Pommier Yves, Sordet Olivier, Antony Smitha, Hayward Richard L, Kohn Kurt W
Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, DHHS, Bethesda, MD 20892, USA.
Oncogene. 2004 Apr 12;23(16):2934-49. doi: 10.1038/sj.onc.1207515.
Intrinsic (innate) and acquired (adaptive) resistance to chemotherapy critically limits the outcome of cancer treatments. For many years, it was assumed that the interaction of a drug with its molecular target would yield a lethal lesion, and that determinants of intrinsic drug resistance should therefore be sought either at the target level (quantitative changes or/and mutations) or upstream of this interaction, in drug metabolism or drug transport mechanisms. It is now apparent that independent of the factors above, cellular responses to a molecular lesion can determine the outcome of therapy. This review will focus on programmed cell death (apoptosis) and on survival pathways (Bcl-2, Apaf-1, AKT, NF-kappaB) involved in multidrug resistance. We will present our molecular interaction mapping conventions to summarize the AKT and IkappaB/NF-kappaB networks. They complement the p53, Chk2 and c-Abl maps published recently. We will also introduce the 'permissive apoptosis-resistance' model for the selection of multidrug-resistant cells.
化疗的内在（先天性）和获得性（适应性）耐药性严重限制了癌症治疗的效果。多年来，人们一直认为药物与其分子靶点的相互作用会产生致命损伤，因此内在耐药性的决定因素应该在靶点水平（定量变化或/和突变）或这种相互作用的上游，即药物代谢或药物转运机制中寻找。现在很明显，独立于上述因素之外，细胞对分子损伤的反应也能决定治疗结果。本综述将聚焦于程序性细胞死亡（凋亡）以及参与多药耐药的生存途径（Bcl-2、Apaf-1、AKT、NF-κB）。我们将展示我们的分子相互作用图谱惯例，以总结AKT和IkappaB/NF-κB网络。它们补充了最近发表的p53、Chk2和c-Abl图谱。我们还将介绍用于选择多药耐药细胞的“允许性凋亡抵抗”模型。
