Hexamethylene bisacetamide (
HMBA;
NSC 95580) is a potent polar-planar differentiating agent of
leukemia and solid tumor cell lines in vitro at clinically achievable concentrations.
HMBA is currently being studied in patients with
myelodysplastic syndrome. Previous phase I trials have demonstrated that
HMBA produces hematologic toxicity in morphologically normal bone marrows of patients with solid
tumors. Because of concern that
HMBA may produce more severe myelotoxicity in patients with
myelodysplastic syndrome since these patients have limited hematopoietic reserves, we studied the effects of
HMBA on myelodysplastic and normal hematopoietic progenitors in vitro.
HMBA concentrations that are optimal for differentiation in vitro (2 to 5 mmol/L) and
HMBA concentrations that are being achieved in clinical trials (1 to 2 mmol/L) inhibited the growth of granulocyte-macrophage colony-forming units and erythroid burst-forming units from all 15 patients with
myelodysplastic syndrome and all 4 normal subjects,
HMBA did not induce proliferation of myelodysplastic or normal progenitors at any concentration; rather, it produced nearly identical inhibition of normal and myelodysplastic hematopoietic progenitors.
HMBA also produced quantitatively similar inhibition of clonogenic leukemic growth of two
myeloid leukemia cell lines. For a differentiating agent to be effective, it will likely have to either produce both differentiation and proliferation of abnormal hematopoietic progenitors or show selective inhibitory effects on abnormal as compared with normal progenitors. Although the mechanisms responsible for the antiproliferative effects of
HMBA cannot be determined from this study, similar inhibitory effects of
HMBA on normal and abnormal hematopoietic progenitors suggest that
HMBA may be of limited utility in producing and sustaining elevations of peripheral blood cell counts in patients with
myelodysplastic syndrome.