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Acute toxicity of a single dose DATR, recombinant soluble human TRAIL mutant, in rodents and crab-eating macaques
1Center for New Drug Evaluation, Institute of Basic Medical Science, Second Military Medical University, Shanghai, China.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to possess activity of inducing apoptosis in variety of tumor cells in preclinical models. Several mutational versions of TRAIL have been studied as promising agents for cancer therapy and the recombinant soluble human TRAIL mutant (DATR) is one of them. The objective of the present study was to provide possible toxic target organs and proposal non-toxic dose level of DATR for clinical usage. Rodents and crab-eating macaques were used to estimate potential adverse effects of DATR following a single dose administration. The median lethal dose (LD(50)) of intravenous injection to rats and mice was determined as 262.0 and 1018.0 mg/kg b.w., respectively. The LD(50) of intraperitoneal administration to mice was found to be 1432.1 mg/kg b.w. The main changes in macaques were found in the following aspects. Hematology analysis revealed an obvious decrease of red blood cell count (RBC), hemoglobin (HB) and hematocrit (HCT) after injection. Serum biochemical analysis showed an apparent increase of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), blood urea nitrogen (BUN) and creatinine (Crea). Furthermore, inflammatory cell infiltrate in liver and kidney was found by microscope. All the disorders suggested that liver, renal and hematological systems might be the target effectors of toxic effect induced by DATR. Based on the results of this study, the no observed-adverse-effect level (NOAEL) and the lowest observed-adverse-effect level of DATR in macaques are 90.0 and 135.0 mg/kg b.w., respectively.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mutant DATR showed toxicity in animal models, primarily affecting the liver, kidneys, and blood. The no observed-adverse-effect level in macaques was determined for safe clinical dosing.
Area of Science:
- Oncology
- Toxicology
- Pharmacology
Background:
- Recombinant soluble human TRAIL mutant (DATR) is a potential cancer therapeutic agent.
- Preclinical studies indicate Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells.
- Understanding DATR's toxicity is crucial for clinical application.
Purpose of the Study:
- To identify potential toxic target organs of DATR.
- To propose a non-toxic dose level of DATR for clinical use.
- To evaluate adverse effects of DATR in rodent and non-human primate models.
Main Methods:
- Median lethal dose (LD50) determination in rats and mice via intravenous and intraperitoneal administration.
- Hematological and serum biochemical analyses in crab-eating macaques post-administration.
- Histopathological examination of liver and kidney tissues in macaques.
Main Results:
- LD50 values varied by administration route and species.
- Macaques exhibited decreased red blood cell count, hemoglobin, and hematocrit.
- Elevated liver enzymes (ALT, AST), bilirubin, BUN, and creatinine were observed in macaques.
- Liver and kidney inflammation was noted in macaques.
- No Observed-Adverse-Effect Level (NOAEL) and Lowest Observed-Adverse-Effect Level (LOAEL) in macaques were 90.0 and 135.0 mg/kg b.w., respectively.
Conclusions:
- Liver, renal, and hematological systems are potential toxic targets of DATR.
- DATR demonstrates dose-dependent toxicity.
- Established NOAEL and LOAEL values provide guidance for DATR's clinical dosing strategy.
