Amifostine protects primitive hematopoietic progenitors against chemotherapy cytotoxicity

Controlled clinical trials indicate that amifostine (WR-2721, Ethyol) confers protection from the cumulative hematologic toxicities associated with alkylating agents and organoplatinums. To determine whether amifostine protects primitive hematopoietic progenitors from the cytotoxicity of functionally diverse antineoplastics, formation of the multipotent hematopoietic progenitors colony-forming units-granulocyte-erythroid, macrophage, megakaryocyte (CFU-GEMM) and erythroid burst-forming units (BFU-E) was evaluated using a clonogenic progenitor inhibition assay. Bone marrow mononuclear cells from normal donors were subjected to a 15-minute exposure of medium, amifostine (500 micromol/L), or WR-1065 (100 micromol/L at concentrations approximating peak plasma levels, washed twice, then treated with the antineoplastic for 1 to 6 hours. Colony growth was scored after 14 days of incubation. Amifostine conferred protection against a broader range of antineoplastics than did WR-1065. Amifostine protected CFU-GEMM against cytotoxicity from daunorubicin, mitoxantrone, and paclitaxel (range, 1.29- to 9.57-fold) (P < .05) but did not afford protection against cisplatin, diaziquone, or thiotepa. Similarly, amifostine protected BFU-E against toxicity from doxorubicin, mitoxantrone, paclitaxel, cisplatin, and diaziquone, yielding 3.4- to 65-fold greater colony recovery compared with controls. The high degree of cytoprotection afforded by amifostine derived largely from stimulation of progenitor growth at sublethal chemotherapy concentrations. In the absence of antineoplastic exposure, preincubation with amifostine or WR-1065 enhanced the colony-forming capacity of bone marrow progenitors from six normal donors, increasing recovery of CFU-GEMM and BFU-E up to sevenfold. We conclude that amifostine protects primitive hematopoietic progenitors from a wide range of antineoplastics. This broad hemoprotective effect derives in part from inherent trophic effects on progenitor growth and survival.