Mechanism of Hb F stimulation by S-stage compounds. In vitro studies with bone marrow cells exposed to 5-azacytidine, Ara-C, or hydroxyurea.
The in vitro effect of S-stage-specific drugs on the fetal hemoglobin (Hb F) potential of erythroid precursors and progenitors was tested by exposing bone marrow cells to 5-aza-2'-deoxycytidine, Ara-C, or hydroxyurea in suspension cultures and reculturing the cells in drug-free clonal cultures. Analysis of Hb F in the erythroblasts present at the end of suspension cultures and in the erythroid colonies formed from treated progenitors showed that 1 X 10(-9)-5 X 10(-8) M 5-aza-2'-deoxycytidine produced a concentration-related increase in the proportion of Hb F-positive erythroblasts, of Hb F-positive erythroid CFU (CFUe) colonies, and at the higher doses used, an increased Hb F expression in erythroid burst-forming unit (BFUe)-derived colonies. Preincubation of bone marrow cells with Ara-C produced significant megaloblastic changes by the end of the 2-d incubation and increased the proportion of Hb F-positive erythroblasts, CFUe colonies, and e-clusters, but BFUe-derived progeny was unaffected. Hydroxyurea failed to produce significant changes in Hb F at the range of concentrations used. The data raise the possibility of more than one mechanism underlying the stimulation of Hb F by S-stage drugs.
D001374:Azacitidine / Q000494:pharmacology*; D001854:Bone Marrow Cells; D003561:Cytarabine / Q000494:pharmacology*; D004920:Erythropoiesis / Q000187:drug effects*; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D066298:In Vitro Techniques; D007399:Interphase / Q000187:drug effects
D003561:Cytarabine; D005319:Fetal Hemoglobin; D001374:Azacitidine; D006918:Hydroxyurea