Amifostine

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, WR1065 treatment activates binding of the redox-sensitive transcription factor NF-KB 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 WR2721 an important agent in the reduction of the carcinogenic risks of environmental exposure to radiation or deleterious chemicals.

Acknowledgments

This work was sponsored by National Institutes of Health/National Cancer Institute Grant CA37435.

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Guarantor: David J. Grdina, PhD

Contributors: David J. Grdina, PhD; Jeffrey S. Murley, PhD; Yasushi Kataoka, PhD; William Epperly, PhD

Department of Radiation and Cellular Oncology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637.

This manuscript was received for review February 2001. The revised manuscript was accepted for publication in November 2001.

Reprint & Copyright by Association of Military Surgeons of U.S., 2002.

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