The potential of amifostine: from cytoprotectant to therapeutic agent

Background and Objectives. Amifostine is an inorganic thiophosphate cytopro tective agent known chemically as ethanethiol, 2-[(3-aminopropyl)amino]dihy drogen phosphate. It is a pro-drug of free thiol that may act as a scavenge r of free radicals generated in tissues exposed to cytotoxic drugs, and bin ds to reactive metabolites of such drugs. Amifostine was originally develop ed as a radioprotective agent in a classified nuclear warfare project. Foll owing declassification of the project it was evaluated as a cytoprotective agent against toxicity of the alkylating drugs and cisplatin. In fact, pret reatment with amifostine was well tolerated and reduced the cumulative hema tologic, renal and neurological toxicity associated with cisplatin, cycloph osphamide 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 chemotherapeu tics, 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 inclu des data published or under publication by the authors as full papers or cl inical protocols. Articles and abstracts published in Journals covered by M edline constitute the other source of information. State of the art and Perspectives. Amifostine, formerly known as WR-2721, i s an organic thiophosphate that was developed to protect normal tissues sel ectively against the toxicities of chemotherapy and radiation. Amifostine i s a pro-drug that is dephosphorylated at the tissue site to its active meta bolite by alkaline phosphatase. Differences in the alkaline phosphatase con centrations of normal versus tumor tissues can result in greater conversion of amifostine in normal tissues. Once inside the cell the free thiol provi des an alternative target to DNA and RNA for the reactive molecules of alky lating or platinum agents and acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation and some chemotherapies. Preclinica l animal studies demonstrated that the administration of amifostine protect ed against a variety of chemotherapy-related toxicities including cisplatin -induced nephrotoxicity, cisplatin-induced neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity, and the cytotoxicities (includin g cardiotoxicity) induced by doxorubicin and related chemotherapeutic agent s. 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 toss of anti tumor activity. Multiple phase I studies were carried out with amifostine i n combination with chemotherapy for various neoplasms. Appropriate doses of amifostine resulted to be 740-910 mg/m(2) in a single dose regimen, and 34 0 mg/m(2) in a multiple dose regimen. Amifostine afforded not only hematolo gic 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 amif ostine. in brief, amifostine gives hematologic protection from cyclophospha mide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and per ipheral nerve protection from cisplatin; mucosa, skin, and salivary gland f rom radiotherapy. In phase I/II studies these properties have been confirme d, together with a generally good tolerability of the drug, hypotension bei ng the most common side effect. It has been observed that amifostine possib ly enhances the anti-tumor effect of carboplatin, nitrogen mustard, melphal an, and cisplatin combined with 5-FU or vinblastine. For ail these characte ristics, amifostine is at present broadly used as supportive treatment duri ng chemotherapy, in lymphomas and solid tumors, and its spectrum of possibl e applications is enlarging. As data have been provided indicating that ami fostine stimulates hematopoiesis, it has been proposed as a possible therap eutic agent in myelodysplasia, in which most clinical complications are rel ated to cytopenia. Several trials have been performed and are at present on -going with the purpose of elucidating the real efficacy of amifostine in r estoring effective hemopoieisis. The first observations reported are genera lly in agreement, indicating a partial response to amifostine, especially i n low-risk MDS. Although synthesized several years ago, amifostine has ente red into clinical use only recently. Its broad cytoprotective effects seem beneficial, particularly in view of the widespread and increasing applicati on 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 neu tropenia 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 pa rtial responses have been reported, in the near future the real significanc e of this compound will be clarified thanks to large and complete clinical trials, and its importance finally discussed and defined. (C) 1999, Ferrata Storti Foundation.