Toxicological Sciences 65, 256-265 (2002)
Copyright © 2002 by the Society of Toxicology
SAFETY EVALUATION |
Porcine Toxicology Studies of SCH 58500, an Adenoviral Vector for the p53 Gene
* Drug Safety, Schering-Plough Research Institute, P.O. Box 32, Lafayette, New Jersey 07848-0032;
Preclinical Development and Therapeutic Antibody Discovery, Millennium Pharmaceuticals, Cambridge, Massachusetts 02139;
Drug Metabolism, Schering-Plough Corporation, Kenilworth, New Jersey 07033; and
Drug Safety and Metabolism, Schering-Plough Research Institute, Lafayette, New Jersey 07848-0032
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 108 plaque-forming units (pfu)/kg (2.2 x 1011 particles/kg), but less than 2.1 x 109 pfu/kg (1.5 x 1012 particles/kg). By the intravenous route it was 1 x 108 pfu/kg, and by the ip route it was greater than or equal to 3 x 108 pfu/kg. In a multicycle intraperitoneal study in pigs, the high dose of 3 x 108 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 108 pfu/kg. At high intrahepatic doses (about 1.5 x 1012 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.
Key Words: p53 gene; adenoviral vector; Yorkshire pigs; gene therapy; safety evaluation; toxicokinetic evaluation.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. E. Morrissey, C. Horvath, E. A. Snyder, J. Patrick, and J. S. MacDonald Rodent Nonclinical Safety Evaluation Studies of SCH 58500, an Adenoviral Vector for the p53 Gene Toxicol. Sci., February 1, 2002; 65(2): 266 - 275. [Abstract] [Full Text] [PDF]
|
|