title: Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus.
abstract: Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0×10(8), 2.5×10(9), and 1.25×10(10) viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0×10(8), 2.5×10(9), and 1.25×10(10) VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose>5×10(10) VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25×10(10) VP/kg) and beagles (2.5×10(9) VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35×10(10) VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67×10(8) VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent.
authors.affiliation: State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, PR China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, PR China; Changchun Brother Biotech Co., Ltd., Changchun, 130000, PR China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Guo
authors.affiliation: Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, PR China; The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122, PR China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Hu
authors.affiliation: Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, PR China; The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122, PR China.
authors.forename: Dongyun
authors.initials: D
authors.lastname: He
authors.affiliation: Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, PR China; School of Clinical Medicine, Jilin University, Changchun 130001, PR China.
authors.forename: Shi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun 130021, PR China.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, PR China; The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122, PR China. Electronic address: lixiao06@mails.jlu.edu.cn.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Head and Neck Surgery, Tumor Hospital of Jilin Province, Changchun 130012, PR China. Electronic address: linjiaxiaoya@163.com.
authors.forename: LiLi
authors.initials: L
authors.lastname: Sun
authors.affiliation: Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, PR China; The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122, PR China. Electronic address: ningyij@126.com.
authors.forename: Ningyi
authors.initials: N
authors.lastname: Jin
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics*; D004285:Dogs; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D019098:Telomerase / Q000235:genetics*
chemical_list: D017500:Adenovirus E1A Proteins; D036022:Capsid Proteins; C091717:VP3 protein, Chicken anemia virus; C509186:TERT protein, human; D019098:Telomerase
keywords: Apoptin; Conditionally replicating adenovirus; Human telomerase reverse transcriptase; Safety evaluation