Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Clin Oncol (R Coll Radiol). 2019 May;31(5):290-302. doi: 10.1016/j.clon.2019.02.004. Epub 2019 Mar 8.
The role of hypoxia in radiation resistance is well established and many approaches to overcome hypoxia in tumours have been explored, with variable success. Two small molecule strategies for targeting hypoxia have dominated preclinical and clinical efforts. One approach has been the use of electron-affinic nitroheterocycles as oxygen-mimetic sensitisers. These agents are best exemplified by the 5-nitroimidazole nimorazole, which has limited use in conjunction with radiotherapy in head and neck squamous cell carcinoma. The second approach seeks to leverage tumour hypoxia as a tumour-specific address for hypoxia-activated prodrugs. These prodrugs are selectively activated by reductases under hypoxia to release cytotoxins, which in some instances may diffuse to kill surrounding oxic tumour tissue. A number of these hypoxia-activated prodrugs have been examined in clinical trial and the merits and shortcomings of recent examples are discussed. There has been an evolution from delivering DNA-interactive cytotoxins to molecularly targeted agents. Efforts to implement these strategies clinically continue today, but success has been elusive. Several issues have been identified that compromised these clinical campaigns. A failure to consider the extravascular transport and the micropharmacokinetic properties of the prodrugs has reduced efficacy. One key element for these 'targeted' approaches is the need to co-develop biomarkers to identify appropriate patients. Hypoxia-activated prodrugs require biomarkers for hypoxia, but also for appropriate activating reductases in tumours, as well as markers of intrinsic sensitivity to the released drug. The field is still evolving and changes in radiation delivery and the impact of immune-oncology will provide fertile ground for future innovation.
缺氧在辐射抗性中的作用已经得到充分证实，已经探索了许多克服肿瘤缺氧的方法，但取得的成功各不相同。两种针对缺氧的小分子策略主导了临床前和临床研究。一种方法是使用电子亲和硝基杂环作为模拟氧的增敏剂。这类药物的最佳代表是 5-硝基咪唑尼莫唑，它在头颈部鳞状细胞癌的放射治疗中联合应用的用途有限。另一种方法是利用肿瘤缺氧作为肿瘤特异性缺氧激活前药的地址。这些前药在缺氧下被还原酶选择性激活，释放细胞毒素，在某些情况下，这些细胞毒素可能扩散到周围的有氧肿瘤组织中杀死肿瘤细胞。许多这些缺氧激活的前药已经在临床试验中进行了检查，讨论了最近的例子的优点和缺点。从传递 DNA 相互作用的细胞毒素到分子靶向药物已经有了发展。目前仍在努力将这些策略应用于临床，但成功仍然难以捉摸。已经确定了一些问题，这些问题影响了这些临床活动。未能考虑到前药的血管外转运和微药代动力学特性降低了疗效。这些“靶向”方法的一个关键要素是需要共同开发生物标志物来识别合适的患者。缺氧激活的前药需要缺氧的生物标志物，但也需要肿瘤中适当的激活还原酶，以及对释放药物的固有敏感性的标志物。该领域仍在不断发展，放射治疗的变化和免疫肿瘤学的影响将为未来的创新提供肥沃的土壤。
