5-AZACYTIDINE STIMULATES FETAL HEMOGLOBIN-SYNTHESIS IN ANEMIC BABOONS
5-AZACYTIDINE STIMULATES FETAL HEMOGLOBIN-SYNTHESIS IN ANEMIC BABOONS
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DOI：
10.1073/pnas.79.14.4428
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发表时间：
1982-01-01
期刊：
影响因子：
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通讯作者：
ZWIERS, D
中科院分区：
文献类型：
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作者：
DESIMONE, J;HELLER, P;ZWIERS, D
在尝试通过红细胞生成应激以外的方式刺激狒狒中的Hb F合成时，考虑了抑制DNA中CpG序列甲基化的药剂可能有效的可能性。5-氮杂胞苷，一种不能被甲基化的胞嘧啶类似物，就是这样一种试剂。红细胞压积维持在约20%的出血患者在12天内每天静脉注射药物（6 mg/kg）10次。这些动物中的Hb F水平在该方案的第5天开始增加，并且在药物末次给药后5-7天达到峰值水平，其比仅通过出血产生的水平高6-30倍。在先前确定为遗传高或低Hb F应答者的动物中，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 mg/kg 5-氮杂胞苷产生最大Hb F增加。药物不会增加含Hb F细胞（F细胞）的百分比（数量），超过单独出血所达到的最大数量，因此其主要作用是增加每个F细胞的Hb F。Hb F合成可以被药物调节到如此高的程度这一发现可能具有治疗意义，例如，镰状细胞性贫血，其中刺激Hb F合成可防止镰状化。
In an attempt to stimulate Hb F synthesis in baboons by means other than erythropoietic stress, the possibility that an agent that inhibits methylation of CpG sequences in DNA may be effective was considered. 5-Azacytidine, a cytosine analog that cannot be methylated, is such an agent. Animals whose packed red cell volume was maintained at .apprx. 20% by bleeding were given 10 daily i.v. 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 increase 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.