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非小细胞肺癌(non-small cell lung cancer,NSCLC)约占肺癌总病例数的80%-85%,对于Ⅲ期患者来说,NSCLC约占肺癌总病例数的40%。不可切除Ⅲ期NSCLC的治疗为以铂类为基础的化疗联合胸部放疗。本文将综述正在研发中且有可能用于联合治疗的新型靶向制剂。其中最具前景的策略之一为表皮生长因子受体(epidermal growth factor receptor,EGFR)通路的抑制。放疗可激活EGFR信号,通过诱导细胞增殖并增强DNA修复而导致放疗抵抗。几项临床前模型研究表明西妥昔单抗与放疗联合具有协同效应。几项Ⅱ期试验评估了西妥昔单抗与放疗同步使用的安全性与疗效,结果喜人。吉非替尼对多种细胞系具有放疗增敏作用,其与放疗的联合已被试验用于不可切除Ⅲ期NSCLC的治疗。然而,放化疗后使用吉非替尼作为维持治疗的结果不容乐观。一项Ⅰ期试验评估了厄洛替尼与放化疗联合的疗效。放疗可通过损伤细胞膜、DNA以及微血管内皮细胞而诱导肿瘤死亡,而这反过来可增加促血管生成生长因子的产生。抗血管生长制剂可降低血管密度,但可改善肿瘤的含氧量。应用血管内皮生长因子受体(vascular endothelial growth factor receptor,VEGFR)抑制剂可通过阻断亚致死量辐射损伤的修复而增强放疗对人NSCLC的疗效。厄洛替尼、贝伐珠单抗与胸部放疗联合试验正在进行中。该三种药物联合治疗的新策略尚需制订。由于放疗可增强HSP90分子伴侣的功能从而引起肺癌细胞的放疗抵抗,此通路的阻断剂可通过抑制HIF-1a和VEGF的表达进而抑制肺癌细胞的生存和血管生成,因而可能用于减少放疗抵抗。在NSCLC和间皮瘤的临床前模型中,Aurora激酶抑制剂似乎对放疗具有增效作用。
Non-small cell lung cancer (NSCLC) accounts for about 80% -85% of the total number of lung cancer cases. For stage III patients, NSCLC accounts for about 40% of the total number of lung cancer cases. Non-resectable stage III NSCLC is treated with platinum-based chemotherapy combined with chest radiotherapy. This article will outline new targeted agents under development and potentially for combination therapy. One of the most promising strategies is the inhibition of the epidermal growth factor receptor (EGFR) pathway. Radiation therapy activates EGFR signaling, leading to radioresistance by inducing cell proliferation and enhancing DNA repair. Several preclinical models indicate that cetuximab has a synergistic effect with radiotherapy. Several Phase II trials evaluated the safety and efficacy of cetuximab in combination with radiotherapy and the results were promising. Gefitinib has radiosensitizing effects on various cell lines, and its combination with radiotherapy has been tested for the treatment of unresectable stage III NSCLC. However, the use of gefitinib as a radiotherapy and chemotherapy after maintenance therapy is not optimistic. A phase I trial evaluated the efficacy of erlotinib in combination with radiotherapy and chemotherapy. Radiation therapy can induce tumor death by damaging cell membranes, DNA, and microvascular endothelial cells, which in turn increases the production of pro-angiogenic growth factors. Anti-angiogenic agents reduce blood vessel density, but improve the tumor’s oxygen content. Application of vascular endothelial growth factor receptor (VEGFR) inhibitors enhances the efficacy of radiotherapy in human NSCLC by blocking the repair of sub-lethal dose radiation injury. Erlotinib, bevacizumab and chest radiotherapy joint trials are underway. The new strategy for the combination of these three drugs still needs to be formulated. Radiotherapy can enhance the function of HSP90 chaperone and cause radioresistance of lung cancer cells. The blocker of this pathway can inhibit the survival and angiogenesis of lung cancer cells by inhibiting the expression of HIF-1a and VEGF and thus may be used to reduce the radioresistance . Aurora kinase inhibitors appear to have a synergistic effect on radiotherapy in preclinical models of NSCLC and mesothelioma.