Relationships between cytoprotection and mutation prevention by WR-1065

Abstract

WR-2721, the leading compound that has emerged from the U.S. Army's Drug Synthesis and Development Program, has become the first clinically used cytoprotector in cancer therapy. The ability of its active thiol, WR-1065, to act as an antioxidant to scavenge free radicals, donate hydrogen atoms, and induce auto-oxidation is related to its cytoprotective effectiveness. However, at concentrations 10 to 20 times lower than those required for cytoprotection, this nonprotein thiol also affects gene expression, transcription factor binding, protein phosphorylation levels, and mutagenesis. For example, WR-1065 treatment activates binding of the redox-sensitive transcription factor NF-κB to DNA and affects expression of a number of genes, including thymidine kinase, c-myc, and manganese superoxide dismutase. At these lower drug concentrations, phosphorylation levels and subsequent activities on intracellular enzymes are also inhibited. These observations suggest that the mechanisms of action of WR-2721 and its metabolites to protect against cell killing are different from those that protect against mutagenesis and cancer formation. The ability to affect these postexposure processes makes WR 2721 an important agent in the reduction of the carcinogenic risks of environmental exposure to radiation or deleterious chemicals.