Tetrahydrouridine, cytidine analogues, and hemoglobin F.
5-Azacytidine (azaC) has previously been shown to raise Hb F levels in the repeatedly phlebotomized baboon (PCV: around 20%). The administration of tetrahydrouridine (THU), an inhibitor of the enzymatic conversion of azaC to 5-azauridine, made it possible to reduce the amount of azaC and also of 2-deoxy-5-azacytidine (d-azaC) by more than 90% and still achieve maximal Hb F elevations. However, the granulocytopenia, usually occurring after 5-azaC, was not altered by the lowering of the dosages in the presence of THU. Thus, the granulocytopenia is not due to 5-azauridine or other catabolic products resulting from deamination. It is also unlikely that it is caused by a direct influence of azaC on RNA since d-azaC also causes granulocytopenia. The persistence of reticulocytosis throughout the treatment with azaC or d-azaC makes it appear likely that the observed increase in Hb F levels to more than 60% of total hemoglobin is not due to a cytotoxic effect on erythropoiesis resulting in a shift of cell populations toward greater immaturity, but to a direct influence of the drug on the regulation of gamma globin chain production.
DeSimone
J
J
Heller
P
P
Molokie
R E
RE
Hall
L
L
Zwiers
D
D
D000380:Agranulocytosis / Q000209:etiology; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000633:toxicity; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors; D000077209:Decitabine; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005914:Globins / Q000235:genetics; D006098:Granulocytes / Q000201:enzymology; D010215:Papio; D013767:Tetrahydrouridine / Q000494:pharmacology*; D014529:Uridine / Q000031:analogs & derivatives*
D013767:Tetrahydrouridine; D000077209:Decitabine; D005914:Globins; D005319:Fetal Hemoglobin; D003564:Cytidine Deaminase; D001374:Azacitidine; D014529:Uridine