title: Development of an optimized conditionally replicative adenoviral agent for ovarian cancer.
abstract: Human ovarian cancer is a highly lethal malignant neoplasm in woman with no effective treatment if conventional chemotherapy fails. In this regard, conditionally replicative adenoviruses (CRAds) represent a promising new modality for the treatment of cancer. A key contribution to the development of CRAds was the introduction of tumor-selective viral replication to restrict amplification to the neoplastic cell population. Under ideal conditions following cellular infection, the viruses replicate selectively in the infected tumor cells, killing the cells by cytolysis, leaving normal cells unaffected. However, to date, there have been limitations to the clinical application of these CRAd agents i.e. poor viral infectivity, poor tumor specificity and high toxicity. Here, we report the in vitro and in vivo comparison of four CRAd agents developed for ovarian cancer application, specifically, Ad-Delta24.F5/3, CRAd-C.F5/3, CRAd-M.F5/3 and CRAd-S.F5/3. All CRAd agents contained fiber knob chimeras of adenovirus serotype 3, which enhanced the viral infectivity at the transductional level via a non-Coxsackie-Adenovirus Receptor alternative pathway. In addition, these CRAds embodied distinct mechanisms for the achievement of replication specificity. Tumor cell killing was assessed by using an oncolytic assay and a cell viability assay (MTS) in vitro, while tumor growth was examined in a xenograft model in vivo by using a bioluminescent imaging assay. In addition, the replication rates of the CRAd agents were determined in human liver slices. Both the Ad-Delta24.F5/3 and CRAd-S.F5/3 were demonstrated to have higher tumor killing effects in tumor cells and a lower viral replication rate in human liver. These agents are thus excellent candidates for clinical trials of CRAd agents against human ovarian cancer.
authors.affiliation: Division of Human Gene Therapy, Departments of Medicine, Pathology, Surgery, Ob/Gyn and the Gene Therapy Center, University of Alabama at Birmingham, AL 35291, USA.
authors.forename: Zeng B
authors.initials: ZB
authors.lastname: Zhu
authors.forename: Baogen
authors.initials: B
authors.lastname: Lu
authors.forename: Miey
authors.initials: M
authors.lastname: Park
authors.forename: Sharmila K
authors.initials: SK
authors.lastname: Makhija
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Numnum
authors.forename: James E
authors.initials: JE
authors.lastname: Kendrick
authors.forename: Minghui
authors.initials: M
authors.lastname: Wang
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuruta
authors.forename: Paul
authors.initials: P
authors.lastname: Fisher
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.forename: Fen
authors.initials: F
authors.lastname: Zhou
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Hongju
authors.initials: H
authors.lastname: Wu
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays