Department of Radiation Oncology, Washington University in Saint Louis, St. Louis, MO 63108, USA.
Cancer J. 2013 May-Jun;19(3):238-46. doi: 10.1097/PPO.0b013e31829a68eb.
Approximately one third of patients with non-small cell lung cancer have unresectable stage IIIA or stage IIIB disease; combined cytotoxic chemotherapy and radiation therapy delivered concurrently has been established as the standard treatment for such patients. Despite many clinical trials that tested several different radiochemotherapy combinations, it seems that a plateau of efficiencies at the acceptable risk of complications has been reached. Clinical studies indicate that the improved efficacy of radiochemotherapy is associated with the radiosensitizing effects of chemotherapy. Improvement of outcomes of this combined modality by developing novel radiosensitizers is a viable therapeutic strategy. In addition to causing cell death, ionizing radiation also induces a many-faceted signaling response, which activates numerous prosurvival pathways that lead to enhanced proliferation in the endothelial cells and increased vascularization in tumors. Radiation at doses used in the clinic activates cytoplasmic phospholipase A2, leading to increased production of arachidonic acid and lysophosphatidylcholine. The former is the initial step in the generation of eicosanoids, while the later is the initial step in the formation of lysophosphatidic acid, leading to the activation of inflammatory pathways. The echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) is member of the insulin superfamily of receptor tyrosine kinases. The EML4-ALK fusion gene appears unique to lung cancer and signals through extracellular signal regulated kinase and phosphoinositide 3-kinase. Heat shock protein 90 (Hsp90) is often overexpressed and present in an activated multichaperone complex in cancer cells, and it is now regarded as essential for malignant transformation and progression. In this review we focus on radiosensitizing strategies involving the targeting of membrane phospholipids, EML4-ALK, and Hsp90 with specific inhibitors and briefly discuss the combination of radiation with antivascular agents.
大约三分之一的非小细胞肺癌患者患有不可切除的 IIIA 期或 IIIB 期疾病；联合细胞毒性化疗和放射治疗已被确立为此类患者的标准治疗方法。尽管进行了许多临床试验来测试几种不同的放化疗组合，但似乎已经达到了可接受并发症风险的效率高原。临床研究表明，放化疗疗效的提高与化疗的放射增敏作用有关。通过开发新型放射增敏剂来改善这种联合治疗方式的疗效是一种可行的治疗策略。除了导致细胞死亡外，电离辐射还会引起多方面的信号反应，激活许多促生存途径，导致内皮细胞增殖增强和肿瘤血管生成增加。临床使用剂量的辐射会激活细胞质磷脂酶 A2，导致花生四烯酸和溶血磷脂酰胆碱的产量增加。前者是生成类二十烷酸的初始步骤，而后者是溶血磷脂酸形成的初始步骤，导致炎症途径的激活。棘皮动物微管相关蛋白样 4 间变性淋巴瘤激酶（EML4-ALK）是胰岛素受体酪氨酸激酶超家族的成员。EML4-ALK 融合基因似乎是肺癌所特有的，通过细胞外信号调节激酶和磷酸肌醇 3-激酶信号转导。热休克蛋白 90（Hsp90）在癌细胞中通常过表达并存在于激活的多伴侣复合物中，现在被认为是恶性转化和进展所必需的。在这篇综述中，我们重点讨论了涉及针对膜磷脂、EML4-ALK 和 Hsp90 的放射增敏策略，使用了特异性抑制剂，并简要讨论了与抗血管生成剂联合应用的问题。
