Amifostine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as a radioprotector and cytotoxic chemoprotector

Abstract

Amifostine (WR-2721) was originally developed as a radioprotective agent. In animals, it protects normal tissues from the damaging effects of irradiation and, as shown in more recent studies, of several cytotoxic agents. Protection of tumours is generally reduced compared with that of normal tissues in animals, suggesting that amifostine may increase the therapeutic window of cytotoxic therapies. Clinical data concerning amifostine suggest that cytotoxic chemotherapy-induced haematological toxicity and cisplatin-induced neurotoxicity, nephrotoxicity and ototoxicity are decreased upon administration of amifostine prior to cytotoxic drugs. Similarly, amifostine reduces damage to normal tissues caused by radiotherapy. Available data show that this protection is achieved without adversely affecting tumour response or patient survival. In 1 large trial, the reduction in cyclophosphamide- and cisplatin-related toxicities manifested as a decrease in the incidence and severity of neutropenia-related fever and sepsis and in the number of patients with ovarian cancer who discontinue therapy before completion of treatment, thus improving the tolerability of this antineoplastic regimen. In addition, the incidences of cisplatin-induced nephro- and neurotoxicity were reduced. Increased doses of cytotoxic therapy have also been administered when amifostine was given prior to therapy, which may increase tumour response. The predominant adverse effect associated with amifostine are hypotension, nausea and vomiting, somnolence and sneezing. Thus, amifostine is likely to be a useful adjuvant to the treatment of patients with malignancy, particularly those receiving cyclophosphamide plus cisplatin. discontinued therapy before completion of treatment, thus improving the tolerability of this antineoplastic regimen. In addition, the incidences of cisplatin-induced.