Loukopoulos D
First Department of Medicine, University of Athens, Laikon Hospital, Greece.
J Intern Med Suppl. 1997;740:43-8.
Re-activation of the fetal globin genes is the most realistic approach to correct the deranged pathophysiology of the haemoglobinopathies because the presence of gamma-chains can neutralize the toxic effects of the unbound alpha-globin chains in the beta-thalassaemias and inhibit the polymerization of Hb S in the sickle cell syndromes. Re-induction of fetal haemoglobin synthesis can be brought about either by direct activation of the respective promoter genes and possibly other positively acting elements, or by recruitment into proliferation and differentiation of a population of erythroid precursors which retain the gamma-chain synthesis programme but remain dormant in the bone marrow of the adult unless called up in cases of acute erythroid expansion. Examples of the first group include the butyric acid and derivatives and 5' azacytidine. The second group comprises erythropoietin and a series of cytostatics, with hydroxyurea as the main representative. The activity of most of the above agents has already been studied in cell cultures and animals and confirmed in several patients, both at the haematological and biochemical level as well as through their frank clinical improvement. However, application of these drugs at large is not yet justified because a series of questions concerning their long-term efficacy, the correct dosage and timing, their tolerance and toxicity, and the potential long-term dangers, including mutagenicity are still unresolved.
重新激活胎儿珠蛋白基因是纠正血红蛋白病紊乱病理生理过程最切实可行的方法，因为γ链的存在可中和β地中海贫血中未结合的α珠蛋白链的毒性作用，并抑制镰状细胞综合征中Hb S的聚合。胎儿血红蛋白合成的重新诱导可通过直接激活各自的启动子基因及可能的其他正向作用元件来实现，或者通过促使一群保留γ链合成程序但在成人骨髓中处于休眠状态的红系前体细胞进入增殖和分化过程来实现，除非在急性红系扩张情况下被激活。第一类的例子包括丁酸及其衍生物和5'氮杂胞苷。第二类包括促红细胞生成素和一系列细胞抑制剂，其中羟基脲是主要代表。上述大多数药物的活性已在细胞培养和动物实验中进行了研究，并在一些患者中得到证实，无论是在血液学和生化水平上，还是通过明显的临床改善。然而，大规模应用这些药物目前尚无充分理由，因为一系列关于它们的长期疗效、正确剂量和用药时间、耐受性和毒性以及潜在的长期风险（包括致突变性）的问题仍未解决。
