title: Preclinical toxicity of DATR, a recombinant soluble human TRAIL mutant, in rats and cynomolgus monkeys.
abstract: The recombinant soluble human TRAIL mutant (DATR), derived from tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), is a promising agent for cancer therapy. The present study evaluated the toxicity of DATR in rats and monkeys. Based on the results, the safety and toxic doses of DATR intravenously injected to rats for 50 days were 60 and 180 mg/kg, respectively, and when delivered intravenously guttae to monkeys for 50 days, these levels were 10 and 30 mg/kg, respectively. The main toxic effects in rats were red blood cell count and haemoglobin decreases; blood urea nitrogen and creatinine increases. The main toxic effects in monkeys included red blood cell count and haemoglobin decreases; alanine aminotransferase and aspartate aminotransferase increases; high proliferation of karyocytes of the erythrocyte series; and regional hydropic degeneration of hepatic parenchymal cells. The TUNEL assay showed both 90 mg/kg DATR- and TRAIL-induced apoptosis of the liver in monkeys, which confirmed the hepatotoxicity of DATR. These findings indicated that the target toxic organs of DATR might be the haematological system. Furthermore, kidney in rats and liver in monkeys are also likely target toxic organs. The toxicity was reversible and did not differ from that associated with TRAIL administered at the same dosage.
authors.affiliation: Centre for New Drug Evaluation, Institute of Basic Medical Science, The Second Military Medical University, Shanghai 200433, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zou
authors.forename: Yu
authors.initials: Y
authors.lastname: Mao
authors.forename: Mao
authors.initials: M
authors.lastname: Huang
authors.forename: Bojun
authors.initials: B
authors.lastname: Yuan
authors.forename: Guocai
authors.initials: G
authors.lastname: Lu
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000633:toxicity; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000633:toxicity*
chemical_list: D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human