Auckland Cancer Society Research Centre, The University of Auckland, New Zealand.
Future Oncol. 2010 Mar;6(3):419-28. doi: 10.2217/fon.10.1.
The hypoxic cells common in solid tumors (because of their inefficient blood supply) limit the effectiveness of radiotherapy and many cytotoxic drugs. Nontoxic prodrugs that generate active species in hypoxic tissue by selective bioreduction have long been explored, and the first examples, representing a variety of different chemistries, have now reached advanced clinical trials. In the process, a great deal has been learnt about the properties that such drugs require to be successful, notably, efficient extravascular diffusion, appropriate reduction chemistry and kinetics, and an effective biological profile of the activated species, including a good bystander effect. The critical importance of prodrug diffusion and techniques to quantify this have assisted the development of models to predict the killing of tumor cells, which promises to help accelerate new drug evaluation. A cell cycle-independent mechanism of killing by the released cytotoxin is also a potential advantage, although it is likely that much of the killing will be when out-of-cycle hypoxic cells reoxygenate and resume division.
实体肿瘤中常见的缺氧细胞（由于其血液供应效率低下）限制了放射治疗和许多细胞毒性药物的效果。人们长期以来一直在探索能够通过选择性生物还原在缺氧组织中产生活性物质的无毒前药，现在已经有第一批代表各种不同化学性质的前药进入了临床试验。在此过程中，人们已经了解到此类药物需要具备的成功特性，特别是有效的血管外扩散、适当的还原化学和动力学以及活性物质的有效生物学特征，包括良好的旁观者效应。前药扩散的重要性以及量化这些特性的技术，有助于开发预测肿瘤细胞杀伤的模型，这有望有助于加快新药评估。释放的细胞毒素通过非细胞周期依赖性机制杀伤也是一个潜在优势，尽管当处于非周期缺氧状态的细胞重新供氧并恢复分裂时，大部分杀伤可能会发生。
