Ciardiello F, Tortora G
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, Via S. Pansini 5, 80131 Naples, Italy.
Clin Cancer Res. 2001 Oct;7(10):2958-70.
The epidermal growth factor receptor (EGFR) autocrine pathway contributes to a number of processes important to cancer development and progression, including cell proliferation, apoptosis, angiogenesis, and metastatic spread. The critical role the EGFR plays in cancer has led to an extensive search for selective inhibitors of the EGFR signaling pathway. The results of a large body of preclinical studies and the early clinical trials thus far conducted suggest that targeting the EGFR could represent a significant contribution to cancer therapy. A variety of different approaches are currently being used to target the EGFR. The most promising strategies in clinical development include monoclonal antibodies to prevent ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity to inhibit autophosphorylation and downstream intracellular signaling. At least five blocking monoclonal antibodies have been developed against the EGFR. Among these, IMC-225 is a chimeric human-mouse monoclonal IgG1 antibody that has been the first anti-EGFR targeted therapy to enter clinical evaluation in cancer patients in Phase II and III studies, alone or in combination with conventional therapies, such as radiotherapy and chemotherapy. A number of small molecule inhibitors of the EGFR tyrosine kinase enzymatic activity is also in development. OSI-774 and ZD1839 (Iressa) are currently in Phase II and III development, respectively. ZD1839, a p.o. active, selective quinazoline derivative has demonstrated promising in vitro and in vivo antitumor activity. Preliminary results from Phase I and II trials in patients with advanced disease demonstrate that ZD1839 and OSI-774 have an acceptable tolerability profile and promising clinical efficacy in patients with a variety of tumor types. This mini-review describes the EGFR inhibitors in clinical development.
表皮生长因子受体（EGFR）自分泌途径参与了许多对癌症发生和发展至关重要的过程，包括细胞增殖、凋亡、血管生成和转移扩散。EGFR在癌症中所起的关键作用促使人们广泛寻找EGFR信号通路的选择性抑制剂。大量临床前研究和迄今为止进行的早期临床试验结果表明，靶向EGFR可能对癌症治疗做出重大贡献。目前正在使用多种不同方法来靶向EGFR。临床开发中最有前景的策略包括防止配体结合的单克隆抗体以及抑制酪氨酸激酶酶活性以抑制自身磷酸化和下游细胞内信号传导的小分子抑制剂。已经开发出至少五种针对EGFR的阻断性单克隆抗体。其中，IMC-225是一种人鼠嵌合单克隆IgG1抗体，是首个进入II期和III期研究用于癌症患者临床评估的抗EGFR靶向疗法，可单独使用或与放疗和化疗等传统疗法联合使用。多种EGFR酪氨酸激酶酶活性的小分子抑制剂也在研发中。OSI-774和ZD1839（易瑞沙）目前分别处于II期和III期开发阶段。ZD1839是一种口服活性选择性喹唑啉衍生物，已显示出有前景的体外和体内抗肿瘤活性。晚期疾病患者I期和II期试验的初步结果表明，ZD1839和OSI-774具有可接受的耐受性，并且在多种肿瘤类型患者中具有有前景的临床疗效。本综述介绍了处于临床开发阶段的EGFR抑制剂。
