HYDROXYUREA ENHANCES FETAL HEMOGLOBIN PRODUCTION IN SICKLE-CELL-ANEMIA
HYDROXYUREA ENHANCES FETAL HEMOGLOBIN PRODUCTION IN SICKLE-CELL-ANEMIA
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DOI：
10.1172/jci111464
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发表时间：
1984-01-01
影响因子：
15.9
通讯作者：
NATHAN, DG
中科院分区：
文献类型：
--
作者：
PLATT, OS;ORKIN, SH;NATHAN, DG
羟基脲是一种广泛使用的细胞毒性/细胞抑制剂，不影响 DNA 碱基的甲基化，可增加贫血猴中胎儿血红蛋白的产生。为了确定其对镰状细胞性贫血的作用，我们对两名患者进行了总共 4 个 5 天的疗程（每天 50 mg/kg，分为 3 次口服剂量）进行治疗。每个疗程，胎儿网织红细胞在48-72小时内增加，在7-11天达到峰值，并在18-21天下降。在患者 I 中，胎儿网织红细胞在三个连续疗程中从 16.0 +/- 2.0% 增加到峰值 37.7 +/- 1.2、40.0 +/- 2.0 和 32.0 +/- 1.4%。在患者 II 中，增加值从 8.7 +/- 1.2 增加到 50.0 +/- 2.0%。患者 I 的胎儿血红蛋白从 7.9% 增加到 12.3%，患者 II 的胎儿血红蛋白从 5.3% 增加到 7.4%。患者 I 的血红蛋白从 9.0 g/dl 增加到 10.5 g/dl，患者 II 从 6.7 g/dl 增加到 9.9 g/dl。每 7-20 天额外的单日羟基脲疗程将患者 I 的胎儿血红蛋白维持在 10.8-14.4%，并且总血红蛋白在另外 60 天中维持在 8.7-10.8 g/dl。最低粒细胞绝对计数为1,600/mm3；最低血小板计数为390,000/mm3。每个红细胞爆裂集落形成单位 (BFU-E) 衍生集落细胞的胎儿血红蛋白量没有变化，但每个 BFU-E 衍生集落的细胞数量增加。虽然体外红系骨髓细胞 DNA 合成检查显示甲基胞苷掺入没有减少，但 DNA 的 Eco RI + Hpa II 消化显示治疗后体内发生了 γ 基因的低甲基化。这一观察结果表明，羟基脲是治疗镰状细胞性贫血的潜在有用药物，并且γ-珠蛋白基因的去甲基化伴随着γ-珠蛋白基因活性的增加。
Hydroxyurea, a widely used cytotoxic/cytostatic agent that does not influence methylation of DNA bases, increases fetal hemoglobin production in anemic monkeys. To determine its effect in sickle cell anemia, we treated two patients with a total of four, 5-d courses (50 mg/kg per d, divided into three oral doses). With each course, fetal reticulocytes increased within 48-72 h, peaked in 7-11 d, and fell by 18-21 d. In patient I, fetal reticulocytes increased from 16.0 +/- 2.0% to peaks of 37.7 +/- 1.2, 40.0 +/- 2.0, and 32.0 +/- 1.4% in three successive courses. In patient II the increase was from 8.7 +/- 1.2 to 50.0 +/- 2.0%. Fetal hemoglobin increased from 7.9 to 12.3% in patient I and from 5.3 to 7.4% in patient II. Hemoglobin of patient I increased from 9.0 to 10.5 g/dl and in patient II from 6.7 to 9.9 g/dl. Additional single-day courses of hydroxyurea every 7-20 d maintained the fetal hemoglobin of patient I t 10.8-14.4%, and the total hemoglobin at 8.7-10.8 g/dl for an additional 60 d. The lowest absolute granulocyte count was 1,600/mm3; the lowest platelet count was 390,000/mm3. The amount of fetal hemoglobin per erythroid burst colony-forming unit (BFU-E)-derived colony cell was unchanged, but the number of cells per BFU-E-derived colony increased. Although examination of DNA synthesis in erythroid marrow cells in vitro revealed no decreased methylcytidine incorporation, Eco RI + Hpa II digestion of DNA revealed that hypomethylation of gamma-genes had taken place in vivo after treatment. This observation suggests that hydroxyurea is a potentially useful agent for the treatment of sickle cell anemia and that demethylation of the gamma-globin genes accompanies increased gamma-globin gene activity.Images