Amifostine: Mechanisms of Action Underlying Cytoprotection and Chemoprevention

Abstract

Amifostine is an important drug in the new field of cytoprotection. It was developed by the Antiradiation Drug Development Program of the US Army Medical Research and Development Command as a radioprotective compound and was the first drug from that Program to be approved for clinical use in the protection of dose limiting normal tissues in patients against the damaging effects of radiation and chemotherapy. Its unique polyamine-like structure and attached sulfhydryl group give it the potential to participate in a range of cellular processes that make it an exciting candidate for use in both cytoprotection and chemoprevention. Amifostine protects against the DNA damaging effects of ionizing radiation and chemotherapy drug associated reactive species. It possesses anti-mutagenic and anti-carcinogenic properties. At the molecular level, it has been demonstrated to affect redox sensitive transcription factors, gene expression, chromatin stability, and enzymatic activity. At the cellular level it has important effects on growth and cell cycle progression. This review focuses on relating its unique chemical design to mechanisms of action that underlie its broad usefulness as both a cytoprotective and chemopreventive agent for use in cancer therapy.