title: Rodent nonclinical safety evaluation studies of SCH 58500, an adenoviral vector for the p53 gene.
abstract: SCH 58500 is a replication-defective recombinant adenoviral vector containing the cloned human wild-type (normal) tumor suppressor gene p53. SCH 58500 is in trials to evaluate potential clinical utility. A series of toxicology studies in rats and mice were conducted via multiple routes of exposure to support these programs. The nonlethal and asymptomatic dose in rats following a 14-day observation period was equal to 7.5 x 10(7) plaque-forming units (pfu)/kg (5.6 x 10(10) particles/kg) by intravenous or intraperitoneal route and was similar by the ip route, following 4 weeks of dosing. The high dose of 1.5 x 10(9) pfu/kg (1.1 x 10(12) particles/kg) was lethal by the i.v. route and inflammatory to the peritoneal cavity by the ip route. SCH 58500 was rapidly cleared from the systemic circulation in rats (serum t(1/2) of 7 to 9 min) following iv administration. Administration by other routes resulted in no (sc) or delayed (ip) serum levels. Since most rats in the i.v. rat study died within 24 h postdose, another study to evaluate potential mechanisms of toxicity in rats was designed in which rats were killed at intervals following a single i.v. dosing. A single high i.v. dose of SCH 58500 (1.1 x 10(12) pfu/kg) was associated with lethargy, soft feces, a ruffled-hair coat, and death within 1 h postdose. Potential mechanisms of toxicity appeared to include a mild coagulopathy and/or vasculopathy, resulting in consumption of platelets and clotting factors, leakage or loss of intravascular fluid, hemoconcentration, electrolyte and/or fluid shifts, a moderate stress and/or inflammatory response, and a mild, direct or indirect toxic effect on liver and/or kidney tissue. These findings suggest a multifocal cause for acute lethality following i.v. dosing in rats.
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: James S
authors.initials: JS
authors.lastname: MacDonald
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000254:growth & development; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects; D003673:Defective Viruses; D004305:Dose-Response Relationship, Drug; D005260:Female; D016158:Genes, p53; D005822:Genetic Vectors / Q000633:toxicity*; D006386:Hemagglutination Tests; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D012449:Safety; D018675:Toxicity Tests
chemical_list: D000914:Antibodies, Viral