On the mechanism of Hb F elevations in the baboon by erythropoietic stress and pharmacologic manipulation.
Maximal fetal hemoglobin (Hb F) elevations in the baboon subsequent to phenyl hydrazine-induced hemolytic anemia, bleeding, bleeding plus hydroxyurea (HU), or cytosine arabinoside were two to three times lower than those achieved with bleeding plus 5-azacytidine (azaC). Because, in the baboon, maximal elevations in F cell numbers occurred with bleeding alone, changes in the levels of Hb F in hemolysates and in Hb F per F cell could be considered to be due to the administered drugs. Erythropoietic toxicity of azaC was minimal, making it unlikely that the marked elevations of Hb F were due to shifts in the population of erythroid progenitors and precursors and more likely that they were related to a biochemical effect of the drug on DNA. The data indicate marked DNA hypomethylation. This was also found to be associated, but to a much lesser extent, with the modest Hb F elevations after bleeding, hemolysis, and treatment with HU. This drug had greater erythroid toxicity than azaC, and it appeared that the Hb F elevations occurred mainly on the rebound from the early cytotoxicity. The explanation of the molecular DNA changes with this drug and in erythropoietic stress alone remains unknown.
Lavelle
D
D
DeSimone
J
J
Heller
P
P
Zwiers
D
D
Hall
L
L
D000743:Anemia, Hemolytic / Q000097:blood* / Q000139:chemically induced; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects*; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006470:Hemorrhage / Q000097:blood*; D006918:Hydroxyurea / Q000494:pharmacology; D007958:Leukocyte Count / Q000187:drug effects; D008745:Methylation; D009693:Nucleic Acid Hybridization / Q000187:drug effects; D010215:Papio; D012156:Reticulocytes / Q000187:drug effects
D003561:Cytarabine; D004247:DNA; D005319:Fetal Hemoglobin; D001374:Azacitidine; D006918:Hydroxyurea