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首页> 外文期刊>Drugs of today: Medicamentos de actualidad >Cetuximab: An epidermal growth factor receptor chemeric human-murine monoclonal antibody.
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Cetuximab: An epidermal growth factor receptor chemeric human-murine monoclonal antibody.

机译：西妥昔单抗：一种表皮生长因子受体嵌合人鼠单克隆抗体。

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摘要

The epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptors. It is composed of extracellular domains, including a ligand-binding domain, a hydrophobic transmembrane region and a tyrosine kinase-containing cytoplasmic region. Stimulation of the EGFR by endogenous ligands, EGF or transforming growth factor-alpha (TGF-alpha), results in a conformational change in the receptor, permitting it to enter into dimers and other oligomers. Dimerization results in activation of intracellular tyrosine kinase, protein phosphorylation and stimulation of various cell signaling pathways that mediate gene transcription and cell cycle progression. The EGFR is expressed on normal human cells but higher levels of expression of the receptor have also been shown to be correlated with malignancy in a variety of cancers. In addition, expression of the EGFR by malignant cells is associated with poor prognosis and resistance to therapy. Cetuximab is a chimeric human-murine monoclonal antibody that binds competitively and with high affinity to the EGFR. Binding of the antibody to the EGFR prevents stimulation of the receptor by endogenous ligands and results in inhibition of cell proliferation, enhanced apoptosis, and reduced angiogenesis, invasiveness and metastasis. Binding of cetuximab to the receptor also results in internalization of the antibody-receptor complex which leads to an overall downregulation of EGFR expression. The EGFR is a prime target for new anticancer therapy, and other agents in development include small molecular tyrosine kinase inhibitors and antisense therapies. Preclinical studies have demonstrated that cetuximab reduces chemotherapy and radiotherapy resistance in human tumor cell lines in vitro and in nude mice bearing xenografts of human tumors. In clinical and preclinical studies cetuximab has been shown to induce response to treatment when used in combination with chemotherapy in patients previously refractory to chemotherapy. Based on these studies, cetuximab can be addedto regimens using docetaxel, cisplatin, carboplatin, irinotecan, paclitaxel and fluorouracil and may add to treatment efficacy. Phase I dose-finding studies showed that saturation of cetuximab clearance occurred after administration of 400 mg/m(2) as a loading dose followed by weekly infusions of 250 mg/m(2). The most commonly reported adverse event associated with cetuximab treatment is an acneiform rash that occurs in 70-80% of patients treated with cetuximab. The rash is rarely dose- or treatment-limiting, and may diminish in intensity with continued exposure to cetuximab. Improvement may be seen after treatment with topical antibiotic preparations, topical steroids or topical retinoids. The rash resolves fully after discontinuation of cetuximab treatment. EGFR is widely expressed in skin and skin biopsies in areas involved with the characteristic cetuximab eruption demonstrate neutrophilic folliculitis. In fact, analysis of four phase II clinical trials of cetuximab in combination with chemotherapy in patients with colorectal cancer, squamous cell carcinoma of the head and neck, or pancreatic cancer showed that development of the acneiform rash was significantly correlated with response to treatment; grade 3 rash may be especially predictive of response. It is possible that development of acneiform rash may become an important clinical prognostic marker. Serious cetuximab-related toxicities include hypersensitivity, infusion reactions and interstitial lung disease. Results of a large phase II study have shown response when used in combination with irinotecan in 22.9% of patients with EGFR-expressing, irinotecan-refractory, colorectal cancer. Cetuximab has recently been approved for this indication in the United States, Switzerland, Iceland, Norway and the 25 member states of the European Union. Other phase II and III studies show significant response to treatment in variable proportions of patients with squamous cell carcino
机译：表皮生长因子受体（EGFR）是ErbB受体家族的成员。它由胞外域组成，包括配体结合域，疏水跨膜区和含酪氨酸激酶的胞质区。内源性配体，EGF或转化生长因子-α（TGF-α）刺激EGFR导致受体的构象变化，使其进入二聚体和其他寡聚体。二聚化导致细胞内酪氨酸激酶的激活，蛋白磷酸化和介导基因转录和细胞周期进程的各种细胞信号通路的刺激。 EGFR在正常人细胞上表达，但在多种癌症中，受体的高水平表达也被证明与恶性肿瘤相关。另外，恶性细胞表达EGFR与不良预后和对治疗的抗性有关。西妥昔单抗是一种嵌合的人鼠单克隆抗体，与EGFR竞争性结合并具有高亲和力。抗体与EGFR的结合可防止内源性配体刺激受体，并导致细胞增殖受到抑制，细胞凋亡增加，血管生成，侵袭和转移减少。西妥昔单抗与受体的结合还导致抗体-受体复合物的内在化，这导致EGFR表达的总体下调。 EGFR是新的抗癌治疗的主要靶标，正在开发的其他药物包括小分子酪氨酸激酶抑制剂和反义疗法。临床前研究表明，西妥昔单抗可降低体外人肿瘤细胞系和携带人肿瘤异种移植物的裸鼠的化学疗法和放射疗法抗性。在临床和临床前研究中，西妥昔单抗与以前化疗无效的患者联合使用时，已显示出可诱导对治疗的反应。基于这些研究，可以使用多西他赛，顺铂，卡铂，伊立替康，紫杉醇和氟尿嘧啶将西妥昔单抗添加到治疗方案中，并可能增加治疗效果。 I期剂量寻找研究表明，西妥昔单抗清除率在以400 mg / m（2）作为负荷剂量给药后出现，随后每周输注250 mg / m（2）。与西妥昔单抗治疗相关的最常见的不良事件是痤疮样皮疹，发生于70-80％的西妥昔单抗治疗的患者中。皮疹很少受到剂量或治疗的限制，并且在持续接触西妥昔单抗的情况下，皮疹的强度可能会降低。用局部抗生素制剂，局部类固醇或局部类维生素A治疗后可看到改善。停用西妥昔单抗治疗后，皮疹完全消退。 EGFR在皮肤和皮肤活检组织中广泛表达，与西妥昔单抗特征性喷发有关，表明嗜中性毛囊炎。实际上，对西妥昔单抗联合化疗在结直肠癌，头颈鳞状细胞癌或胰腺癌患者中进行的四项II期临床试验的分析表明，痤疮样皮疹的发生与治疗反应显着相关; 3级皮疹可能特别可预测反应。痤疮样皮疹的发展可能会成为重要的临床预后标志物。与西妥昔单抗相关的严重毒性包括超敏反应，输注反应和间质性肺疾病。一项大型II期研究的结果显示，与22.9％EGFR表达，伊立替康难治性结直肠癌患者联合使用伊立替康时，反应良好。西妥昔单抗最近在美国，瑞士，冰岛，挪威和欧盟的25个成员国中被批准用于这种适应症。其他的II期和III期研究显示，鳞状上皮癌患者对不同比例的治疗都有显着反应

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