在关键性一线结直肠癌临床试验中Vectibix达到预期目标

Amgen公司的靶向EGFR的人单克隆抗体Vectibix（panitumumab）在对新诊断的带野生型KRAS基因转移性结直肠癌（meRC）患者的关键性PRIMEⅢ期临床试验中达到它的无病情进展生存（PFS）一级评价终点。目前,Vectibix已在美国和欧盟获准,用于表达EGFR并带有野生型KRAS的晚期结直肠癌患者在几个化疗方案治疗失败后作为三线治疗药。     

西妥昔单抗获准用于结直肠癌的一线治疗

靶向表皮生长因子受体（EGFR）的单克隆抗体现已被批准与化疗药物合用,治疗可表达EGFR、KRAS基因（位于EGFR基因下游区域的一种原癌基因）为野生型且手术不能切除的晚期或复发性肿瘤。礼来ImCloneSystems／默克KmgaA／百时美施贵宝公司合作开发的西妥昔单抗（Erbitux）目前已在日本获准用于转移性结直肠癌的一线治疗。     

结直肠癌靶向药物治疗研究进展

1分子标志物与靶向药物疗效 近年来。结直肠癌的研究重点还是分子靶向治疗,其中最引人注目的是KRAS突变与抗表皮生长因子受体（EGFR）单克隆抗体疗效之间的关系。     

RegⅣ、EGFR 和 survivin 在结直肠癌组织中的表达及临床意义

目的：研究 RegⅣ、EGFR 与 survivin 在结直肠癌组织及正常黏膜内的表达并分析其与临床病理特征的关系。方法采用免疫组化结合组织芯片法,检测150例结直肠癌组织及相应正常黏膜内 RegⅣ、EGFR 与 survivin 的表达情况,并分析其与临床病理特征的关系及三者的相关性。结果结直肠癌组织中 RegⅣ和 EGFR 与 survivin 的蛋白表达均高于与正常黏膜（P ﹤0.05）。RegⅣ和 EGFR 与结直肠癌的分化程度、淋巴结转移及病理分期密切相关,sur-vivin 与结直肠癌的淋巴结转移及病理分期密切相关（ P ﹤0.01）。结直肠癌组织内 RegⅣ与 EGFR、RegⅣ与 survivin、EGFR 与 survivin 表达均呈正相关（P ﹤0.05）。结论 RegⅣ、EGFR 与 survivin 在结直肠癌组织内的表达均增高,提示三者共同参与了结直肠癌的发生与发展,且与结直肠癌的病理分期密切相关,联合检测有利于对结直肠癌的预后进行评估,并为研发靶向药物提供理论支持。     

结直肠癌遗传流行病与药物基因组学研究概述

结直肠癌的发病率与死亡率均位居恶性肿瘤前列,全基因组关联研究开展以来发现了许多与结直肠癌发病有关的位点,基因-基因与基因-环境相互作用研究也有助于阐明结直肠癌的发病机制和影响因素,同时,化疗药物和分子靶向治疗药物的药物基因组学研究也发现药物代谢途径相关的基因突变在药物的疗效和不良反应中起到了关键作用。     

基因多态性与结直肠癌化疗毒性及疗效的关系

摘要： 结直肠癌是发病率和死亡率双高的一种癌症， 化疗是临床中最常用的治疗手段之一， 但不同患者对同样的化疗方案的不良反应和药物敏感性相差很大。越来越多的研究证实这种个体差异与基因多态性密切相关。目前， 基因多态性在结直肠癌靶向治疗中的研究已经普遍被人们接受， 在化疗中的研究也越来越广泛。联合化疗在结直肠癌临床治疗中效果更显著， 明确这些基因多态性位点对于结直肠癌的精准化疗及联合化疗等治疗方法具有重要的指导意义。本文对临床上结直肠癌常用的化疗药物和化疗方案相关的基因多态性及其意义做一综述。     

西妥昔单抗在结直肠癌中的研究与应用

结直肠癌在我国发病呈明显的上升趋势,由于其难以早期发现,患者在接受治疗时往往已经是中晚期,传统的化疗药物不能取得满意的疗效,并且毒副作用明显,患者难以耐受。分子靶向治疗药物以其低毒高效的特点在临床肿瘤治疗中发展迅速,为肿瘤患者个体化治疗开辟了新的道路。表皮生长因子受体(EGFR)在结直肠癌中高表达,它是一种跨膜酪氨酸激酶(TKs)受体,与肿瘤细胞耐药及患者预后密切相关,针对表皮生长因子受体的靶向治疗药物——西妥昔单抗的研发成功为临床结直肠癌的治疗带来了新希望。西妥昔单抗(Cetuximab)是一种嵌合型单克隆抗体,可与肿瘤细胞上的靶向表皮生长因子受体(EGFR)特异性结合,提高肿瘤对化疗的敏感性。本文将就西妥昔单抗在结直肠癌治疗中的作用进行阐述。     

EGFR靶向药物治疗晚期结直肠癌最新进展

随着对肿瘤生长的分子生物学机制研究的不断深入,肿瘤治疗进入了分子靶向治疗的时代,一些新型分子靶向药物用于结直肠癌的治疗取得令人鼓舞的疗效,并成为结直肠癌的标准内科治疗,表皮生长因子受体是结直肠癌靶向治疗的主要靶点之一。     

