Pretreatment with A Small-Molecule Tumor Necrosis Factor-Alpha (TNF-α) Inhibitor, UTL-5g, Reduced Radiation-Induced Acute Liver Toxicity in Mice

Radiation-induced liver toxicity is a major limitation to the use of radiation in the treatment of intrahepatic cancers. The purpose of this study was to evaluate the potential radioprotective effect of a smallmolecule tumor necrosis factor alpha (TNF-) inhibitor, UTL-5g, against radiation-induced acute liver injury. Mice were pre-treated by i.p. injection with UTL-5g and control vehicle one hr prior to liver irradiation at 15 Gy. Blood and liver were collected 2 hr after irradiation and analyzed for levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in serum and TNF- in liver tissue extracts. Both AST and ALT in serum and TNF- in liver induced by irradiation were significantly reduced by UTL-5g in a drug dose-dependent manner. The reductions of AST, ALT and TNF- appeared to correlate with the reduction of liver apoptosis detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. A radiation dose escalation study (5, 15 and 25 Gy) showed that UTL-5g at 60 mg/kg was effective as a radioprotective agent at 5 and 15 Gy; the protection was only modest at 25 Gy. In summary, our results suggest that the TNF- inhibitor, UTL-5g, is potentially radioprotective against acute phase of radiation-induced liver injury.