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.

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

“…The radioprotective effect, however, diminishes rapidly as the concentration of WR1065 is reduced [12,13,27]. At a concentration of 40 μM, WR1065 is ineffective for protection against cell killing but is sufficient for preventing radiation-induced mutagenesis through a distinctly separate mechanism of action [13]. Presented in Fig.…”

“…Two concentrations of WR1065 were chosen for investigation. WR1065 when present during irradiation at a concentration of 4 mM can significantly protect cells from radiation toxicity [12,13,27]. This effect is best described as immediate radioprotection and is routinely demonstrated by administering WR1065 30 min prior to irradiation.…”

“…Immediately prior to use, WR1065 was dissolved at a concentration of 1 M in phosphate-buffered saline (PBS; 8.1 mM Na 2 HPO 4 , 1.5 mM KH 2 PO 4 , 140 mM NaCl; Gibco/BRL). Final concentrations were chosen to reflect the optimum dose affording either the maximum level of immediate radioprotection (4 mM) or the prevention of mutation induction (40 μM) [13,27]. It is important to note that while millimolar levels of WR1065 are not achievable under in vivo conditions, concentrations of 40 μM are readily detectable in the serum of patients treated with radioprotective doses of amifostine [28].…”

“…Therefore, to be effective agents such as amifostine must be administered shortly before radiation exposure. Administration following irradiation is ineffective in affording protection against free radical damage [12,13].…”

“…Two different doses of WR1065 are used, 40 μM and 4 mM. These concentrations of WR1065 have been demonstrated to be maximally effective in protecting against radiation-induced mutagenesis and cell killing, respectively [13].…”