-knob region. The selectivity and efficacy of these constructs were analyzed with cell lines in vitro. The in vivo therapeutic effect and viral replication were analyzed with a xenograft model. Pathology of the major organs and E1 RNA levels in the liver were also studied after systemic administration.


RESULTS
The COX-2 CRAds showed a selective cytocidal effect in vitro in COX-2-positive cells and killed most of the pancreatic cancer cells. In vivo, intratumoral administration of the infectivity-enhanced COX-2 CRAds (10(9) particles) showed a strong antitumor effect comparable to wild-type virus, whereas the COX-2 CRAds without infectivity enhancement showed a limited effect. Viral replication was confirmed in the xenograft tumors. Systemic administration did not cause any detectable toxicity; the E1 RNA level in the liver after COX-2 CRAd administration was minimal.


CONCLUSIONS
Infectivity-enhanced COX-2 CRAd is a promising agent for the treatment of pancreatic cancer.
D000256:Adenoviridae / Q000235:genetics* / Q000254:growth & development; D017498:Adenovirus E1 Proteins / Q000235:genetics; D000818:Animals; D051546:Cyclooxygenase 2; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008175:Lung Neoplasms; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000628:therapy*; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D013274:Stomach Neoplasms; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000235:genetics*
D017498:Adenovirus E1 Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases