Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production.
Initial alterations in fetal hemoglobin (HbF) production among eight sickle cell anemia subjects treated with hydroxyurea (Hu) are summarized. Four of these subjects had been previously treated with 5-azacytidine (5-aza). All subjects treated with Hu (50 mg/kg/d for three to five days) had suppression of their total reticulocyte counts by seven days, whereas the four subjects previously treated with 5-aza (2 mg/kg/d for three to five days) had increased reticulocyte counts at day 7. The effect of Hu on increasing the number of HbF-containing reticulocytes (F reticulocytes) is extremely variable, ranging from ten-to less than onefold differences in maximal posttherapy v pretherapy levels. Recovery from marrow suppression did not result in greater than twofold increases in F reticulocyte counts. Mean day 7 F reticulocyte levels in the four subjects treated with both Hu and 5-aza were 4.1 X 10/microL and 15.4 X 10(4)/microL, respectively. Among Hu-treated subjects, increased F reticulocyte production was correlated with low serum creatinine levels and rapid removal of Hu from the plasma. Furthermore, suppression of CFU-E colony formation on day 2 of therapy with Hu was inversely correlated with maximal F reticulocyte response. We conclude that where Hu treatment results in marrow toxicity (decreased reticulocyte counts, decreased CFU-E colony formation) HbF production is less likely to increase. Those sickle cell anemia subjects with minimal renal dysfunction (serum creatinine level, greater than 1.0 mg/dL) exhibit the most cytotoxicity and least F reticulocyte response to Hu.
Dover
G J
GJ
Humphries
R K
RK
Moore
J G
JG
Ley
T J
TJ
Young
N S
NS
Charache
S
S
Nienhuis
A W
AW
D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000378:metabolism*; D001374:Azacitidine / Q000494:pharmacology; D004920:Erythropoiesis / Q000187:drug effects*; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D006918:Hydroxyurea / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D012156:Reticulocytes / Q000187:drug effects
D005319:Fetal Hemoglobin; D001374:Azacitidine; D006918:Hydroxyurea