Rodent nonclinical safety evaluation studies of SCH 58500, an adenoviral vector for the p53 gene

• Published in: Toxicological sciences Vol. 65; no. 2; pp. 266 - 275
• Main Authors: MORRISSEY, Richard E, HORVATH, Christopher, SNYDER, Eileen A, PATRICK, James, MACDONALD, James S
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 01-02-2002
• Subjects: Adenoviridae - genetics; Adenoviridae - growth & development; Animals; Antibodies, Viral - blood; Biological and medical sciences; Blood Coagulation - drug effects; Defective Viruses; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Female; Genes, p53; Genetic Vectors - toxicity; Hemagglutination Tests; Kidney - drug effects; Liver - drug effects; Male; Medical sciences; Mice; Mice, Inbred ICR; Miscellaneous (drug allergy, mutagens, teratogens...); Other treatments; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Safety; Toxicity Tests; Treatment. General aspects; Tumors; Antineoplastic agent; Intraperitoneal administration; Intravenous administration; Rat; Toxicity; Sex; Drug carrier; Hemopathy; Route of administration; Blood; Tissue; TP53 Gene; Subcutaneous administration; Tumor suppressor gene; Acute; Rodentia; Genetic transfer; Toxicokinetics; Vertebrata; Chronic; Mammalia; Mouse; Animal; Distribution; Kinetics; Gene therapy; Coagulopathy
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/65.2.266

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.