Kofler R, Schmidt S, Kofler A, Ausserlechner M J
Tyrolean Cancer Research Institute at the University of Innsbruck, Austria.
J Endocrinol. 2003 Jul;178(1):19-27. doi: 10.1677/joe.0.1780019.
Glucocorticoid (GC) resistance is a phenomenon of major significance in a number of clinical situations, including the therapy of lymphoid malignancies. Resistance may concern all, or just selected, GC effects, it may be absolute or just reflect a state of reduced sensitivity and, clinically relevant, be reversible or irreversible. Numerous molecular mechanisms can be envisaged acting either 'upstream' in the GC-triggered signaling pathway, i.e. at the level of the GC receptor (GR), or 'downstream' at the level of the GC-regulated genes responsible for individual GC effects. In lymphoid malignancies, GCs have anti-leukemic effects through the induction of apoptosis and/or cell cycle arrest. In this condition evidence for only a small number of mechanisms for GC resistance has been provided, mostly at the level of the GR. Herein, we review reports and hypotheses regarding 'upstream' and 'downstream' mechanisms for GC resistance in lymphoblastic leukemia and present an in vitro GC resistance model that might allow identification of resistance mechanisms.
糖皮质激素（GC）抵抗是多种临床情况下的一种重要现象，包括在淋巴系统恶性肿瘤的治疗中。抵抗可能涉及所有或仅部分GC效应，可能是绝对的，也可能仅反映敏感性降低的状态，并且在临床上相关的是，可能是可逆的或不可逆的。可以设想许多分子机制在GC触发的信号通路中“上游”起作用，即在糖皮质激素受体（GR）水平，或在负责个体GC效应的GC调节基因水平“下游”起作用。在淋巴系统恶性肿瘤中，GC通过诱导凋亡和/或细胞周期停滞发挥抗白血病作用。在这种情况下，仅提供了少数GC抵抗机制的证据，主要是在GR水平。在此，我们综述了关于淋巴细胞白血病中GC抵抗的“上游”和“下游”机制的报道和假说，并提出了一种体外GC抵抗模型，该模型可能有助于识别抵抗机制。
