Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer
Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer
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DOI：
10.1634/theoncologist.12-2-191
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发表时间：
2007-01-01
期刊：
影响因子：
5.8
通讯作者：
Rossi, Antonio
中科院分区：
文献类型：
--
作者：
Gridelli, Cesare;Maione, Paolo;Rossi, Antonio
尽管化疗方案不断优化，但晚期非小细胞肺癌（NSCLC）的治疗结果仍然令人失望。因此，新的治疗策略的临床研究是必要的。几种靶向药物已被引入非小细胞肺癌的临床试验，但迄今为止，这些新药中只有少数可能对疾病的自然历史产生重大影响。一些肺癌靶向治疗临床试验失败的主要原因之一是，新的生物制剂的靶点之间存在多层次的交叉刺激，沿着几种信号转导途径导致肿瘤事件；正如大多数第一代靶向药物所做的那样，仅阻断这些途径中的一条，就允许其他途径作为癌细胞的挽救或逃逸机制。索拉非尼和舒尼替尼是两种口服多靶向受体酪氨酸激酶抑制剂。Sorafenib是一种多激酶抑制剂，可抑制C-RAF和B-RAF的激酶活性，靶向血管内皮生长因子受体家族（VEGFR-2和VEGFR-3）和血小板衍生生长因子受体家族（pdgfr - β和干细胞因子受体[KIT]）。舒尼替尼是一种多靶点PDGFR、KIT、fms样酪氨酸激酶3和VEGFR抑制剂。索拉非尼和舒尼替尼靶向和抑制的激酶直接或间接调节肿瘤生长、存活和血管生成，这可能会导致广泛的抗肿瘤疗效。索拉非尼和舒尼替尼已被美国食品和药物管理局批准用于治疗转移性肾细胞癌；舒尼替尼也被批准用于胃肠道间质瘤的治疗。它们的作用机制、临床前数据和II期研究表明，它们对晚期非小细胞肺癌的治疗有效。
Despite the optimization of chemotherapy regimens, treatment outcomes for advanced non-small cell lung cancer (NSCLC) are still considered to be disappointing. Thus, clinical research of new treatment strategies is warranted. Several targeted agents have been introduced into clinical trials in NSCLC, but to date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. One of the main reasons for the failure of several clinical trials of targeted therapy in lung cancer is that there is multi-level cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events; blocking only one of these pathways, as most first-generation targeted agents do, allows others to act as salvage or escape mechanisms for cancer cells. Sorafenib and sunitinib are two oral multitargeted receptor tyrosine kinase inhibitors. Sorafenib is a multikinase inhibitor that inhibits the kinase activity of both C-RAF and B-RAF and targets the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and stem cell factor receptor [ KIT]). Sunitinib is a multitargeted inhibitor of PDGFR, KIT, fms-like tyrosine kinase 3, and VEGFR. The kinases targeted and inhibited by sorafenib and sunitinib directly and indirectly regulate tumor growth, survival, and angiogenesis, and this might be expected to result in broad antitumor efficacy. Sorafenib and sunitinib have been approved by the U. S. Food and Drug Administration for the treatment of metastatic renal cell carcinoma; sunitinib has also been approved for the treatment of gastrointestinal stromal tumors. Their mechanism of action, preclinical data, and phase II studies suggest efficacy in the treatment of advanced NSCLC.