The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine.

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Capizzi RL

The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine.

Semin Oncol. 1999 Apr;26(2 Suppl 7):3-21.

PubMed ID

10348255 [ View in PubMed

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Abstract

Administered before cytotoxic chemotherapy or radiation, the aminothiol, amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA), provides broad-spectrum cytoprotection of various normal tissues without attenuating antitumor 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. In contrast, uptake into tumor tissue is slow to negligible. Pretreatment with amifostine provides protection of normal tissues from the cytotoxic effects of alkylating agents, organoplatinums, anthracyclines, taxanes, and radiation. Additionally, the mutagenic and carcinogenic effects of these modalities are also attenuated. Preclinical studies show significant protection of marrow progenitor cells. Synergistic effects in marrow recovery are noted with the sequential use of amifostine and granulocyte colony-stimulating factor. Protection of kidneys and neural tissues from cisplatin toxicity has been shown, as well as protection of the heart, intestinal crypt cells, and pulmonary tissues from chemotherapy and radiation, and vasculoconnective and musculoconnective tissue in an irradiated field. Comparative in vitro and in vivo studies using murine and human tumor xenografts show no protection of antitumor effects of these same therapies despite the protection of normal organs. The unique preclinical profile of amifostine serves as the basis for the clinical development program for this new broad-spectrum cytoprotective agent.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Amifostine	Alkaline phosphatase, germ cell type	Protein	Humans	Yes	Inducer	Details