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首页> 外文期刊>Drugs of today: Medicamentos de actualidad >Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment.
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Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment.

机译：口服多激酶抑制剂索拉非尼在癌症治疗中的临床前和临床开发。

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Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated.
机译：肿瘤的存活，生长和转移取决于有效的肿瘤细胞增殖和肿瘤血管生成，并且同时靶向这两个过程可能证明与治疗相关。 RAS / RAF信号通路是肿瘤细胞增殖和血管生成的重要介质，由于存在激活的Ras或突变的B-Raf或生长因子受体的升高，在人类肿瘤中通常被异常激活。基于对Raf-1的强抑制作用及其有利的激酶选择性，选择了化学上属于双芳基脲类的索拉非尼，进行进一步的药理鉴定。进一步的表征表明索拉非尼在体外抑制野生型和V599E突变型B-Raf活性。此外，索拉非尼对多种参与新血管形成和肿瘤进展的受体酪氨酸激酶具有显着活性，其中包括血管内皮生长因子（VEGFR）-2，VEGFR-3，血小板衍生生长因子（PDGFR）-βFlt-3和c-KIT。临床前，索拉非尼在结肠癌，乳腺癌和非小细胞肺癌异种移植模型中显示出广谱抗肿瘤活性。使用口服索拉非尼作为单一药物的总共四个I期研究已经完成，该化合物显示出良好的安全性，其中轻度至中度腹泻是最常见的治疗相关不良事件。最大耐受剂量为400 mg b.i.d.连续。迄今为止，单药II期试验报告表明，索拉非尼在肝细胞癌，肉瘤和肾细胞癌（RCC）患者中具有抗肿瘤活性。根据RCC患者的II期结果，进行了安慰剂对照的III期研究，该研究对905位患者进行了随机分组，其中大多数患者之前已经接受过治疗。索拉非尼的部分缓解率为2％，安慰剂为0％。索拉非尼和安慰剂组分别有78％和55％的患者观察到稳定的疾病。在所有评估的患者亚组中，与安慰剂（12周）相比，索拉非尼显着延长了中位无进展生存期（24周）。美国食品药品监督管理局（US Food and Drug Administration）批准索拉非尼用于该适应症。 RCC中的一线III期研究以及肝细胞癌和转移性黑色素瘤的III期研究已经启动。

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