New Molecular Targeted Therapies Integrated With Radiation Therapy in Lung Cancer
New Molecular Targeted Therapies Integrated With Radiation Therapy in Lung Cancer
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DOI：
10.3816/clc.2010.n.012
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发表时间：
2010-03-01
影响因子：
3.6
通讯作者：
Valcarcel, Francisco
中科院分区：
文献类型：
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作者：
Provencio, Mariano;Sanchez, Antonio;Valcarcel, Francisco
非小细胞肺癌（NSCLC）约占所有肺癌病例的80%-85%;对于III期疾病患者，约占所有病例的40%。不可切除的III期NSCLC的治疗是铂类化疗和胸部放疗的组合。在这篇文章中，新的靶向药物正在调查可能整合到联合治疗进行审查。最有前途的策略之一是抑制表皮生长因子受体（EGFR）途径。辐射激活EGFR信号传导，通过诱导细胞增殖和增强DNA修复导致辐射抗性。当西妥昔单抗与放射治疗联合时，几种临床前模型显示出协同活性。一些II期临床试验已经评估了西妥昔单抗和放射治疗同步的安全性和有效性，结果令人鼓舞。吉非替尼对细胞系具有放射增敏作用，并已在不可切除的III期NSCLC的放射治疗中进行了研究。然而，在放化疗后使用吉非替尼维持治疗中观察到令人失望的结果。厄洛替尼已在I期试验中与放化疗一起进行了测试。放射通过损伤细胞膜、DNA和微血管内皮细胞诱导肿瘤死亡，其作为响应增加促血管生成生长因子。抗血管生成剂降低血管密度但改善肿瘤氧合。血管内皮生长因子受体（VEGFR）抑制剂的使用通过阻碍亚致死性辐射损伤的修复来增强人NSCLC的辐射治疗效果。厄洛替尼和贝伐单抗联合胸部放疗的试验正在进行中。必须制定新的战略来整合这种三联疗法。由于放射疗法增强HSP 90伴侣蛋白功能，导致放射抗性肺癌细胞，阻断该途径的治疗剂可能是通过抑制HIF-1 α和VEGF表达从而抑制肺癌细胞的存活和血管生成潜力来降低放射抗性的候选物。极光激酶抑制剂与放射治疗似乎在NSCLC和间皮瘤的临床前模型中具有叠加效应。
Non-small-cell lung cancer (NSCLC) accounts for approximately 80%-85% of all cases of lung cancer; for patients with stage III disease, it accounts for approximately 40% of all cases. The treatment for unresectable stage III NSCLC is the combination of platinum-based chemotherapy and thoracic radiation. In this article, new targeted agents under investigation for possible integration into the combined therapy are reviewed. One of the most promising strategies is the inhibition of the epidermal growth factor receptor (EGFR) pathway. Radiation activates EGFR signaling, leading to radio-resistance by inducing cell proliferation and enhanced DNA repair. Several preclinical models have shown synergistic activity when cetuximab was combined with radiation therapy. Some phase II trials have evaluated the safety and efficacy of synchronous cetuximab and radiation therapy with promising results. Gefitinib has a radiosensitizing effect on cell lines and has been investigated in combination with radiation therapy for unresectable stage III NSCLC. However, disappointing results were observed in the maintenance treatment with gefitinib after chemoradiation therapy. Erlotinib has been tested in a phase I trial with chemoradiation therapy. Radiation induces tumor death by damaging cell membranes, DNA, and microvascular endothelial cells, which in response increase proangiogenic growth factors. Antiangiogenic agents reduce vascular density but improve tumor oxygenation. Use of vascular endothelial growth factor receptor (VEGFR) inhibitors enhances the therapeutic efficacy of irradiation in human NSCLC by hindering the repair of sublethal radiation damage. Trials combining erlotinib and bevacizumab with thoracic radiation are ongoing. New strategies must be developed for the integration of this triple-combination treatment. As radiation therapy enhances HSP90 chaperone function, causing radio-resistant lung cancer cells, therapeutic agents that block this path are likely candidates for decreasing radio-resistance by suppressing HIF-1 alpha and VEGF expression and thus inhibiting the survival and angiogenic potential of lung cancer cells. Aurora kinase inhibitors with radiation therapy seem to have an additive effect in preclinical models in NSCLC and mesothelioma.