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

¹21^st Century Therapeutics, Inc., Ferndale, MI 48220, USA

²Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA

³Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA

⁴Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA

*Corresponding author:

J. Shaw, Ph.D.

21^st Century Therapeutics, Inc..

1366 Hilton Rd., Ferndale

Michigan 48220, USA

Telephone: 734-330-6052

E-mail: jshaw@21-cti.com

Abstract

       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 small-molecule tumor necrosis factor alpha (TNF-a) 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-α in liver tissue extracts. Both AST and ALT in serum and TNF-α in liver induced by irradiation were significantly reduced by UTL-5g in a drug dose-dependent manner. The reductions of AST, ALT and TNF-α 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-α inhibitor, UTL-5g, is potentially radioprotective against acute phase of radiation-induced liver injury.

Keywords: liver, radiation, radioprotective, TNF-α, UTL-5g.

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