Grant S, Jarvis W D, Turner A J, Wallace H J, Pettit G R
Department of Medicine, Medical College of Virginia, Richmond 23298-0230.
Br J Haematol. 1992 Nov;82(3):522-8. doi: 10.1111/j.1365-2141.1992.tb06462.x.
The effects of the protein kinase C activator bryostatin 1, either with or without recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF) were examined with respect to the in vitro metabolism of ara-C in leukaemic myeloblasts obtained from 10 patients with acute myelogenous leukaemia (AML). Coincubation of cells with 12.5 x 10(-9) M bryostatin 1 and 10(-5) M ara-C for 4 h resulted in a significant increase in ara-CTP formation (compared to controls) in 6/10 specimens (mean increase 106%; range 38-255%), and no change in the remainder. In contrast, coincubation of cells with 1.25 ng/ml rGM-CSF resulted in a significant increase in only one specimen, and decreases in two. Bryostatin 1 also significantly increased ara-C DNA incorporation in 6/9 evaluable samples, including two which did not display an increase in ara-CTP formation. Coincubation of cells with both bryostatin 1 and rGM-CSF did not lead to a further increase in ara-CTP formation or ara-C DNA incorporation compared to values obtained with either agent alone. Finally, exposure of blasts to bryostatin 1 for 24 h before ara-C led to an increase in ara-CTP formation in 3/8 additional specimens, and a decrease in one sample displaying evidence of bryostatin 1-induced macrophage differentiation. Incubation of cells with both rGM-CSF and bryostatin 1 for this period resulted in ara-CTP levels equivalent to those obtained with bryostatin 1 alone. These studies indicate that while bryostatin 1 exerts a heterogeneous effect on ara-C metabolism in leukaemic myeloblasts, it is capable of potentiating ara-C phosphorylation in a subset of patient samples, including some that do not exhibit an increase in response to rGM-CSF. They also raise the possibility that bryostatin 1-induced potentiation of ara-C metabolism in some leukaemic cells may contribute, at least in part, to the antileukaemic efficacy of this drug combination.
研究了蛋白激酶C激活剂苔藓抑素1单独或与重组粒细胞巨噬细胞集落刺激因子（rGM-CSF）联合使用时，对10例急性髓性白血病（AML）患者的白血病成髓细胞中阿糖胞苷体外代谢的影响。细胞与12.5×10⁻⁹M苔藓抑素1和10⁻⁵M阿糖胞苷共孵育4小时后，6/10个样本中阿糖胞苷三磷酸（ara-CTP）的形成显著增加（与对照组相比）（平均增加106%；范围38 - 255%），其余样本无变化。相比之下，细胞与1.25 ng/ml rGM-CSF共孵育后，只有1个样本显著增加，2个样本减少。苔藓抑素1还使9/9个可评估样本中的阿糖胞苷掺入DNA显著增加，其中包括2个阿糖胞苷三磷酸形成未增加的样本。与单独使用任一药物相比，细胞与苔藓抑素1和rGM-CSF共同孵育并未导致阿糖胞苷三磷酸形成或阿糖胞苷掺入DNA进一步增加。最后，在阿糖胞苷处理前，将母细胞暴露于苔藓抑素1 24小时，3/8个额外样本中阿糖胞苷三磷酸形成增加，1个显示苔藓抑素1诱导巨噬细胞分化证据的样本减少。在此期间，细胞与rGM-CSF和苔藓抑素1共同孵育导致阿糖胞苷三磷酸水平与单独使用苔藓抑素1时相当。这些研究表明，虽然苔藓抑素1对白血病成髓细胞中阿糖胞苷代谢有不同的影响，但它能够增强一部分患者样本中阿糖胞苷的磷酸化，包括一些对rGM-CSF无反应增加的样本。它们还提出了一种可能性，即苔藓抑素1在某些白血病细胞中诱导的阿糖胞苷代谢增强可能至少部分有助于这种药物组合的抗白血病疗效。
