Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; email:
Laboratory of Molecular Cancer Biology, Molecular Physiology Research Unit-URPhyM, Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, B-5000 Namur, Belgium; email:
Annu Rev Pharmacol Toxicol. 2016;56:85-102. doi: 10.1146/annurev-pharmtox-010715-103111. Epub 2015 Oct 28.
Resistance to anticancer drugs is a complex process that results from alterations in drug targets; development of alternative pathways for growth activation; changes in cellular pharmacology, including increased drug efflux; regulatory changes that alter differentiation pathways or pathways for response to environmental adversity; and/or changes in the local physiology of the cancer, such as blood supply, tissue hydrodynamics, behavior of neighboring cells, and immune system response. All of these specific mechanisms are facilitated by the intrinsic hallmarks of cancer, such as tumor cell heterogeneity, redundancy of growth-promoting pathways, increased mutation rate and/or epigenetic alterations, and the dynamic variation of tumor behavior in time and space. Understanding the relative contribution of each of these factors is further complicated by the lack of adequate in vitro models that mimic clinical cancers. Several strategies to use current knowledge of drug resistance to improve treatment of cancer are suggested.
抗癌药物耐药性是一个复杂的过程，源于药物靶点的改变；生长激活的替代途径的发展；细胞药理学的变化，包括增加药物外排；调节变化，改变分化途径或对环境逆境的反应途径；以及/或者癌症局部生理学的变化，如血液供应、组织流体动力学、相邻细胞的行为和免疫系统反应。所有这些特定机制都受到癌症内在特征的促进，例如肿瘤细胞异质性、促进生长途径的冗余、突变率增加和/或表观遗传改变，以及肿瘤行为在时间和空间上的动态变化。由于缺乏模拟临床癌症的充分体外模型，理解这些因素中的每一个的相对贡献更加复杂。提出了几种利用现有耐药性知识来改善癌症治疗的策略。
