西妥昔单抗:表皮生长因子受体chemeric human-murine单克隆抗体。
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哈丁J, Burtness B
西妥昔单抗:表皮生长因子受体chemeric human-murine单克隆抗体。
今天药物(巴克)。2005年2月,41(2):107 - 27所示。doi: 10.1358 / dot.2005.41.2.882662。
- PubMed ID
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15821783 (在PubMed]
- 文摘
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表皮生长因子受体(EGFR)受体ErbB家族的一员。它由细胞外的领域,包括一个配体结合域,疏水跨膜区域和酪氨酸kinase-containing胞质区域。刺激表皮生长因子受体的内源性配体,表皮生长因子、转化生长因子-α(是),导致受体的构象变化,允许它进入二聚体和其他低聚物。二聚作用导致激活细胞内酪氨酸激酶,蛋白质磷酸化和刺激多种细胞信号通路介导基因转录和细胞周期进程。表皮生长因子受体表达在正常的人类细胞,但高水平表达的受体也被证明是与恶性肿瘤在各种癌症。此外,恶性肿瘤细胞表皮生长因子受体的表达与预后不良相关和抵抗治疗。西妥昔单抗是一种嵌合human-murine单克隆抗体,结合竞争力和高表皮生长因子受体的亲和力。绑定的表皮生长因子受体抗体阻止刺激受体的内源性配体,导致细胞增殖,抑制增强细胞凋亡,减少血管生成,侵袭性和转移。结合西妥昔单抗的受体还导致内化antibody-receptor复杂的表皮生长因子受体表达的差别导致整体对这些。表皮生长因子受体是一种新的抗癌治疗的主要目标,和其他代理的发展包括小分子酪氨酸激酶抑制剂和反义疗法。 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 added to 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/m2 as a loading dose followed by weekly infusions of 250 mg/m2. 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 carcinoma of the head and neck, non-small cell lung cancer and pancreatic cancer when cetuximab is used first or second line in combination with chemotherapy. Thus, cetuximab is emerging as a very promising new therapy to be used in conjunction with existing therapies for the treatment of a spectrum of solid tumors.