Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression

作     者：MacVittie, TJ Farese, AM Smith, WG Baum, CM Burton, E McKearn, JP 

作者机构：Univ Maryland Greenebaum Canc Ctr Baltimore MD 21201 USA Monsanto Co Searle R&D St Louis MO USA 

出 版 物：《BLOOD》 (血液)

年 卷 期：2000年第95卷第3期

页      面：837-845页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

主　　题：血细胞计数/药物作用 输血 骨髓疾病/病因学 细胞谱系 集落形成单位测定 剂量效应关系 辐射 药物设计 药物评价 临床前 粒细胞集落刺激因子 重组 血细胞生成/药物作用 造血细胞生长因子/化学 造血细胞生长因子/药理学 造血细胞生长因子/治疗应用 白细胞介素3 恒河猴 中性粒细胞减少/药物疗法 中性粒细胞减少/病因学 蛋白质工程 辐射损伤 实验性/药物疗法 受体 粒细胞集落刺激因子/激动剂 受体 白细胞介素3/激动剂 重组融合蛋白质类 血小板减少/药物疗法 血小板减少/病因学 动物 男(雄)性 

摘      要：Myelopoietins (MPOs) constitute a family of engineered, chimeric molecules that bind and activate the IL-3 and G-CSF receptors on hematopoietic cells, This study investigated the in vivo hematopoietic response of rhesus monkeys administered MPO after radiation-induced myelosuppression, Animals were total body irradiated (TBI) in 2 series, with biologically equivalent doses consisting of either a 700 cGy dose of Cobalt-60 (Co-60) gamma-radiation or 600 cGy, 250 kVp x-irradiation. First series: On day 1 after 700 cGy irradiation, cohorts of animals were subcutaneously (SC) administered MPO at 200 mu g/kg/d (n = 4), or 50 mu g/kg/d (n = 2), twice daily, or human serum albumin (HSA) (n = 10), Second series: The 600 cGy x-irradiated cohorts of animals were administered either MPO at 200 mu g/kg/d, in a daily schedule(n = 4) or 0.1% autologous serum (AS), daily, SC (n = 11) for 23 days. MPO regardless of administration schedule (twice a day or every day) significantly reduced the mean durations of neutropenia (absolute neutrophil count [ANC] 500/mu L) and thrombocytopenia (platelet 20 000/mu L) Versus respective control-treated cohorts. Mean neutrophil and platelet nadirs were significantly improved and time to recovery for neutrophills (ANC to 500/mu L) and platelets (PLT 20 000/mu L) were significantly enhanced in the MPO-treated cohorts Versus controls. Red cell recovery was further improved relative to control-treated cohorts that received whole blood transfusions. Significant increases in bone marrow-derived clonogenic activity was observed by day 14 after TBI in MPO-treated cohorts versus respective time-matched controls. Thus, MPO, administered daily was as effective as a twice daily schedule for multilineage recovery in nonhuman primates after high-dose, radiation-induced myelosuppression. (C) 2000 by The American Society of Hematology.