Wardman P
University of Oxford, Gray Cancer Institute, PO Box 100, Mount Vernon Hospital, Northwood HA6 2JR, UK.
Clin Oncol (R Coll Radiol). 2007 Aug;19(6):397-417. doi: 10.1016/j.clon.2007.03.010. Epub 2007 May 2.
Radiosensitizers are intended to enhance tumour cell killing while having much less effect on normal tissues. Some drugs target different physiological characteristics of the tumour, particularly hypoxia associated with radioresistance. Oxygen is the definitive hypoxic cell radiosensitizer, the large differential radiosensitivity of oxic vs hypoxic cells being an attractive factor. The combination of nicotinamide to reduce acute hypoxia with normobaric carbogen breathing is showing clinical promise. 'Electron-affinic' chemicals that react with DNA free radicals have the potential for universal activity to combat hypoxia-associated radioresistance; a nitroimidazole, nimorazole, is clinically effective at tolerable doses. Hypoxia-specific cytotoxins, such as tirapazamine, are valuable adjuncts to radiotherapy. Nitric oxide is a potent hypoxic cell radiosensitizer; variations in endogenous levels might have prognostic significance, and routes to deliver nitric oxide specifically to tumours are being developed. In principle, many drugs can be delivered selectively to hypoxic tumours using either reductase enzymes or radiation-produced free radicals to activate drug release from electron-affinic prodrugs. A redox-active agent based on a gadolinium chelate is being evaluated clinically. Pyrimidines substituted with bromine or iodine are incorporated into DNA and enhance free radical damage; fluoropyrimidines act by different mechanisms. A wide variety of drugs that influence the nature or repair of DNA damage are being evaluated in conjunction with radiation; it is often difficult to define the mechanisms underlying chemoradiation regimens. Drugs being evaluated include topoisomerase inhibitors (e.g. camptothecin, topotecan), and the hypoxia-activated anthraquinone AQ4N; alkylating agents include temozolomide. Drugs involved in DNA repair pathways being investigated include the potent poly(ADP ribose)polymerase inhibitor, AG14,361. Proteins involved in cell signalling, such as the Ras family, are attractive targets linked to radioresistance, as are epidermal growth factor receptors and linked kinases (drugs including vandetanib [ZD6,474], cetuximab and gefitinib), and cyclooxygenase-2 (celecoxib). The suppression of radioprotective thiols seems to offer more potential with alkylating agents than with radiotherapy, although it remains a strategy worthy of exploration.
放射增敏剂旨在增强肿瘤细胞杀伤作用，同时对正常组织的影响要小得多。一些药物针对肿瘤的不同生理特性，特别是与放射抗性相关的缺氧。氧气是确定的缺氧细胞放射增敏剂，有氧细胞与缺氧细胞之间巨大的放射敏感性差异是一个有吸引力的因素。烟酰胺与常压碳合气呼吸联合使用以减轻急性缺氧的方法显示出临床应用前景。与DNA自由基发生反应的“亲电子”化学物质具有对抗缺氧相关放射抗性的普遍活性潜力；一种硝基咪唑类药物尼莫唑在可耐受剂量下具有临床疗效。缺氧特异性细胞毒素，如替拉扎明，是放射治疗的重要辅助药物。一氧化氮是一种有效的缺氧细胞放射增敏剂；内源性水平的变化可能具有预后意义，目前正在开发将一氧化氮特异性递送至肿瘤的途径。原则上，许多药物可以利用还原酶或辐射产生的自由基选择性地递送至缺氧肿瘤，以激活亲电子前药的药物释放。一种基于钆螯合物的氧化还原活性剂正在进行临床评估。用溴或碘取代的嘧啶被掺入DNA中并增强自由基损伤；氟嘧啶通过不同机制起作用。正在结合放射治疗评估多种影响DNA损伤性质或修复的药物；通常很难确定放化疗方案的潜在机制。正在评估的药物包括拓扑异构酶抑制剂（如喜树碱、拓扑替康），以及缺氧激活的蒽醌AQ4N；烷化剂包括替莫唑胺。正在研究的参与DNA修复途径的药物包括强效的聚（ADP核糖）聚合酶抑制剂AG14361。参与细胞信号传导的蛋白质，如Ras家族，是与放射抗性相关的有吸引力的靶点，表皮生长因子受体和相关激酶（包括凡德他尼[ZD6474]、西妥昔单抗和吉非替尼等药物）以及环氧合酶-2（塞来昔布）也是如此。抑制放射防护性硫醇似乎在烷化剂方面比放射治疗提供了更多潜力，尽管它仍然是一个值得探索的策略。
