Hoyes K P, Jones H M, Abeysinghe R D, Hider R C, Porter J B
Department of Clinical Haematology, University College and Middlesex School of Medicine, London, UK.
Exp Hematol. 1993 Jan;21(1):86-92.
The effects of 3-hydroxypyridin-4-one (HPO) iron chelators and desferrioxamine (DFO) on murine hemopoiesis in vivo and in vitro have been compared in order to investigate the mechanism by which leucopenia in mice and granulocytopenia in man occurs with 1,2-,dimethyl-HPO (CP20). Administration of 60 doses of 200 mg/kg CP20 to Balb/c mice resulted in significant anemia, lymphopenia and granulocytopenia accompanied by bone marrow hypocellularity. DFO and CP94 (1,2,diethyl-HPO) at the same dose also caused lymphopenia but marrow cellularity was unaffected. When marrow from untreated mice was incubated with HPOs and DFO, erythroid burst-forming cells (BFU-E) and granulocyte/macrophage colony forming units (CFU-G+Mac), colony growth was inhibited in a dose-dependent manner at micromolar concentrations. The addition of iron to saturate the chelators abrogated the effects of DFO, but not those of the HPOs. With the HPO-iron complexes, addition of sufficient iron to saturate the transferrin in the medium reversed the inhibitory effects of the relatively hydrophilic CP20-iron complex but not those of the more lipophilic CP94-iron complex. Addition of further iron-saturated transferrin also corrected inhibition by the CP94-iron complex. These results show that HPO-iron complexes potentially have antiproliferative effects unlike DFO-iron complex (FO). The difference in the relative effects of CP20 to CP94 on hemopoiesis in vivo and in vitro suggests that additional factors to those inhibiting hemopoiesis in marrow cultures may operate with the long-term administration of iron chelators in vivo.
为了研究1,2 - 二甲基 - 3 - 羟基吡啶 - 4 - 酮（CP20）导致小鼠白细胞减少和人类粒细胞减少的机制，比较了3 - 羟基吡啶 - 4 - 酮（HPO）铁螯合剂和去铁胺（DFO）对小鼠体内和体外造血的影响。给Balb / c小鼠注射60剂200mg / kg的CP20，导致显著的贫血、淋巴细胞减少和粒细胞减少，并伴有骨髓细胞减少。相同剂量的DFO和CP94（1,2 - 二乙基 - HPO）也导致淋巴细胞减少，但骨髓细胞数量未受影响。当将未处理小鼠的骨髓与HPO和DFO一起孵育时，红系爆式集落形成细胞（BFU - E）和粒细胞/巨噬细胞集落形成单位（CFU - G + Mac）的集落生长在微摩尔浓度下以剂量依赖性方式受到抑制。添加铁使螯合剂饱和可消除DFO的作用，但不能消除HPO的作用。对于HPO - 铁复合物，添加足够的铁使培养基中的转铁蛋白饱和可逆转相对亲水性的CP20 - 铁复合物的抑制作用，但不能逆转亲脂性更强的CP94 - 铁复合物的抑制作用。添加更多铁饱和的转铁蛋白也可纠正CP94 - 铁复合物的抑制作用。这些结果表明，与DFO - 铁复合物（FO）不同，HPO - 铁复合物可能具有抗增殖作用。CP20和CP94在体内和体外对造血作用的相对影响差异表明，除了抑制骨髓培养中造血的因素外，其他因素可能在体内长期给予铁螯合剂时起作用。
