Broxmeyer H E, Cooper S, Williams D E, Hangoc G, Gutterman J U, Vadhan-Raj S
Department of Medicine (Hematology/Oncology). Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46223.
Exp Hematol. 1988 Aug;16(7):594-602.
Bone marrow cells from patients with leukemia, myelodysplastic syndromes, cancer, and other disorders on a phase I clinical trial with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) were assessed in vitro for numbers of granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells, and for growth patterns (colony-to-cluster ratio) of CFU-GM, cycling rates of CFU-GM, and responsiveness in vitro to colony-stimulating and colony-inhibiting factors. The colony-to-cluster ratio of CFU-GM and the dose-response curves of CFU-GM to stimulation by rhGM-CSF in vitro did not change during the clinical trial. However, the percentage of CFU-GM in DNA synthesis, which is a measure of the proliferative rates of these cells, determined by the high specific activity tritiated thymidine kill technique in vitro, was markedly enhanced in a reversible fashion after administration in vivo of rhGM-CSF. The increased cycling rates of CFU-GM were consistent with the induced increase in neutrophil counts in these patients that has been reported elsewhere. Additionally, marrow CFU-GM from patients given rhGM-CSF in vivo were increased in sensitivity to inhibition in vitro by recombinant human H-subunit (acidic) ferritin in two of eight cases, and were increased in sensitivity to inhibition by lower dosages of recombinant human tumor necrosis factor alpha in all patients evaluated. The sensitivity of CFU-GM to inhibition in vitro by recombinant human interferon gamma and prostaglandin E1 did not change during the clinical trial. These studies demonstrate that the rhGM-CSF is having an effect on CFU-GM in the patients on the phase I clinical trial. This information may be of significance in planning future clinical studies combining rhGM-CSF with chemotherapy and/or other biotherapy.
在一项使用重组人粒细胞巨噬细胞集落刺激因子（rhGM-CSF）的I期临床试验中，对患有白血病、骨髓增生异常综合征、癌症及其他病症的患者的骨髓细胞进行了体外评估，以检测粒细胞巨噬细胞（CFU-GM）、红系（BFU-E）和多能（CFU-GEMM）祖细胞的数量，以及CFU-GM的生长模式（集落与集簇比率）、CFU-GM的循环率和体外对集落刺激因子及集落抑制因子的反应性。在临床试验期间，CFU-GM的集落与集簇比率以及CFU-GM对体外rhGM-CSF刺激的剂量反应曲线未发生变化。然而，通过体外高比活度氚标记胸腺嘧啶核苷杀伤技术测定的、作为这些细胞增殖率指标的处于DNA合成期的CFU-GM百分比，在体内给予rhGM-CSF后以可逆方式显著提高。CFU-GM循环率的增加与这些患者中性粒细胞计数的诱导性增加一致，这在其他地方已有报道。此外，在八例患者中的两例中，体内给予rhGM-CSF的患者的骨髓CFU-GM对重组人H亚基（酸性）铁蛋白体外抑制的敏感性增加，并且在所有评估的患者中，对较低剂量重组人肿瘤坏死因子α抑制的敏感性增加。在临床试验期间，CFU-GM对重组人干扰素γ和前列腺素E1体外抑制的敏感性未发生变化。这些研究表明，rhGM-CSF在I期临床试验患者中对CFU-GM有作用。该信息对于规划未来将rhGM-CSF与化疗和/或其他生物疗法联合使用的临床研究可能具有重要意义。
