Zeng Y T, Huang S Z, Ren Z R, Lu Z H, Zeng F Y, Schechter A N, Rodgers G P
Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, China.
Br J Haematol. 1995 Jul;90(3):557-63. doi: 10.1111/j.1365-2141.1995.tb05584.x.
The beta-thalassaemias represent a heterogenous group of diseases resulting from decreased erythroid beta-globin mRNA expression and imbalanced alpha/beta-globin chain synthesis which are manifest clinically by ineffective erythropoiesis and excessive haemolysis. Increasing levels of haemoglobin F (HbF) by pharmacological agents has been proposed to ameliorate the severity of the disease by improving the balance in globin chain synthesis. Hydroxyurea (HU), as an effective agent with low toxicity for activating gamma-globin gene, has been shown to enhance HbF synthesis in experimental animals and in patients with sickle cell anaemia. However, previous trials of HU in beta-thalassaemia patients are ambiguous, with a small number having increased HbF synthesis. In a recent study of HU effects in Chinese beta-thalassaemia patients we unexpectedly found that two unrelated patients with beta-thalassaemia intermedia demonstrated an improvement in the effectiveness of erythropoiesis reflected by an increase in haemoglobin concentration (from 4.1 to 6.3 g/dl, patient 1; from 6.5 to 9.7 g/dl, patient 2) and in red cell volume (from 68 to 104 fl, patient 1; from 68 to 85 fl, patient 2) after a period of excess of 300d of low-dosage HU treatment. These effects, however, appear to be due to increased beta-globin biosynthesis, because the percentage of HbF decreased in each patient as total Hb increased. This was reflected by changes in the beta/alpha ratio (from 0.301 to 0.581, patient 1; from 0.348 to 0.487, patient 2) with minimal changes in gamma-globin biosynthesis. We conclude that in addition to its known effects in stimulating gamma-globin production, hydroxyurea may have a more general role in augmenting globin synthesis, including beta-globin in some thalassaemia intermedia patients who maintain the capacity to express normal beta-globin chains.
β地中海贫血是一组异质性疾病，由红系β珠蛋白mRNA表达降低和α/β珠蛋白链合成失衡所致，临床上表现为无效造血和过度溶血。有人提出通过药物提高血红蛋白F（HbF）水平，以改善珠蛋白链合成平衡，从而减轻疾病严重程度。羟基脲（HU）作为一种激活γ珠蛋白基因的低毒有效药物，已被证明可在实验动物和镰状细胞贫血患者中增强HbF合成。然而，先前在β地中海贫血患者中进行的HU试验结果并不明确，只有少数患者的HbF合成增加。在最近一项关于HU对中国β地中海贫血患者影响的研究中，我们意外地发现，两名无关的中间型β地中海贫血患者在接受超过300天的低剂量HU治疗后，红细胞生成有效性有所改善，表现为血红蛋白浓度升高（患者1从4.1g/dl升至6.3g/dl；患者2从6.5g/dl升至9.7g/dl）和红细胞体积增大（患者1从68fl升至104fl；患者2从68fl升至85fl）。然而，这些效果似乎是由于β珠蛋白生物合成增加所致，因为随着总血红蛋白增加，每名患者的HbF百分比均下降。这表现为β/α比值的变化（患者1从0.301变为0.581；患者2从0.348变为0.487），而γ珠蛋白生物合成变化极小。我们得出结论，除了其刺激γ珠蛋白生成的已知作用外，羟基脲可能在增强珠蛋白合成方面具有更广泛的作用，包括在一些仍有能力表达正常β珠蛋白链的中间型地中海贫血患者中增强β珠蛋白合成。
