Beran M, McCredie K B, Keating M J, Gutterman J U
University of Texas M.D. Anderson Hospital and Tumor Institute, Department of Hematology, Houston 77030.
Blood. 1988 Aug;72(2):728-38.
The effect of recombinant human tumor necrosis factor alpha (rTNF-alpha) on human myelogenous leukemia clonogenic cells growing either in semisolid media or in suspension cultures was studied and compared with the effect on normal granulocyte-macrophage progenitors (GM-CFC). Exposure of cells to a range of rTNF-alpha doses including pharmacologically achievable plasma concentrations revealed a large heterogeneity in the response of leukemic clonogenic growth to rTNF-alpha. Only one of 13 specimens was highly resistant to rTNF-alpha. Eight of ten leukemic samples were significantly more sensitive than were normal GM-CFC, particularly within the in vivo achievable dose range (1 x 10(0) to 1 x 10(2) ng/mL). No significantly increased inhibition of either normal or leukemic clonogenic growth could be achieved by increasing the rTNF-alpha concentration above 250 ng/mL. Proliferation of leukemic clonogenic cells (L-CFC) was studied in suspension cultures. In five cases the clonogenic cells were significantly inhibited by rTNF-alpha while in one case no inhibition was observed. The inhibition of L-CFC growth by rTNF-alpha was dose dependent between 1 x 10(0) and 1 x 10(2) ng/mL. In suspension cultures, the TNF effect on L-CFC was a function of time of exposure, particularly with low concentrations of TNF. A remarkably higher inhibition of L-CFC as compared with the total leukemic population was observed in suspension cultures. Stimulation of L-CFC growth by rTNF-alpha was not observed. Normal GM-CFC were inhibited by alpha and gamma interferons (INF-alpha, -gamma) in a dose-related manner, with higher sensitivity of colonies than clusters. The response of GM-CFC to combination of recombinant IFNs and TNF was influenced by the size of clones scored and the source of colony-stimulating activity. The response of L-CFC to recombinant IFN-alpha and/or -gamma was highly variable, and sensitivity to one of the lymphokines did not predict for sensitivity to another. The response of L-CFC to combinations of rTNF-alpha and either IFN-alpha or IFN-gamma was complex, varying from synergistic to additive and indifferent. In three of six specimens, IFN-gamma acted antagonistically with rTNF-alpha, a phenomenon not observed with IFN-alpha. These observations suggest that the action of rTNF-alpha in acute myelogenous leukemia could be exploited therapeutically and the dose-time-response relationship should be considered in designing treatment schedules.(ABSTRACT TRUNCATED AT 400 WORDS)
研究了重组人肿瘤坏死因子α（rTNF-α）对在半固体培养基或悬浮培养中生长的人髓性白血病克隆形成细胞的作用，并与对正常粒细胞-巨噬细胞祖细胞（GM-CFC）的作用进行了比较。将细胞暴露于一系列rTNF-α剂量，包括药理学上可达到的血浆浓度，结果显示白血病克隆形成生长对rTNF-α的反应存在很大异质性。13个标本中只有1个对rTNF-α高度耐药。10个白血病样本中有8个比正常GM-CFC对rTNF-α敏感得多，特别是在体内可达到的剂量范围内（1×10⁰至1×10² ng/mL）。将rTNF-α浓度提高到250 ng/mL以上并不能显著增强对正常或白血病克隆形成生长的抑制作用。在悬浮培养中研究了白血病克隆形成细胞（L-CFC）的增殖。在5个病例中，克隆形成细胞被rTNF-α显著抑制，而在1个病例中未观察到抑制作用。在1×10⁰至1×10² ng/mL之间，rTNF-α对L-CFC生长的抑制作用呈剂量依赖性。在悬浮培养中，TNF对L-CFC的作用是暴露时间的函数，特别是在低浓度TNF时。在悬浮培养中观察到，与总的白血病细胞群体相比，L-CFC受到的抑制作用明显更高。未观察到rTNF-α对L-CFC生长的刺激作用。正常GM-CFC被α和γ干扰素（INF-α、-γ）以剂量相关的方式抑制，集落比集簇更敏感。GM-CFC对重组IFN和TNF联合作用的反应受计分克隆大小和集落刺激活性来源的影响。L-CFC对重组IFN-α和/或-γ的反应高度可变，对一种淋巴因子的敏感性并不能预测对另一种的敏感性。L-CFC对rTNF-α与IFN-α或IFN-γ联合作用的反应很复杂，从协同到相加再到无作用都有。在6个标本中的3个中，IFN-γ与rTNF-α起拮抗作用，而IFN-α未观察到这种现象。这些观察结果表明，rTNF-α在急性髓性白血病中的作用可用于治疗，在设计治疗方案时应考虑剂量-时间-反应关系。（摘要截短至400字）
