WR-2721 (Ethyol®): Reduction in Toxicity of Anticancer Therapy without Loss of Efficacy
WR-2721 (amifostine, Ethyol) is an organic thiophosphate which selectively protects normal, but not neoplastic, tissues against the toxicity of platinum, alkylating agents and radiotherapy. This compound was originally synthesized for the Antiradiation Drug Development Program of the Walter Reed Army Institute of Research (Davidson et al., 1980), which was established to develop radioprotective agents that could be used by military personnel in the event of nuclear warfare. The rationale for its synthesis was based upon an observation made approximately 40 years ago that the sulfhydryl-amino acid, cysteine, possessed radiation protective properties (Pratt et al., 1949). It is postulated that sulfhydryl compounds, such as cysteine, protect by scavenging free radicals (Alexander et al., 1955) or, in the setting of chemotherapy, by directly binding to alkylating agents thereby preventing damage to the structure and function of critical macromolecules. Phosphorylated aminothiols, compared to simple amino acids, represented major improvements in regard to potency, tolerance and duration of action. Of the 4400 compounds tested in this program, S-2-(3-aminopropylamino)ethyl phosphorothioic acid (WR-2721) was recognized as the best radioprotective compound. WR-2721 was capable of reducing or eliminating the toxicity and lethality associated with gamma and neutron irradiation while providing an improved therapeutic index relative to earlier radioprotectors (Davidson et al., 1980). The principal shortcoming of WR-2721, which limited its use for self-administration by military populations, was the requirement that it be given intravenously. Nevertheless, the protective properties of WR-2721 for therapeutic radiation and chemotherapy, including platinum agents, were subsequently pursued.
KeywordsAutologous Bone Marrow Transplantation Nitrogen Mustard Sulfhydryl Compound Simple Amino Acid Differential Protection
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