title: An acute toxicology study with INGN 007, an oncolytic adenovirus vector, in mice and permissive Syrian hamsters; comparisons with wild-type Ad5 and a replication-defective adenovirus vector.
abstract: Oncolytic (replication-competent) adenoviruses as anticancer agents provide new, promising tools to fight cancer. In support of a Phase I clinical trial, here we report safety data with INGN 007 (VRX-007), an oncolytic adenovirus with increased anti-tumor efficacy due to overexpression of the adenovirus-encoded ADP protein. Wild-type adenovirus type 5 (Ad5) and a replication-defective version of Ad5 were also studied as controls. A parallel study investigating the biodistribution of these viruses is described elsewhere in this issue. The toxicology experiments were conducted in two species, the Syrian hamster, which is permissive for INGN 007 and Ad5 replication and the poorly permissive mouse. The studies demonstrated that the safety profile of INGN 007 is similar to Ad5. Both viruses caused transient liver damage upon intravenous injection that resolved by 28 days post-infection. The No-Observable-Adverse-Effect-Level (NOAEL) for INGN 007 in hamsters was 3 x 10(10) viral particles per kg. In hamsters, the replication-defective vector caused less toxicity, indicating that replication of Ad vectors in the host is an important factor in pathogenesis. With mice, INGN 007 and Ad5 caused toxicity comparable to the replication-defective adenovirus vector. Partially based on these results, the FDA granted permission to enter into a Phase I clinical trial with INGN 007.
authors.affiliation: VirRx, Inc., St Louis, MO 63104, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Lichtenstein
authors.forename: J F
authors.initials: JF
authors.lastname: Spencer
authors.forename: K
authors.initials: K
authors.lastname: Doronin
authors.forename: D
authors.initials: D
authors.lastname: Patra
authors.forename: J M
authors.initials: JM
authors.lastname: Meyer
authors.forename: E V
authors.initials: EV
authors.lastname: Shashkova
authors.forename: M
authors.initials: M
authors.lastname: Kuppuswamy
authors.forename: D
authors.initials: D
authors.lastname: Dhar
authors.forename: M A
authors.initials: MA
authors.lastname: Thomas
authors.forename: A E
authors.initials: AE
authors.lastname: Tollefson
authors.forename: L A
authors.initials: LA
authors.lastname: Zumstein
authors.forename: W S M
authors.initials: WS
authors.lastname: Wold
authors.forename: K
authors.initials: K
authors.lastname: Toth
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D017503:Adenovirus E3 Proteins / Q000096:biosynthesis; D000818:Animals; D001772:Blood Cell Count; D002460:Cell Line; D006224:Cricetinae; D004920:Erythropoiesis; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000473:pathology / Q000821:virology; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D050504:Oncolytic Viruses; D014779:Virus Replication
chemical_list: D017503:Adenovirus E3 Proteins; C099609:adenovirus death protein, Adenovirus