Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety
| Autor: | S K, Kelley, L A, Harris, D, Xie, L, Deforge, K, Totpal, J, Bussiere, J A, Fox |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Membrane Glycoproteins Pan troglodytes Tumor Necrosis Factor-alpha Transplantation Heterologous Mice Nude Antineoplastic Agents Apoptosis Rats Rats Sprague-Dawley TNF-Related Apoptosis-Inducing Ligand Macaca fascicularis Mice Species Specificity Injections Intravenous Animals Humans Female Apoptosis Regulatory Proteins Colorectal Neoplasms Algorithms Neoplasm Transplantation |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 299(1) |
| ISSN: | 0022-3565 |
| Popis: | Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a member of the tumor necrosis factor gene family known to induce apoptosis in a number of cancer cell lines and may have broad-spectrum activity against human malignancies. These studies have evaluated the potency of recombinant soluble human Apo2L/TRAIL in a mouse xenograft model and the disposition and safety of Apo2L/TRAIL in rodents and nonhuman primates. Mice with established COLO205 tumors were given daily i.v. injections of Apo2L/TRAIL (30-120 mg/kg/day). Control tumors doubled in size every 2 to 3 days, while time to tumor doubling in the treatment groups was significantly longer and related to dose (14-21 days). For pharmacokinetic studies, Apo2L/TRAIL was given as an i.v. bolus to mice (10 mg/kg), rats (10 mg/kg), cynomolgus monkeys (1, 5, and 50 mg/kg), and chimpanzees (1 and 5 mg/kg). Apo2L/TRAIL was rapidly eliminated from the serum of all species studied. Half-lives were approximately 3 to 5 min in rodents and approximately 23 to 31 min in nonhuman primates. Allometric scaling provided estimates of Apo2L/TRAIL kinetics in humans, suggesting that on a milligram per kilogram basis, doses significantly lower than those used in xenograft studies could be effective in humans. Apo2L/TRAIL clearance was highly correlated with glomerular filtration rate across species, indicating that the kidneys play a critical role in the elimination of this molecule. Safety evaluations in cynomolgus monkeys and chimpanzees revealed no abnormalities associated with Apo2L/TRAIL exposure. In conclusion, these studies have characterized the disposition of Apo2L/TRAIL in rodents and primates and provide information that will be used to predict the pharmacokinetics of Apo2L/TRAIL in humans. |
| Databáze: | OpenAIRE |
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