Wörmann B, Reuter C, Zühlsdorf M, Büchner T, Hiddemann W
Department of Internal Medicine, University of Göttingen, Germany.
Semin Oncol. 1994 Dec;21(6 Suppl 16):39-43.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) not only stimulates hematopoiesis, but also induces the proliferation and differentiation of leukemic myeloid cells. The observation that clonogenic growth of malignant cells can be induced in vitro has led to the development of therapeutic concepts that aim to increase the sensitivity of cells to cytostatic and cytotoxic agents by priming them with GM-CSF. In in vitro experiments, preincubating leukemic cells with recombinant cytokines including GM-CSF led to a consistent, dose-dependent increase in the cytotoxicity of cytosine arabinoside (Ara-C). This effect has since been observed in patients with acute myeloid leukemia (AML) although its mechanism is not yet entirely clear. It seems that GM-CSF increases the relative number of cells in the S phase of the cell cycle and enhances the activity of DNA polymerases, enzymes that are essential to nucleotide incorporation into DNA. Based on these experimental results, numerous clinical trials have investigated the role of GM-CSF in priming leukemic blasts before chemotherapy. These studies will allow us to determine whether our in vitro observations of increased cytotoxicity translate into higher remission rates and durations, and will help us to identify the patient subgroups most likely to benefit from this therapeutic approach.
粒细胞巨噬细胞集落刺激因子（GM-CSF）不仅能刺激造血，还能诱导白血病髓系细胞的增殖和分化。体外可诱导恶性细胞克隆生长这一观察结果，促使了旨在通过用GM-CSF预处理来提高细胞对细胞抑制药和细胞毒性药敏感性的治疗理念的发展。在体外实验中，用包括GM-CSF在内的重组细胞因子预孵育白血病细胞，会导致阿糖胞苷（Ara-C）的细胞毒性呈一致的剂量依赖性增加。此后在急性髓系白血病（AML）患者中也观察到了这种效应，但其机制尚未完全明确。GM-CSF似乎增加了细胞周期S期的细胞相对数量，并增强了DNA聚合酶的活性，DNA聚合酶是核苷酸掺入DNA所必需的酶。基于这些实验结果，众多临床试验研究了GM-CSF在化疗前预处理白血病原始细胞中的作用。这些研究将使我们能够确定体外观察到的细胞毒性增加是否能转化为更高的缓解率和缓解持续时间，并将帮助我们识别最可能从这种治疗方法中获益的患者亚组。
