title: Porcine toxicology studies of SCH 58500, an adenoviral vector for the p53 gene.
abstract: Adenoviral vectors are being actively investigated for their potential utility in gene therapy. SCH 58500, a replication-deficient adenoviral vector, carries the normal p53 tumor suppressor gene, which is frequently mutated or absent in several human cancers. To assess the potential toxicity associated with adenoviral use, Yorkshire pigs were dosed by intravenous, intrahepatic, or local routes (subcutaneous and intradermal) to support a variety of potential clinical indications. Porcine cells were shown to support replication of wild-type human adenovirus. The nonlethal and asymptomatic dose in pigs following dosing via the intrahepatic route was greater than 3 x 10(8) plaque-forming units (pfu)/kg (2.2 x 10(11) particles/kg), but less than 2.1 x 10(9) pfu/kg (1.5 x 10(12) particles/kg). By the intravenous route it was 1 x 10(8) pfu/kg, and by the ip route it was greater than or equal to 3 x 10(8) pfu/kg. In a multicycle intraperitoneal study in pigs, the high dose of 3 x 10(8) pfu/kg caused an increased antibody and/or an inflammatory response. By the intravenous route, plaque-forming units were present in most pigs at 5 min postdose, but only in a few at 10 min postdose. No expression was found in gonadal tissue approximately 3 weeks after a single intravenous injection of 3 x 10(8) pfu/kg. At high intrahepatic doses (about 1.5 x 10(12) particles/kg), acute cardiovascular and hemodynamic effects were found, which in subsequent studies were also present at high doses by intravenous administration. Based on these findings, careful evaluation of hemodynamic parameters in patients receiving systemic doses of SCH 58500 is warranted.
authors.affiliation: Drug Safety, Schering-Plough Research Institute, P.O. Box 32, Lafayette, New Jersey 07848-0032, USA. richard.morrissey@spcorp.com
authors.forename: Richard E
authors.initials: RE
authors.lastname: Morrissey
authors.forename: Christopher
authors.initials: C
authors.lastname: Horvath
authors.forename: Eileen A
authors.initials: EA
authors.lastname: Snyder
authors.forename: James
authors.initials: J
authors.lastname: Patrick
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Collins
authors.forename: Ellen
authors.initials: E
authors.lastname: Evans
authors.forename: James S
authors.initials: JS
authors.lastname: MacDonald
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology; D004279:DNA, Viral / Q000032:analysis; D003673:Defective Viruses; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D016158:Genes, p53; D005822:Genetic Vectors / Q000633:toxicity*; D006386:Hemagglutination Tests; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012449:Safety; D013552:Swine; D018675:Toxicity Tests
chemical_list: D000914:Antibodies, Viral; D004279:DNA, Viral