Details

Autor(en) / Beteiligte

• Wang, Min
• Tang, Delia C.
• Liu, Wenli
• Chin, Kyung
• Zhu, Jianqion G.
• Fibach, Eitan
• Rodgers, Griffin P.

Titel

Hydroxyurea exerts bi‐modal dose‐dependent effects on erythropoiesis in human cultured erythroid cells via distinct pathways

Ist Teil von

• British journal of haematology, 2002-12, Vol.119 (4), p.1098-1105

Ort / Verlag

Oxford, UK: Blackwell Science Ltd

Erscheinungsjahr

2002

Link zum Volltext

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Hydroxyurea (HU) has been shown to increase the proportion of fetal haemoglobin (HbF) in most sickle cell patients. A low‐dosage regimen increased total haemoglobin (Hb) levels in some thalassaemia intermedia patients by preferentially increasing β‐globin biosynthesis. To further characterize these apparent dose‐dependent effects of HU, we examined erythroid cells exposed to HU (5–100 µmol/l) in two‐phase liquid culture. Low doses (from 5 to 25 µmol/l) increased Hb levels by up to 2·7‐fold, and a high dose (100 µmol/l) increased Hb levels when added at d 3–6 of phase II, with no significant changes in response to HU during the late stage of phase II culture (≥ 9 d). HU exposure during d 0–3 of phase II culture increased the number of erythroid colonies to a maximum of fivefold at 5 µmol/l HU. GATA‐1 mRNA was downregulated at a high dose and GATA‐2 was dose dependently upregulated over a lower dosage range. Treatment with 100 µmol/l HU dramatically upregulated the death receptor DR‐5, caspase 3, as determined by cDNA microarray analysis. In contrast, 10 µmol/l HU modestly upregulated mRNA levels of the early growth response gene. Our results suggest that HU exerts concentration‐dependent effects on HbF production and erythropoiesis and that these two effects are mediated by distinct molecular mechanisms.