The potential of amifostine: From cytoprotectant to therapeutic agent

Background and Objectives. Amifostine is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[(3- aminopropyl)amino]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 chemotherapyrelated 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/m² in a single dose regimen, and 340 mg/m² 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 spectrum of possible applications is enlarging. As data have been provided indicating that amifostine stimulates hematopoiesis, it has been proposed as a possible therapeutic agent in myelodysplasia, in which most clinical complications are related to cytopenia. Several trials have been performed and are at present on-going with the purpose of elucidating the real efficacy of amifostine in restoring effective hemopoielsis. The first observations reported are generally in agreement, indicating a partial response to amifostine, especially in low-risk MDS. Although synthesized several years ago, amifostine has entered into clinical use only recently. Its broad cytoprotective effects seem beneficial, particularly in view of the widespread and increasing application of high-dose chemotherapy, even in elderly patients. Amifostine possibly parallels the action of growth factors as supportive agents, with which it also shares a relatively limited toxicity. In fact, it can reduce both neutropenia and thrombocytopenia induced by cytotoxic therapy. In this sense, the use of this cytoprotectant should be encouraged. Challenging data came from the early application of amifostine as a single therapeutic agent in myelodysplastic syndromes. Although at present only partial responses have been reported, in the near future the real significance of this compound will be clarified thanks to large and complete clinical trials, and its importance finally discussed and defined.