Harrison J, Kappas A, Levere R D, Lutton J D, Chertkov J L, Jiang S, Abraham N G
Department of Medicine, New York Medical College, Valhalla 10595.
Blood. 1993 Dec 15;82(12):3574-9.
The ability of combination treatment with erythropoietin (Epo) and heme to rescue hematopoietic activity in mice from the suppressive effect of azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked anemia, thrombocytopenia, neutropenia, and weight loss, whereas mice that received Epo and heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT-treated animals and reduced the severe anemia and thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced anemia, although, when combined with heme, there was a great improvement in recovery of erythropoiesis. The combination of heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus, heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT therapy.
研究了促红细胞生成素（Epo）与血红素联合治疗能否挽救小鼠造血活性，使其免受叠氮胸苷（AZT）的抑制作用。将小鼠暴露于AZT 5周会导致明显的贫血、血小板减少、中性粒细胞减少和体重减轻，而随后连续3周接受Epo和血红素治疗的小鼠，其AZT细胞毒性得到了显著缓解。用Epo（10 U，每周5次）治疗可刺激AZT处理动物的造血恢复，并在3周内减轻严重贫血和血小板减少。给予较低剂量的Epo（1 U Epo）仅能适度延缓AZT诱导的贫血，不过，当与血红素联合使用时，红细胞生成的恢复有了很大改善。血红素与Epo（10 U）联合产生了最佳反应，在AZT治疗后3周结束时，骨髓细胞数量几乎恢复正常，同时红系爆式集落形成单位（BFU-E）和脾造血祖细胞含量（脾集落形成单位[CFU-S]）也得以恢复。单独使用血红素治疗可显著提高AZT治疗后BFU-E和CFU-S的恢复以及体重；然而，这种恢复程度不如与Epo（10 U）联合使用时。从暴露于AZT 8周的小鼠建立的长期骨髓培养（LTBMC）显示细胞数量显著减少，当小鼠在接受AZT 5周后再接受3周的血红素和Epo（10 U）治疗时，这种情况完全得到缓解。在LTBMC中，血红素和Epo在BFU-E产生以及CFU-S产生方面具有相加作用。因此，血红素对体内造血祖细胞具有显著的保护作用，在AZT治疗中与Epo联合使用可能具有潜在的临床应用价值，以促进有效的红细胞生成。
