Development and clinical indications of cetuximab
Development and clinical indications of cetuximab
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DOI：
10.5301/jbm.2008.4051
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发表时间：
2007-01-01
影响因子：
2
通讯作者：
Garassino, M. C.
中科院分区：
文献类型：
--
作者：
Labianca, R.;La Verde, N.;Garassino, M. C.
西妥昔单抗是一种针对表皮生长因子受体(EGFR)胞外区的嵌合免疫球蛋白G1单抗，具有高度的特异性和亲和力。它竞争性地抑制内源性配体结合，从而抑制随后的EGFR激活。EGFR信号通路调节细胞的分化、增殖、迁移、血管生成和凋亡，所有这些在癌细胞中都处于失控状态。EGFR是癌症治疗的重要靶点，许多研究表明西妥昔单抗在几种类型的癌症中都是有效的，特别是结直肠癌和头颈癌。西妥昔单抗增强了包括伊立替康在内的许多标准细胞毒剂的效果，与化疗相结合，它可以在以前对化疗无效的肿瘤中引发抗肿瘤反应。西妥昔单抗还可增强辐射诱导的细胞凋亡。根据一项关键的欧洲随机研究(BOND研究)和在美国进行的两项临床研究，西妥昔单抗已被批准与伊立替康联合用于服用伊立替康失败后受EGFR表达的转移性结肠癌影响的患者。转移性结直肠癌的一线治疗只有几个小的II期试验，但结果表明西妥昔单抗与伊立替康或奥沙利铂联合应用具有良好的活性。有证据表明，EGFR抑制剂与血管内皮生长因子受体抑制剂(如贝伐单抗)联合使用可以达到相加疗效。已经观察到反应和主要毒性(粉刺样皮肤反应)之间的相关性，但尚不清楚。作为EGFR抑制剂的特异性标志物，EGFR的状态存在争议。目前，EGFR的表达似乎不是对EGFR抑制剂反应的预测因素。
Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody that targets the extracellular domain of the epidermal growth factor receptor (EGFR) with high specificity and affinity. It competitively inhibits endogenous ligand binding and thereby inhibits subsequent EGFR activation. The EGFR signaling pathways regulate cell differentiation, proliferation, migration, angiogenesis and apoptosis, all of which become deregulated in cancer cells. EGFR is an important target for cancer therapy and many studies have demonstrated that cetuximab is active in several types of cancer, particularly colorectal and head and neck cancer. Cetuximab enhances the effects of many standard cytotoxic agents, including irinotecan, and in combination with chemotherapy it can elicit antitumor responses in tumors that previously failed to respond to that chemotherapy. Cetuximab also enhances radiation-induced apoptosis. On the basis of a pivotal European randomized study (the BOND study) and of 2 clinical studies conducted in the USA, cetuximab has been approved in combination with irinotecan for patients affected by EGFR-expressing metastatic colon cancer after failure with irinotecan. There have only been a few small phase II trials on first-line treatment in metastatic colorectal cancer, but the results suggest promising activity of cetuximab together with irinotecan or oxaliplatin. There is some evidence that additive efficacy can be achieved using EGFR inhibitors in combination with vascular endothelial growth factor receptor inhibitors such as bevacizumab. A correlation between response and the main toxicity (acne-like skin reaction) has been observed but is unclear. EGFR status as a specific marker for EGFR inhibitors is controversial. At the moment, EGFR expression does not appear to be a predictive factor for response to EGFR inhibitors.