Amifostine does not preferentially stimulate the growth of residual polyclonal progenitor cells in myelodysplastic syndromes

Abstract 

Amifostine is a phosphorylated aminothiol that has besides anti-oxidative and cytoprotective properties, also survival- and growth-promoting effects on hematopoietic progenitor cells. Clinical studies have demonstrated that infusions with amifostine are able to increase erythro-, myelo-, and thrombopoiesis in some patients with myelodysplastic syndromes (MDS). Since clonal and non-clonal progenitors can coexist in early phase MDS, we have studied if amifostine exerts a selective growth-promoting effect on clonal or non-clonal cells. For this purpose, purified CD34⁺ marrow progenitors from nine female MDS patients were grown in short- and long-term cultures. Clonality was studied on individual colonies using polymorphisms in the human androgen receptor assay (HUMARA) locus. Three patients had growth of residual non-clonal progenitors at baseline. Continuous exposure to 100nM amifostine exerted a growth-promoting effect on progenitors in 50% of the patients. HUMARA patterns of individual colony-forming unit granulocyte macrophage (CFU-GM; 5/9) and 5 week long-term culture-initiating cells (LTC-IC; 2/9) were compared without and with amifostine exposure. We did not observe preferential stimulation of clonal or non-clonal progenitors. Based on these results, the stimulation of committed and immature progenitor growth in MDS by amifostine, is non-selective and does not favor nor suppress the growth of residual non-clonal cells.

Abbreviations: ATG, antithymocyte globulin, BFU-E, burst forming unit-erythroid, CFC, colony-forming cell, CFU-GM, colony-forming unit granulocyte macrophage, CFU-GEMM, colony-forming unit granulocyte erythroid monocyte megakaryocyte, DNA, deoxyribonucleic acid, EPO, erythropoietin, FAB, French–American–British, FAM, 6-carboxyfluorescein, G-CSF, granulocyte-colony stimulating factor, HUMARA, human androgen receptor assay, IL-3, interleukin-3, LTBMC, long-term bone marrow culture, LTC-IC, long-term culture-initiating cells, MDS, myelodysplastic syndromes, NF, nuclear factor, PBS, phosphate buffered saline, PCR, polymerase chain reaction, RA, refractory anemia, RARS, refractory anemia with ringed sideroblasts, RAEB, refractory anemia with excess of blasts, RAEB-t, refractory anemia with excess of blasts in transformation, SCF, stem cell factor

Keywords: Myelodysplasia, Amifostine, HUMARA, Hematopoietic progenitor, Short-term culture, Long-term culture