Rodgers G P
Laboratory of Chemical Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Semin Oncol. 1992 Jun;19(3 Suppl 9):67-73.
Hydroxyurea is one of several cytostatic agents that increase fetal hemoglobin (HbF) production in some patients with sickle-cell disease, although their mechanisms of action remain to be defined. We have studied the effects of hydroxyurea in several hospitalized patients with sickle-cell disease treated for 3 months, who were then maintained on outpatient therapy. Among hydroxyurea-treated patients, we found that about 75% respond with at least a twofold increase in the percentages of F reticulocytes and HbF. Among the responders, HbF levels increased twofold to 10-fold, with three patients achieving levels of 10% to 15%. Statistical analysis of the three cellular variables that determine HbF levels in patients with sickle-cell disease--namely, increased F-cell production, F-cell survival, and HbF/F cells--disclosed that HbF production, as measured by an increase in F reticulocytes, accounted for about 70% of the HbF elevation, with smaller contributions coming from augmentation of HbF/F cells and preferential survival of F cells. Four responders were re-treated with their optimal weekly hydroxyurea dose, given either in daily fractions or over 4 consecutive days, after a 1- to 3-month washout period. Greater HbF responses were attained with the optimal hydroxyurea dose than with the dose-regimen escalation, and usually occurred after a lag period. Furthermore, increases in HbF and F-cell levels were more rapid in patients receiving therapy on 4 out of 7 days rather than on a daily schedule. Our calculations show that the increases in HbF/F and F cells and the decrease in the fraction of dense cells during limited hydroxyurea administration should cause a significant improvement in intracellular sickle hemoglobin polymerization tendency. Controlled prospective trials are necessary to establish whether these effects lead to clinical benefit. Alternate schedules of hydroxyurea administration, or its use in conjunction with other means to elevate HbF or reduce mean cell hemoglobin concentration, may achieve greater inhibition of polymerization and thus be more likely to result in unequivocal amelioration of disease manifestations.
羟基脲是几种细胞抑制剂之一，可使一些镰状细胞病患者的胎儿血红蛋白（HbF）生成增加，尽管其作用机制尚待明确。我们研究了羟基脲对几名住院治疗3个月的镰状细胞病患者的影响，之后这些患者接受门诊治疗。在接受羟基脲治疗的患者中，我们发现约75%的患者出现反应，F网织红细胞和HbF百分比至少增加两倍。在有反应的患者中，HbF水平增加了两倍至十倍，三名患者的HbF水平达到了10%至15%。对决定镰状细胞病患者HbF水平的三个细胞变量进行统计分析，即F细胞生成增加、F细胞存活以及HbF/F细胞，结果显示，以F网织红细胞增加来衡量的HbF生成约占HbF升高的70%，HbF/F细胞增加和F细胞优先存活的贡献较小。四名有反应的患者在1至3个月的洗脱期后，以最佳的每周羟基脲剂量重新治疗，该剂量以每日分次给药或连续4天给药。与剂量递增方案相比，最佳羟基脲剂量能使HbF反应更大，且通常在一段延迟期后出现。此外，每周7天中有4天接受治疗的患者，其HbF和F细胞水平的增加比每日给药的患者更快。我们的计算表明，在有限的羟基脲给药期间，HbF/F和F细胞的增加以及致密细胞比例的降低应会显著改善细胞内镰状血红蛋白的聚合倾向。有必要进行对照前瞻性试验，以确定这些效应是否会带来临床益处。羟基脲给药的替代方案或将其与其他提高HbF或降低平均细胞血红蛋白浓度的方法联合使用，可能会对聚合产生更大的抑制作用，并因此更有可能明确改善疾病表现。
