BACKGROUND AND OBJECTIVE: Amifostine is an inorganic thiophosphate 
cytoprotective agent known chemically as ethanethiol, 
2-&#91;(3-aminopropyl)amino&#93;dihydrogen phosphate. It is a pro-drug of free 
thiol that may act as a scavenger of free radicals generated in tissues exposed 
to cytotoxic drugs, and binds to reactive metabolites of such drugs. Amifostine 
was originally developed as a radioprotective agent in a classified nuclear 
warfare project. Following declassification of the project it was evaluated as a 
cytoprotective agent against toxicity of the alkylating drugs and cisplatin. In 
fact, pretreatment with amifostine was well tolerated and reduced the cumulative 
hematologic, renal and neurological toxicity associated with cisplatin, 
cyclophosphamide and vinblastine therapy of advanced and metastatic solid 
tumors. The objective of this review is to focus the importance of amifostine as 
a myeloprotective and cytoprotective drug during treatment with 
chemotherapeutics, presenting the most recent results, and to discuss the 
application of amifostine in the therapy of myelodysplastic syndromes.
EVIDENCE AND INFORMATION SOURCES: The material analyzed in this study includes 
data published or under publication by the authors as full papers or clinical 
protocols. Articles and abstracts published in Journals covered by Medline 
constitute the other source of information.
STATE OF THE ART AND PERSPECTIVES: Amifostine, formerly known as WR-2721, is an 
organic thiophosphate that was developed to protect normal tissues selectively 
against the toxicities of chemotherapy and radiation. Amifostine is a pro-drug 
that is dephosphorylated at the tissue site to its active metabolite by alkaline 
phosphatase. Differences in the alkaline phosphatase concentrations of normal 
versus tumor tissues can result in greater conversion of amifostine in normal 
tissues. Once inside the cell the free thiol provides an alternative target to 
DNA and RNA for the reactive molecules of alkylating or platinum agents and acts 
as a potent scavenger of the oxygen free radicals induced by ionizing radiation 
and some chemotherapies. Preclinical animal studies demonstrated that the 
administration of amifostine protected against a variety of chemotherapy-related 
toxicities including cisplatin-induced nephrotoxicity, cisplatin-induced 
neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity, and 
the cytotoxicities (including cardiotoxicity) induced by doxorubicin and related 
chemotherapeutic agents. Amifostine was shown to protect a variety of animal 
species from lethal doses of radiation. Studies in tumor-bearing animals 
demonstrated that the administration of amifostine results in cytoprotection 
without loss of antitumor activity. Multiple phase I studies were carried out 
with amifostine in combination with chemotherapy for various neoplasms. 
Appropriate doses of amifostine resulted to be 740-910 mg/m(2) in a single dose 
regimen, and 340 mg/m(2) in a multiple dose regimen. Amifostine afforded not 
only hematologic protection, but also other organ protection from cytotoxic 
agents such as nephrotoxicity, mucositis and peripheral neuropathy from 
cisplatin. Many studies have been performed to investigate cytoprotective 
efficacy of amifostine. In brief, amifostine gives hematologic protection from 
cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal 
and peripheral nerve protection from cisplatin; mucosa, skin, and salivary gland 
from radiotherapy. In phase I/II studies these properties have been confirmed, 
together with a generally good tolerability of the drug, hypotension being the 
most common side effect. It has been observed that amifostine possibly enhances 
the anti-tumor effect of carboplatin, nitrogen mustard, melphalan, and cisplatin 
combined with 5-FU or vinblastine. For all these characteristics, amifostine is 
at present broadly used as supportive treatment during chemotherapy, in 
lymphomas and solid tumors, and its spec