Iyamu E W, Adunyah S E, Elford H L, Fasold H, Turner E A
Comprehensive Sickle Cell Center, Nashville, Tennessee 37208, USA.
Biochem Biophys Res Commun. 1998 Jun 29;247(3):759-64. doi: 10.1006/bbrc.1998.8534.
Trimidox (3,4,5-trihdroxybenzamidoxime) has been shown to reduce the activity of ribonucleotide reductase with accompanied growth inhibition and differentiation of mammalian cells. Hydroxyurea (HU) is the only ribonucleotide reductase inhibitor in clinical use for the treatment and management of sickle cell anemia, since this compound increases fetal hemoglobin (Hb F) production: a potent inhibitor of sickle hemoglobin (Hb SS) polymerization. However, the main limitations of HU is its lack of potency, myelosuppression and short half life. These studies investigated the effects of trimidox on the induction of hemoglobin and F-cells production in K562 erythroleukemia cells. Our study reveals that trimidox exhibits concentration dependent inhibitory effect on K562 cells with increase in benzidine positive normoblasts and F-cells production as well as morphological changes typical of erythroid differentiation. These findings provide the first evidence that the growth inhibitory differentiation of cells induced by trimidox enhance hemoglobin and F-cells production.
三甲氧苄二氨嘧啶（3,4,5-三羟基苯甲脒肟）已被证明可降低核糖核苷酸还原酶的活性，并伴随哺乳动物细胞的生长抑制和分化。羟基脲（HU）是临床上唯一用于治疗和管理镰状细胞贫血的核糖核苷酸还原酶抑制剂，因为这种化合物可增加胎儿血红蛋白（Hb F）的产生：镰状血红蛋白（Hb SS）聚合的有效抑制剂。然而，HU的主要局限性在于其效力不足、骨髓抑制和半衰期短。这些研究调查了三甲氧苄二氨嘧啶对K562红白血病细胞中血红蛋白诱导和F细胞产生的影响。我们的研究表明，三甲氧苄二氨嘧啶对K562细胞具有浓度依赖性抑制作用，同时联苯胺阳性的成红细胞和F细胞数量增加，以及出现典型的红系分化形态变化。这些发现首次证明，三甲氧苄二氨嘧啶诱导的细胞生长抑制性分化可增强血红蛋白和F细胞的产生。
