Biosafety of in vivo adenovirus-p53 intravesical administration in mice

• Published in: Urology (Ridgewood, N.J.) N.J.), 2000-07, Vol.56 (1), p.155-159
• Main Authors: Perrotte, Paul, Wood, Mark, Slaton, Joel W, Wilson, Deborah R, Pagliaro, Lance, Price, Roger E, Dinney, Colin P.N
• Format: Article
• Language: English
• Subjects: Adenoviridae - enzymology; Adenoviridae - isolation & purification; Administration, Intravesical; Animals; Antineoplastic agents; Biological and medical sciences; Female; Genes, p53; Genetic Therapy - adverse effects; Genetic Therapy - methods; Humans; Immunotherapy; Luciferases - metabolism; Medical sciences; Mice; Mice, Inbred BALB C - blood; Pharmacology. Drug treatments
• ISSN: 0090-4295; 1527-9995
• DOI: 10.1016/S0090-4295(00)00537-9

Objectives. To evaluate the biosafety and in vivo biodistribution of intravesical instillation of an adenovirus that contains human p53 gene. Mutations of p53, which are found in as many as 40% of transitional cell carcinomas, are associated with a poor prognosis and resistance to chemotherapy and radiation therapy. Restoration of wild-type p53 status by means of adenoviral-mediated therapy may enhance apoptosis and improve the response to therapy, but the issues of biosafety and toxicity have not yet been addressed. Methods. Adenovirus-p53 (1 × 10 8, 1 × 10 9, and 5 × 10 9 pfu/mL) and luciferase reporter gene (5 × 10 9) were instilled into the bladders of anesthetized female BALB/c mice. The mice were killed on days 1, 3, 6, and 13, and representative samples of the bladder, ureter, kidney, adrenal gland, ovary, liver, heart, and lung were removed for histologic evaluation. Results. No histologic signs of toxicity were found. The hematologic and biochemical profiles of the mice were normal, with the exception of a transient elevation in liver function tests on day 1 in the three treatment groups. Conclusions. Intravesical instillation of adenovirus-p53 was well tolerated; the bladder urothelium appeared to prevent systemic dissemination. The results of these experiments support the safety of intravesical gene transfer by intravesical instillation.