Tetrahydrouridine, cytidine analogues, and hemoglobin F.

Abstract

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.

• Authors: J DeSimone, P Heller, R E Molokie, L Hall, D Zwiers
• Journal: American journal of hematology (Am J Hematol) Vol. 18 Issue 3 Pg. 283-8 (Mar 1985) ISSN: 0361-8609 [Print] United States
• PMID: 2579548 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Tetrahydrouridine
• Decitabine
• Globins
• Fetal Hemoglobin
• Cytidine Deaminase
• Azacitidine
• Uridine

Topics

• Agranulocytosis (etiology)
• Animals
• Azacitidine (analogs & derivatives, pharmacology, toxicity)
• Cytidine Deaminase (antagonists & inhibitors)
• Decitabine
• Fetal Hemoglobin (biosynthesis, genetics)
• Gene Expression Regulation (drug effects)
• Globins (genetics)
• Granulocytes (enzymology)
• Papio
• Tetrahydrouridine (pharmacology)
• Uridine (analogs & derivatives)