title: Toxicology profiles of a novel p53-armed replication-competent oncolytic adenovirus in rodents, felids, and nonhuman primates.
abstract: 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 10(11) viral particles (VP)/kg, 2.0 x 10(11) VP/kg and 4.0 x 10(11) VP/kg doses, and on cat cardiovascular and respiratory systems at 2.0 x 10(10) VP/kg, 4.0 x 10(10) VP/kg, and 8.0 x 10(10) VP/kg doses. In acute toxicity test in mice, the maximum tolerated dose (2.5 x 10(13) 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 10(10) VP/kg each ip and excitated by one iv injection at 1.0 x 10(11) 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 10(11) VP/kg) and cynomolgus monkeys (5.0 x 10(11) 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.
authors.affiliation: Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
authors.forename: Hui
authors.initials: H
authors.lastname: Cao
authors.forename: Shuping
authors.initials: S
authors.lastname: Tan
authors.forename: Yao
authors.initials: Y
authors.lastname: Huang
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Jia
authors.forename: Lixin
authors.initials: L
authors.lastname: Jiang
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Ju
authors.initials: J
authors.lastname: Long
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Liu
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wu
authors.forename: Qijun
authors.initials: Q
authors.lastname: Qian
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000235:genetics; D000707:Anaphylaxis / Q000821:virology; D000818:Animals; D001522:Behavior, Animal; D002319:Cardiovascular System / Q000821:virology; D002415:Cats; D005260:Female; D005822:Genetic Vectors / Q000633:toxicity*; D006168:Guinea Pigs; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009420:Nervous System / Q000821:virology; D050130:Oncolytic Virotherapy / Q000009:adverse effects*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D012137:Respiratory System / Q000821:virology; D019098:Telomerase / Q000235:genetics; D013997:Time Factors; D018675:Toxicity Tests; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D016159:Tumor Suppressor Protein p53; C509186:TERT protein, human; D019098:Telomerase