Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

• Published in: Toxicology and applied pharmacology Vol. 280; no. 2; pp. 362 - 369
• Main Authors: Qi, Yanxin, Guo, Huanhuan, Hu, Ningning, He, Dongyun, Zhang, Shi, Chu, Yunjie, Huang, Yubin, Li, Xiao, Sun, LiLi, Jin, Ningyi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15-10-2014; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Adenoviridae - genetics; ADENOVIRUS; Adenovirus E1A Proteins - genetics; ANAPHYLAXIS; Animals; ANTIBODIES; Apoptin; APOPTOSIS; BEAGLES; Biological and medical sciences; BONE MARROW; Capsid Proteins - genetics; Conditionally replicating adenovirus; DIGESTIVE SYSTEM; Dogs; Female; GENES; Genetic Therapy - adverse effects; GUINEA PIGS; Human telomerase reverse transcriptase; INFLAMMATION; INTRAPERITONEAL INJECTION; INTRAVENOUS INJECTION; Male; Medical sciences; MICE; Mice, Inbred BALB C; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); MUSCLES; NEOPLASMS; NERVOUS SYSTEM; Oncolytic Virotherapy - adverse effects; RATS; Rats, Wistar; RESPIRATORY SYSTEM; Safety evaluation; Telomerase - genetics; TOXICITY; Toxicology; Tumors; Conditionally replicating adenovirus; Apoptin; Safety evaluation; Human telomerase reverse transcriptase; Human; Catalytic subunit; Evaluation; RNA-directed DNA polymerase; Enzyme; Toxicity; Transferases; Preclinical trial; Reverse transcription; Pharmacology; Malignant tumor; Oncolytic virus; Nucleotidyltransferases; Safety; Telomerase; Cancer
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2014.08.008

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 5.0×108, 2.5×109, and 1.25×1010 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 5.0×108, 2.5×109, and 1.25×1010 VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose>5×1010 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 (1.25×1010 VP/kg) and beagles (2.5×109 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 1.35×1010 VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67×108 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.
•We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin.•Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent.•Demonstrate the safety and feasibility dose of injected Ad-hTERT-E1a-Apoptin