Tavakkoli Fatemeh, Nahavandi Masoud, Wyche Melville Q, Perlin Elliott
Department of Anesthesiology, College of Medicine, Howard University, Washington, DC 20060, USA.
Hematology. 2004 Feb;9(1):61-4. doi: 10.1080/1024533032000158869.
Hydroxyurea (HU), a chemotherapeutic agent, used increasingly in the treatment of sickle cell disease (SCD) stimulates the release of a tumor necrosis factor (TNF-alpha) from human macrophages in vitro and the concentration of TNF-alpha is greater than normal in subjects affected by SCD. It is widely accepted that HU may inhibit vaso-occlusive crisis (VOC) by stimulating the production of fetal hemoglobin (HbF) and nitric oxide (NO) in SCD; however, the beneficial effects of HU in vivo may be counteracted by the release of TNF-alpha and, in turn, the expression of a vascular cell adhesion molecule (VCAM-1) on leukocytes. Previous studies have shown that the severity of SCD increases with the leukocyte count. Therefore, we examined the relationship between plasma levels of TNF-alpha and HbF in SCD patients during steady-state (StSt) conditions (in the absence of VOC) and during VOC conditions after the acute administration of HU. Venous blood was collected in SCD patients over 6 h after administering a single dose of HU. Plasma TNF-alpha was found to be greater in SCD subjects than in reported normal adult controls (p<0.05). TNF-alpha in the StSt group was not significantly different than in the VOC group; however, the plasma TNF-alpha tended to greater in the VOC group (p>0.1). An increase in the HbF concentration after acute administration of HU (p<0.01) was not associated with a significant change in plasma TNF-alpha (p>0.1). Contrary to the results of in vitro studies, HU did not increase the plasma concentration of TNF-alpha. These findings suggest that a HU-induced increase in TNF-alpha does not contribute to VOC and sickle cell patients can be counseled that the HU-induced increase in TNF-alpha does not counteract the beneficial effects of HU in SCD.
羟基脲（HU）是一种化疗药物，越来越多地用于治疗镰状细胞病（SCD），它在体外可刺激人巨噬细胞释放肿瘤坏死因子（TNF-α），且SCD患者体内的TNF-α浓度高于正常水平。人们普遍认为，HU可能通过刺激SCD患者体内胎儿血红蛋白（HbF）和一氧化氮（NO）的产生来抑制血管闭塞性危机（VOC）；然而，HU在体内的有益作用可能会被TNF-α的释放以及白细胞上血管细胞黏附分子（VCAM-1）的表达所抵消。先前的研究表明，SCD的严重程度随白细胞计数增加而加重。因此，我们研究了SCD患者在稳态（StSt）条件下（无VOC）以及急性给予HU后处于VOC状态时血浆TNF-α水平与HbF之间的关系。在给予单剂量HU后6小时内收集SCD患者的静脉血。发现SCD患者血浆中的TNF-α高于报道的正常成人对照组（p<0.05）。StSt组的TNF-α与VOC组无显著差异；然而，VOC组的血浆TNF-α有升高趋势（p>0.1）。急性给予HU后HbF浓度升高（p<0.01），但血浆TNF-α无显著变化（p>0.1）。与体外研究结果相反，HU并未增加血浆TNF-α浓度。这些发现表明，HU诱导的TNF-α升高并不导致VOC，并且可以告知镰状细胞病患者，HU诱导的TNF-α升高不会抵消HU对SCD的有益作用。
