Protection of normal tissues from the cytotoxic effects of chemotherapy and radiation by amifostine (Ethyol): preclinical aspects.

Amifostine (WR-2721, S-2 [3-aminopropylamino]-ethylphosphorothioic acid; Ethyol, US Bioscience, Inc. West Conshohocken, PA), developed as a radiation protector, has exhibited activity as a chemoprotector. The compound requires activation by dephosphorylation to produce the free thiol, WR-1065. This process is catalyzed by capillary alkaline phosphatase that is close to the desired site of protection. Additionally, the neutral pH of normal tissues, compared with the slightly acidic pH of tumors, favors selective activation. The protective mechanism against radiation damage is produced, and is, most probably, different from that of chemotherapy. The most likely mechanism for radioprotection involves free radical scavenging and hydrogen donation to repair damaged DNA. The hydrogen ion donation by the thiol group is required for both chemoprotection and radioprotection. Chemoprotection is presumed to be mediated by inactivation of the charged carbonium ions of activated alkylating agents through a nucleophilic attack, thereby protecting the nucleic acids from alkylation. Amifostine is able to reduce DNA platination when preincubated or coincubated with cisplatin, but this effect is much weaker when given postincubation. Observations show that maximum protection can only be obtained if amifostine is given before the administration of cytotoxic therapy. Amifostine side effects, as seen in mice, are dose dependent. A dose of 200 mg/kg has been found to be relatively nontoxic, although some hypothermia was observed.