Influence of cell cycle phase-specific agents on simian fetal hemoglobin synthesis.
Influence of cell cycle phase-specific agents on simian fetal hemoglobin synthesis.
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细胞周期阶段特异性药物对猿胎儿血红蛋白合成的影响。
DOI：
10.1172/jci111918
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发表时间：
1985
期刊：
影响因子：
--
通讯作者：
D. Nathan
中科院分区：
文献类型：
--
作者：
N. Letvin;D. Linch;G. Beardsley;K. McIntyre;B. Miller;D. Nathan
为了确定细胞周期特异性药物对灵长类造血和胎儿血红蛋白产生的影响，对两只幼年食蟹猴（Macaca fasciculis）反复放血，以将其血红蛋白维持在约 6.5 g/dl，胎儿血红蛋白水平维持在 3-5%。然后在接下来的 200 天内以每天 100 mg/kg 的剂量进行 6 个单独的 5 天疗程的羟基脲，同时继续放血。这些羟基脲疗程逐渐将胎儿血红蛋白水平分别提高至 17% 和 18%。该药物对骨髓中未成熟红系祖细胞（BFU-E）的频率影响很小，但导致晚期祖细胞（CFU-E）的频率显着降低，并且网织红细胞计数短暂下降。羟基脲疗程结束后，F 细胞数量和胎儿血红蛋白水平在 4 周内降至基线。当用相同的羟基脲方案治疗时，两只未进行静脉切开术的对照动物未显示出可检测到的F细胞或胎儿血红蛋白的增加。然后对每只静脉切开的动物给予5天疗程的5-氮杂胞苷，剂量为每天8mg/kg。这产生了更严重但短暂的网织红细胞减少症、CFU-E/BFU-E 比率下降以及胎儿血红蛋白迅速增加至甚至高于单次 5 天羟基脲疗程（100 mg/kg/d）后观察到的水平。随后，给动物注射0.4 mg/kg单剂量的长春花碱，其减少网织红细胞和CFU-E的程度与羟基脲相同；然而，该剂量的长春花碱对血红蛋白 F (HbF) 的产生没有影响。相比之下，当以 0.2 mg/kg/d 的剂量向静脉切开的猴子施用 5 天疗程的长春花碱时，观察到长期网织红细胞减少症，随后出现剧烈的 F 细胞和 HbF 反应。随后使用两种不同的方案联合施用单剂量长春碱和 5 天疗程的羟基脲。当动物在 5 天羟基脲疗程的第一天接受长春花碱时，F 细胞反应是单独羟基脲治疗后的两倍。相比之下，当在羟基脲治疗的最后一天给予长春花碱时，F细胞反应的强度与单独羟基脲治疗后发生的相同，但上升的开始延迟了4天，并且HbF/F细胞反应要高得多。这些结果确立了灵长类动物模型中胎儿血红蛋白对细胞毒性药物反应的几个重要特征。该反应需要加速红细胞生成，并且之前会出现短暂的网织红细胞减少。当以足够的剂量和适当的时间表给予时，S期和M期特异性药物会产生反应。红细胞祖细胞通过 M 期似乎对于 S 期药物产生的效果的表达是必要的。给予细胞毒性药物诱导的胎儿血红蛋白反应发生在骨髓抑制后红细胞生成的恢复期间。
To determine the influence of cell cycle-specific agents on primate hematopoiesis and fetal hemoglobin production, two juvenile cynomolgus monkeys (Macaca fascicularis) were repeatedly bled to maintain their hemoglobins at approximately 6.5 g/dl and fetal hemoglobin levels at 3-5%. Six separate 5-d courses of hydroxyurea at 100 mg/kg per d were then administered over the next 200 d while phlebotomy was continued. These courses of hydroxyurea progressively raised the fetal hemoglobin levels to 17 and 18%, respectively. The drug had very little effect on the frequency of immature erythroid progenitors (BFU-E) in the bone marrow, but caused a marked reduction in the frequency of later progenitors (CFU-E) and a transient fall in the reticulocyte count. Following the courses of hydroxyurea, the number of F cells and the fetal hemoglobin level fell to base line over a period of 4 wk. Two control animals which were not phlebotomized showed no detectable increase in F cells or fetal hemoglobin when treated with the same regimen of hydroxyurea. A 5-d course of 5-azacytidine at 8 mg/kg per d was then given to each of the phlebotomized animals. This produced a more profound, albeit transient, reticulocytopenia, a fall in the CFU-E/BFU-E ratio, and a prompt increase in the fetal hemoglobin to levels even higher than were seen following a single 5-d course of hydroxyurea at 100 mg/kg/d. Subsequently, the animals were given a single dose of vinblastine at 0.4 mg/kg which reduced reticulocytes and CFU-E to the same extent as hydroxyurea; however, vinblastine at this dose had no effect on hemoglobin F (HbF) production. In contrast, when vinblastine was administered to the phlebotomized monkeys as a 5-d course at 0.2 mg/kg/d, prolonged reticulocytopenia followed by dramatic F cell and HbF responses were seen. Combinations of single dose vinblastine and a 5-d course of hydroxyurea were subsequently administered using two different schedules. When the animals received vinblastine on the first day of a 5-d course of hydroxyurea, the F cell response was double that seen following hydroxyurea treatment alone. In contrast, when vinblastine was administered on the final day of hydroxyurea treatment, the magnitude of the F cell response was the same as that which occurred following hydroxyurea treatment alone, but the onset of the rise was delayed for 4 d and HbF/F cell response was much higher. These results establish several important features of the fetal hemoglobin response to cytotoxic agents in the primate model. The response requires accelerated erythropoiesis and is preceded by transient reticulocytopenia. The response is produced by S phase- and M phase-specific agents when given in sufficient doses and at appropriate schedules. Passage of erythrocyte progenitors through M phase appears to be necessary for expression of the effect produced by S phase agents. The fetal hemoglobin response induced by cytotoxic drug administration occurs during the recovery of erythropoiesis following marrow suppression.
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镰状细胞性贫血基因治疗后每个红细胞的胎儿血红蛋白 (HbF/F-cell)。
影响因子：
12.8
作者：
Sebastiani,Paola;Steinberg,MartinH
通讯作者：
Steinberg,MartinH
DOI：
10.1016/s0021-9258(17)43493-4
发表时间：
1984-02
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
B. Mariani;R. Schimke
通讯作者：
B. Mariani;R. Schimke
人祖源性红细胞中血红蛋白 F 程序的测定。
DOI：
10.1172/jci111837
发表时间：
1985
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Friedman,AD;Linch,DC;Miller,B;Lipton,JM;Javid,J;Nathan,DG
通讯作者：
Nathan,DG
红细胞生成和血红蛋白 F 产生的调节。
DOI：
--
发表时间：
1983
期刊：
Progress in clinical and biological research
影响因子：
--
作者：
Nathan,DG
通讯作者：
Nathan,DG
影响因子：
15.9
作者：
PLATT, OS;ORKIN, SH;NATHAN, DG
通讯作者：
NATHAN, DG