Mistry Ishna N, Thomas Matthew, Calder Ewen D D, Conway Stuart J, Hammond Ester M
Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom.
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
Int J Radiat Oncol Biol Phys. 2017 Aug 1;98(5):1183-1196. doi: 10.1016/j.ijrobp.2017.03.024. Epub 2017 Mar 22.
With the increasing incidence of cancer worldwide, the need for specific, effective therapies is ever more urgent. One example of targeted cancer therapeutics is hypoxia-activated prodrugs (HAPs), also known as bioreductive prodrugs. These prodrugs are inactive in cells with normal oxygen levels but in hypoxic cells (with low oxygen levels) undergo chemical reduction to the active compound. Hypoxia is a common feature of solid tumors and is associated with a more aggressive phenotype and resistance to all modes of therapy. Therefore, the combination of radiation therapy and bioreductive drugs presents an attractive opportunity for synergistic effects, because the HAP targets the radiation-resistant hypoxic cells. Hypoxia-activated prodrugs have typically been precursors of DNA-damaging agents, but a new generation of molecularly targeted HAPs is emerging. By targeting proteins associated with tumorigenesis and survival, these compounds may result in greater selectivity over healthy tissue. We review the clinical progress of HAPs as adjuncts to radiation therapy and conclude that the use of HAPs alongside radiation is vastly underexplored at the clinical level.
随着全球癌症发病率的不断上升，对特定、有效治疗方法的需求变得愈发迫切。靶向癌症治疗的一个例子是缺氧激活前药（HAPs），也称为生物还原前药。这些前药在氧水平正常的细胞中无活性，但在缺氧细胞（氧水平低）中会发生化学还原成为活性化合物。缺氧是实体瘤的一个常见特征，与更具侵袭性的表型以及对所有治疗方式的抗性相关。因此，放射治疗与生物还原药物的联合使用为协同效应提供了一个有吸引力的机会，因为缺氧激活前药靶向耐辐射的缺氧细胞。缺氧激活前药通常一直是DNA损伤剂的前体，但新一代分子靶向缺氧激活前药正在出现。通过靶向与肿瘤发生和存活相关的蛋白质，这些化合物可能对健康组织具有更高的选择性。我们综述了缺氧激活前药作为放射治疗辅助药物的临床进展，并得出结论，在临床层面，将缺氧激活前药与放射治疗一起使用的情况仍未得到充分探索。
