Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: Current status and future directions
Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: Current status and future directions
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DOI：
10.1634/theoncologist.11-7-753
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发表时间：
2006-07-01
期刊：
影响因子：
5.8
通讯作者：
Perrone, Francesco
中科院分区：
文献类型：
--
作者：
Morabito, Alessandro;De Maio, Ermelinda;Perrone, Francesco
血管生成在肿瘤生长和转移转移过程中起着核心作用。血管内皮生长因子(VEGF)家族的多肽生长因子及其受体是这一过程的关键调节因子。针对血管内皮生长因子或血管内皮生长因子受体(VEGFRs)的药物已经开发出来。VEGFRs的酪氨酸激酶抑制剂是一种小分子的类似于ATP的蛋白质，它与VEGFRs酪氨酸激酶结构域的ATP结合催化部位结合，从而阻断细胞内的信号转导。其中几种药物目前处于不同的临床开发阶段。大型随机III期试验已经证明，舒尼替尼和索拉非尼分别对标准疗法无效的胃肠道间质瘤和肾癌患者有疗效。在以前治疗过的非小细胞肺癌患者中，ZD6474联合化疗也有阳性结果的报道。对于其他药物，如vatalanib，已经报道了转移性结直肠癌患者的对比结果：这些试验的最终结果预计将在2006年公布。然而，仍有几个关键问题需要解决，如选择适当的剂量或时间表，是否存在“非靶点”效应，长期给药的安全性，以及研究新的临床终点或方法学方法，以实现这些药物的最佳临床开发。
Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of peptide growth factors and receptors are key regulators of this process. Agents directed either against VEGF or VEGF receptors (VEGFRs) have been developed. The tyrosine kinase inhibitors of VEGFRs are low-molecular-weight, ATP-mimetic proteins that bind to the ATP-binding catalytic site of the tyrosine kinase domain of VEGFRs, resulting in blockade of intracellular signaling. Several of these agents are currently in different phases of clinical development. Large randomized phase III trials have demonstrated the efficacy of sunitinib and sorafenib in the treatment of patients affected by gastrointestinal stromal tumors and renal cancer refractory to standard therapies, respectively. Positive results also have been reported with the combination of ZD6474 and chemotherapy in previously treated non-small cell lung cancer patients. For other agents, such as vatalanib, contrasting outcomes in metastatic colorectal cancer patients have been reported: the final results of these trials are expected in 2006. However, several key questions remain to be addressed, regarding the choice of an adequate dose or schedule, the presence of "off-target" effects, the safety of long-term administration, and the research of new clinical end points or methodological approaches for the optimal clinical development of these agents.