Cytoprotection in Chemo – and Radiotherapy with Amifostine (Ethyol): A New Strategy in Oncology

Abstract

Amifostine (WR-2721, Ethyol), a phosphorylated aminothiol, was originally developed as a radioprotective agent. Since numerous preclinical studies showed that, following dephos-phorylation to the active thiol WR-1065, amifostine selectively protected normal tissues from the damaging effects of irradiation and of several cytotoxic agents without reducing the anti-tumor activity, an intensive clinical development in chemo- and radiotherapy studies was performed. In clinical trials, amifostine proved to be an effective cytoprotector in patients receiving treatment with antineoplastic agents or irradiation. It significantly reduced the incidence and severity of acute, cumulative and delayed toxicities associated with antineoplastic therapy, allowing better patient tolerance of current regimens and possible dose escalation. This protection is achieved without any reduction in the antitumor efficacy. Thus, the integration of amifostine into oncological regimens represents a new ‘preventive’ strategy for a more tolerable and selective therapy.

Preclinical and clinical aspects on the use of amifostine as chemoprotectorin neuroblastoma patients

“…Amifostine is a phosphorylated aminothiol that emerged from a United States army nuclear warfare research project in the 1960s as the lead radioprotective compound [1]. Subsequently, amifostine turned out to be a potent protector of normal tissues during radio-and chemotherapy [1][2][3][4][5][6][7][8].…”

“…At the same time, amifostine did not reduce the antiproliferative potential of chemotherapeutic drugs in most experimental systems [1][2][3][4]9]. In clinical studies, no protective effect on the tumor was observed as assessed by response rates or survival of patients [1][2][3][4][5][6][7][8].…”

“…Amifostine is a prodrug, which is converted to a free thiol compound by the enzyme alkaline phosphatase, which is bound to the plasma membrane [1,3,9]. The active metabolite, WR-1065, is transported into the cells and exerts its effect as a scavenger of free radicals generated by the action of cytotoxic drugs.…”