title: Activity of the adenoviral E1A deletion mutant dl922-947 in ovarian cancer: comparison with E1A wild-type viruses, bioluminescence monitoring, and intraperitoneal delivery in icodextrin.
abstract: The adenoviral mutant dl922-947 has potent activity in a variety of tumors. We investigated the efficacy of dl922-947 in ovarian carcinoma; compared its activity to wild-type adenovirus, dl309, and dl1520; and investigated the use of icodextrin to enhance activity in vivo. We also assessed the utility of luciferase bioluminescence imaging to quantify the response of human ovarian carcinoma xenografts to dl922-947. Ovarian carcinoma cell lines were transfected in vitro with dl922-947, adenovirus 5 wild-type (Ad5 WT), dl309, and dl1520 and monitored for S-phase induction, viral protein expression, replication, and overall survival. In vivo, the efficacy of dl922-947 when delivered in PBS or icodextrin to female nude mice bearing IGROV1 xenografts was determined. In vitro, dl922-947 induced lysis with greater efficacy than Ad5 WT, dl309, or dl1520 in all ovarian carcinoma cell lines tested, which was associated with earlier expression of viral proteins and S-phase induction. The lytic effect in immortalized ovarian surface epithelial cells confirmed that cellular retinoblastoma pathway status is a strong determinant of dl922-947 activity. In vivo, i.p. delivery of dl922-947 (5 x 10(9) particles daily x 5) increased median survival from 20 to 96 days (P < 0.0001) and delivery in icodextrin-enhanced survival further. However, delayed hepatic toxicity was evident in some dl922-947-treated mice, which was not dependent upon viral replication within tumor cells or the liver. dl922-947 has potency in ovarian carcinoma and i.p. delivery in icodextrin may enhance this activity. Immunocompetent models of ovarian carcinoma are required for further evaluation of hepatotoxicity.
authors.affiliation: Cancer Research UK Molecular Oncology Unit, Barts and the London School of Medicine, Charterhouse Square, London EC1M 6BQ, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lockley
authors.forename: Mario
authors.initials: M
authors.lastname: Fernandez
authors.forename: Yaohe
authors.initials: Y
authors.lastname: Wang
authors.forename: N Fiona
authors.initials: NF
authors.lastname: Li
authors.forename: Susan
authors.initials: S
authors.lastname: Conroy
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lemoine
authors.forename: Iain
authors.initials: I
authors.lastname: McNeish
mesh_terms: D000256:Adenoviridae / Q000472:pathogenicity*; D000818:Animals; D002277:Carcinoma / Q000628:therapy* / Q000821:virology*; D049109:Cell Proliferation; D005260:Female; D016368:Frameshift Mutation; D005936:Glucans / Q000008:administration & dosage / Q000494:pharmacology; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D000077607:Icodextrin; D007121:Immunocompetence; D007263:Infusions, Parenteral; D008099:Liver / Q000473:pathology; D008156:Luciferases / Q000032:analysis / Q000378:metabolism; D008163:Luminescent Measurements; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000628:therapy* / Q000821:virology*; D014162:Transfection; D014183:Transplantation, Heterologous; D014779:Virus Replication
chemical_list: D005936:Glucans; D000077607:Icodextrin; D008156:Luciferases; D005947:Glucose