Rodent Nonclinical Safety Evaluation Studies of SCH 58500, an Adenoviral Vector for the p53 Gene
| Autor: | James E. Patrick, Christopher Horvath, Richard E. Morrissey, Eileen A. Snyder, James S. MacDonald |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Male
Pathology medicine.medical_specialty Genetic Vectors Pharmacology Antibodies Viral Kidney Toxicology Adenoviridae Rats Sprague-Dawley Mice Lethargy Peritoneal cavity Route of administration Toxicity Tests Coagulopathy medicine Animals Dosing Blood Coagulation Clotting factor Mice Inbred ICR Dose-Response Relationship Drug business.industry Genetic transfer Defective Viruses Hemagglutination Tests Genes p53 medicine.disease Rats medicine.anatomical_structure Liver Toxicity Female Safety business |
| Zdroj: | Toxicological Sciences. 65:266-275 |
| ISSN: | 1096-0929 |
| DOI: | 10.1093/toxsci/65.2.266 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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