The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine (Ethyol®)

Abstract

Administered prior to cytotoxic chemotherapy or radiation, the aminothiol amifostine provides broad-spectrum cytoprotection of various normal tissues without attenuating antitumour response. The basis for the selectivity of action resides in the anabolism of amifostine at the normal tissue site by membrane-bound alkaline phosphatase. Dephosphorylation to the free thiol, WR-1065, is followed by rapid uptake into normal tissues by a carrier mediated, facilitated diffusion process; in contrast, uptake into tumour tissue is slow to negligible. Preclinical studies have shown that pretreatment with amifostine provides protection of normal tissues from the cytotoxic effects of alkylating agents, organoplatinums, anthracyclines, taxanes and radiation. Normal tissues protected include bone marrow, kidney, neural tissues, the heart, intestinal crypt cells and pulmonary tissues. Additionally, the mutagenic and carcinogenic effects of these modalities are also attenuated. With respect to bone marrow, preclinical studies have shown significant protection of progenitor cells that give rise to the red and white cells and platelets. Comparative in vitro and in vivo studies using murine and human tumour xenografts show no decrease of antitumour effects of these same therapies despite the protection of normal organs. The unique preclinical profile of amifostine serves as a model for the clinical development programme for this important new broad-spectrum cytoprotective agent.