title: Long-term toxicity study of rAd5-hTERTC27 in SD rats and Cynomolgus monkeys by intravenous injection.
abstract: rAd5-hTERTC27, a replication-defective adenovirus vector carrying hTERTC27, has been proposed for possible use against hepatocellular carcinoma (HCC). In this study, we investigated the long-term toxicity of rAd5-hTERTC27 in SD rats and Cynomolgus monkeys. rAd5-hTERTC27 was administered intravenously once a week for 13 weeks followed by a one-month recovery period. As of 4 months, all animals displayed overall good health. Anti-adenoviral antibodies emerged in a dose-independent manner. The levels of complement components, C3 and C4, in the rAd5-hTERTC27 middle-dose and high-dose groups and C4 in the rAd5-EGFP group increased significantly after the 2nd treatment in monkeys. Slight-mild pathological changes of the liver occurred only in the rAd5-hTERTC27 high-dose group (2/16) in rats and not in any other group in either rats or monkeys. With the increase of the dose, the incidence of lymphocyte depletion in the spleen of rats and reactive hyperplasia of the splenic corpuscle in monkeys increased. However, the changes in the liver and spleen were reversible. Given the above data, intravenous administration of rAd5-hTERTC27 (up to 4×10(10)VP/kg in rats and 0.9×10(10)VP/kg in monkeys) appears to be well-tolerated, providing support for its potentially safe use in clinical trials for the treatment of HCC.
authors.affiliation: Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China.
authors.forename: Pei-jian
authors.initials: PJ
authors.lastname: Yue
authors.affiliation: Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China.
authors.forename: Lei
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China.
authors.forename: Qing-yu
authors.initials: QY
authors.lastname: Shen
authors.affiliation: Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China.
authors.forename: Shu-wei
authors.initials: SW
authors.lastname: Qiu
authors.affiliation: Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China.
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Rong
authors.affiliation: Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China.
authors.forename: Han-xian
authors.initials: HX
authors.lastname: Gong
authors.affiliation: Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China; Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China. Electronic address: docpengy123@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D004435:Eating / Q000187:drug effects; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000633:toxicity*; D007275:Injections, Intravenous; D008113:Liver Neoplasms / Q000188:drug therapy; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D019098:Telomerase / Q000008:administration & dosage* / Q000633:toxicity*; D013997:Time Factors
chemical_list: C509186:TERT protein, human; D019098:Telomerase
keywords: Gene therapy; HCC; Preclinical evaluation; Repeat-dose toxicity; hTERTC27