Kaspers G J, Pieters R, Klumper E, De Waal F C, Veerman A J
Department of Pediatrics, Free University Hospital, Amsterdam, The Netherlands.
Leuk Lymphoma. 1994 Apr;13(3-4):187-201. doi: 10.3109/10428199409056282.
Glucocorticoids (GC) are being used in the treatment of childhood leukemia for several decades, most successfully in newly diagnosed acute lymphoblastic leukemia (ALL). However, GC resistance is seen in 10-30% of untreated ALL patients, and is much more frequent in relapsed ALL and in acute nonlymphoblastic leukemia (ANLL). Sensitivity or resistance to GC can be measured using a cell culture drug resistance assay. For this purpose, we use the colorimetric methyl-thiazol-tetrazolium (MTT) assay. We have shown that GC resistance in childhood leukemia is related to clinical and cell biological features, and to the clinical outcome after multi-drug chemotherapy. These results are summarized in this review. In addition, we describe the apoptotic 'cell-lysis pathway' by which GC exert their antileukemic activity. This description provides a model to discuss the mechanisms of GC resistance, and to summarize the relevant literature. Possible levels of resistance relate to the diffusion of GC through the cell membrane, binding to the GC receptor (GCR), activation of the GC-GCR complex, translocation of the complex into the nucleus, binding to DNA, endonuclease-mediated DNA fragmentation, and DNA repair. A low number of GCR has been shown to be the cause of resistance in some children with ALL. However, GC resistance is likely to be caused at the post-receptor level in most leukemias. Unfortunately, there is still a lack of knowledge relating to the clinical relevance of mechanisms of GC resistance at the post-receptor level. Studies on the mechanisms of GC resistance other than those directly related to the GCR should be initiated, especially if patient material is used, as the results might indicate ways to circumvent or modulate GC resistance. A further increase in our knowledge regarding the relation between GC resistance and patient and cell biological features, the clinical relevance of GC resistance, and the mechanisms of GC resistance in leukemia patients, may contribute to further improvement in the results of GC therapy in leukemia.
几十年来，糖皮质激素（GC）一直用于儿童白血病的治疗，在新诊断的急性淋巴细胞白血病（ALL）中应用最为成功。然而，10%至30%的未经治疗的ALL患者存在GC耐药，在复发的ALL和急性非淋巴细胞白血病（ANLL）中更为常见。对GC的敏感性或耐药性可通过细胞培养耐药试验来测定。为此，我们使用比色法甲基噻唑四氮唑（MTT）试验。我们已经表明，儿童白血病中的GC耐药与临床和细胞生物学特征以及多药化疗后的临床结局有关。这些结果在本综述中进行了总结。此外，我们描述了GC发挥其抗白血病活性的凋亡“细胞溶解途径”。这一描述提供了一个模型，用于讨论GC耐药的机制，并总结相关文献。可能的耐药水平与GC通过细胞膜的扩散、与GC受体（GCR）的结合、GC-GCR复合物的激活、复合物向细胞核的转运、与DNA的结合、内切酶介导的DNA片段化以及DNA修复有关。在一些ALL儿童中，GCR数量低已被证明是耐药的原因。然而，在大多数白血病中，GC耐药可能是在受体后水平引起的。不幸的是，目前仍缺乏关于受体后水平GC耐药机制的临床相关性的知识。应该开展除了与GCR直接相关之外的GC耐药机制的研究，特别是如果使用患者材料，因为结果可能会指明规避或调节GC耐药的方法。我们对GC耐药与患者及细胞生物学特征之间关系、GC耐药的临床相关性以及白血病患者GC耐药机制的进一步了解，可能有助于进一步改善白血病GC治疗的效果。
