ToxSci Advance Access originally published online on August 14, 2008
Toxicological Sciences 2008 106(1):242-250; doi:10.1093/toxsci/kfn168
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Toxicology Profiles of a Novel p53-Armed Replication-Competent Oncolytic Adenovirus in Rodents, Felids, and Nonhuman Primates
,1,1
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* Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China
Vector Gene Technology Company, Ltd., Beijing 100176, China
Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou 310009, China
2 To whom correspondence should be addressed at Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, No. 225 Changhai Road, Shanghai 200438, China. E-mail: qianqj{at}sino-gene.cn.
Received June 11, 2008; accepted August 6, 2008
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Abstract |
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Conditionally replicating adenovirus (CRAd) has demonstrated to be safe in clinical studies. We generated a triple-regulated p53-armed CRAd, SG600-p53, in which the partially deleted E1a and E1b genes are regulated under the human telomerase reverse transcriptase promoter and the hypoxia response element. SG600-p53 was proven to be effective both in vitro and in vivo. In this study, the preclinical safety profiles of SG600-p53 in animal models were investigated. SG600-p53 had no adverse effects on mouse behavioral and nervous systems at 1.0 x 1011 viral particles (VP)/kg, 2.0 x 1011 VP/kg and 4.0 x 1011 VP/kg doses, and on cat cardiovascular and respiratory systems at 2.0 x 1010 VP/kg, 4.0 x 1010 VP/kg, and 8.0 x 1010 VP/kg doses. In acute toxicity test in mice, the maximum tolerated dose (2.5 x 1013 VP/kg) induced cachexia, decreased activity, and eye closure in 9/20 mice which could be self-resolved within 30 min. Sensitized by five repeated ip injections at 1.0 x 1010 VP/kg each ip and excitated by one iv injection at 1.0 x 1011 VP/kg, guinea pigs did not show any sign of systemic anaphylaxis. In repeat-dose toxicological studies, the no-observable-adverse-effect levels of SG600-p53 in rats (1.0 x 1011 VP/kg) and cynomolgus monkeys (5.0 x 1011 VP/kg) were 12-fold and 60-fold of the proposed clinical dose, respectively. Intramuscular injections of SG600-p53 in cynomolgus monkeys caused inflammation at injection sites, which was alleviative at the end of observation period. The anti-virus antibody was produced in animal sera and decreased gradually 4 weeks later. No histopathological changes were found by bone marrow examination. Our data in different animal models suggest that SG600-p53 is a safe antitumor therapeutic agent.
Key Words: conditionally replicating adenovirus; human telomerase reverse transcriptase; hypoxia response element; p53 gene; safety evaluation.
1 These authors contributed equally to this study.