DeSimone J, Heller P, Hall L, Zwiers D
Proc Natl Acad Sci U S A. 1982 Jul;79(14):4428-31. doi: 10.1073/pnas.79.14.4428.
In an attempt to stimulate Hb F synthesis in baboons by means other than erythropoietic stress, we considered the possibility that an agent that inhibits methylation of CpG sequences in DNA may be effective. 5-Azacytidine, a cytosine analogue that cannot be methylated, is such an agent. Animals whose packed red cell volume was maintained at approximately 20% by bleeding were given 10 daily intravenous injections of the drug (6 mg/kg) in 12 days. Hb F levels in these animals started to increase on day 5 of this regimen and peak levels, which were 6-30 times higher than those produced by bleeding alone, occurred 5-7 days after the last dose of the drug. In animals previously identified as genetically "high" or "low" Hb F responders, the maximal Hb F levels were 70-85% and 35-40% respectively. In dose-response studies 5-azacytidine given daily at 3-4 mg/kg produced maximal Hb F increases. The drug did not correlate the percentage (number) of Hb F-containing cells (F cells) beyond the maximal number achieved by bleeding alone and thus its main effect was to increase Hb F per F cell. The finding that Hb F synthesis can be modulated to such a high degree by a drug may have therapeutic implications--e.g., in sickle cell anemia, in which stimulation of Hb F synthesis may prevent sickling.
为了通过除红细胞生成应激以外的其他方法刺激狒狒体内的胎儿血红蛋白（Hb F）合成，我们考虑了一种可能性，即一种抑制DNA中CpG序列甲基化的药物可能有效。5-氮杂胞苷，一种不能被甲基化的胞嘧啶类似物，就是这样一种药物。通过放血使红细胞压积维持在约20%的动物，在12天内每天静脉注射该药物（6毫克/千克），共注射10次。这些动物的Hb F水平在该方案的第5天开始升高，在最后一剂药物注射后5 - 7天达到峰值水平，该峰值水平比仅通过放血产生的水平高6 - 30倍。在先前被确定为遗传上“高”或“低”Hb F反应者的动物中，最大Hb F水平分别为70 - 85%和35 - 40%。在剂量反应研究中，每天给予3 - 4毫克/千克的5-氮杂胞苷可使Hb F达到最大增加。该药物与含Hb F细胞（F细胞）的百分比（数量）之间的关系，不会超过仅通过放血所达到的最大数量，因此其主要作用是增加每个F细胞中的Hb F。药物能够将Hb F合成调节到如此高的程度这一发现可能具有治疗意义，例如在镰状细胞贫血中，刺激Hb F合成可能预防镰变。
