title: Adenovirus serotype 11 causes less long-term intraperitoneal inflammation than serotype 5: implications for ovarian cancer therapy.
abstract: In a phase II/III clinical trial intraperitoneal (i.p.) administration of a group C adenovirus vector (Ad5) caused bowel adhesion formation, perforation and obstruction. However, we had found that i.p. group B, in contrast to group C adenoviruses, did not cause adhesions in nude BALB/c ovarian cancer models, prompting further investigation. Ex vivo, group B Ad11 caused lower inflammatory responses than Ad5 on BALB/c peritoneal macrophages. In vivo, i.p. Ad11 triggered short-term cytokine and cellular responses equal to Ad5 in both human CD46-positive and -negative mice. In contrast, in a long-term study of repeated i.p. administration, Ad11 caused no/mild, whereas Ad5 induced moderate/severe adhesions and substantial liver toxicity accompanied by elevated levels of IFNγ and VEGF and loss of i.p. macrophages, regardless of CD46 expression. It appears that, although i.p. Ad11 evokes immediate inflammation similar to Ad5, repeated administration of Ad11 is better tolerated and long-term fibrotic tissue remodelling is reduced.
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. Electronic address: c.thoma@oxfordalumni.org.
authors.forename: Clemens
authors.initials: C
authors.lastname: Thoma
authors.forename: Veronique
authors.initials: V
authors.lastname: Bachy
authors.forename: Patricia
authors.initials: P
authors.lastname: Seaton
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Green
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
authors.forename: Linda
authors.initials: L
authors.lastname: Klavinskis
authors.forename: Leonard W
authors.initials: LW
authors.lastname: Seymour
authors.forename: Joanne
authors.initials: J
authors.lastname: Morrison
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D059413:Intraabdominal Infections / Q000453:epidemiology / Q000473:pathology / Q000821:virology*; D051379:Mice; D010051:Ovarian Neoplasms / Q000628:therapy
chemical_list: D004337:Drug Carriers
keywords: Ad11; Ad5; Adenovirus; CD46-transgenic mice; Gene therapy; Intraperitoneal inflammation; Ovarian cancer; Virotherapy