P53、EGFR对于结直肠癌术后预后的临床价值

目的研究P53和EGFR对于结直肠癌术后预后的临床价值。方法免疫组化法观察结直肠癌中P53和EGFR的表达,探讨其与结直肠癌术后病理特征的相关性。结果 P53的表达与结直肠癌术后各病理特征相关性不明显。不同的是,EGFR高表达和区域淋巴结转移、肿瘤分期密切相关,差异有统计学意义,但与患者年龄、性别、肿瘤直径、肿瘤分化、肿瘤浸润无明显相关。结论 EGFR的表达可作为结直肠癌术后可靠的预后因子。     

结直肠癌靶向及单抗类药物基因组学和不良反应研究的文献计量学分析

目的 分析结直肠癌靶向和单抗类药物基因组学与不良反应相关研究的现状，探索其发展趋势，为后期相关研究提供参考。方法 以Web of Science核心合集为数据来源，结合CiteSpace软件的可视化功能，采用文献计量学方法对2012—2022年抗结直肠癌靶向及单抗类药物基因组学及不良反应方面相关研究文献的作者、研究机构、发文国家、引用文献、发表期刊及关键词进行分析。结果 经过筛选纳入近10年来5 893篇相关文献。涉及基因组学的相关文献4 509篇，美国、日本、意大利、中国是该领域研究的核心国家，掌握绝大多数核心研究；涉及不良反应的相关文献1 384篇，作者平均发文数量较低，且相对独立，形成少数高产作者引领的作者群。关键词整体指向结直肠癌靶向药物、药物治疗靶点、不良反应、预后的生物标记、分子亚型、抗肿瘤联合化疗、药物基因组学生物标志物等。通过对靶向治疗药物的生物标志物的突显，可以对结直肠癌的晚期治疗或者转移性治疗方案进行预后评估。同时可以寻找与靶向治疗药物代谢相关的特殊诊断靶点，发现其生物标志的标记，将会成为今后的研究热点。结论为研究者准确把握抗结直肠癌靶向及单抗类药物的研究现状和发展...     

Panitumumab

Panitumumab, previously known as ABX-EGF, is the first fully human monoclonal antibody to be shown to be effective as a treatment for solid-tumor cancers. Its target is the epidermal growth factor receptor (EGFR), which when overactive may contribute to the development and progression of cancer and is expressed in several solid tumors, including colorectal cancer. In a recently reported phase III trial, patients with metastatic colorectal cancer who had failed previous treatment with oxaliplatin- and irinotecan-based therapy were randomized to receive single-agent panitumumab and best-supportive care, or best-supportive care alone. This trial demonstrated a significant improvement in progression-free survival with panitumumab treatment in these patients. A rash similar to that which occurs with the other anti-EGFR antibody, cetuximab, has been observed in up to 100% of patients treated with panitumumab in the various clinical trials. As with other EGFR antagonists, EGFR staining by immunohistochemistry has not been shown to be an effective method of selecting patients for treatment, whereas the severity of the rash appears to be predictive of outcome. Ongoing randomized trials are evaluating the use of panitumumab with combination treatment for the first-line treatment of metastatic colorectal cancer. This review summarizes the rationale for targeting the EGFR and the development of panitumumab in preclinical and early phase trials in several tumor types. Clinical trial results in colorectal cancer, in which the development of this agent is most advanced, will also be discussed, as will the rash associated with treatment.     

西妥昔单抗联合NK-DC在肿瘤治疗中的研究进展

目的西妥昔单抗作为一种EGFR的单克隆抗体已广泛应用于结直肠癌、头颈部肿瘤等癌症的治疗中。最近的研究证明其对肿瘤免疫起着重要的作用,尤其是对NK和DC细胞的影响,及对NK介导的ADCC作用。本文总结了西妥昔单抗的抗肿瘤作用,及其对NK-DC的抗肿瘤作用的影响,以便未来对肿瘤过继性免疫治疗提供方案。     

Cetuximab: an IgG(1) monoclonal antibody for the treatment of epidermal growth factor receptor-expressing tumours

The epidermal growth factor receptor (EGFR) plays an essential role in normal cell growth and differentiation and in the survival of healthy and cancerous cells. EGFR expression is a common feature of non-haematological malignancies and is associated with poor clinical prognosis. Cetuximab is an IgG(1) monoclonal antibody that blocks EGFR activation. It has efficacy alone, and in combination with irinotecan, in the treatment of metastatic colorectal cancer that has progressed on irinotecan-containing therapy. It has been approved for use in combination with irinotecan in both Switzerland and the US and as monotherapy in the US. Cetuximab also has efficacy in cancers of the head and neck and non-small cell lung cancer. Cetuximab is well-tolerated and does not exacerbate the side effects of co-administered cytotoxic chemotherapy.     

Cetuximab: an IgG1 monoclonal antibody for the treatment of epidermal growth factor receptor-expressing tumours

The epidermal growth factor receptor (EGFR) plays an essential role in normal cell growth and differentiation and in the survival of healthy and cancerous cells. EGFR expression is a common feature of non-haematological malignancies and is associated with poor clinical prognosis. Cetuximab is an IgG₁ monoclonal antibody that blocks EGFR activation. It has efficacy alone, and in combination with irinotecan, in the treatment of metastatic colorectal cancer that has progressed on irinotecan-containing therapy. It has been approved for use in combination with irinotecan in both Switzerland and the US and as monotherapy in the US. Cetuximab also has efficacy in cancers of the head and neck and non-small cell lung cancer. Cetuximab is well-tolerated and does not exacerbate the side effects of co-administered cytotoxic chemotherapy.     

Molecularly targeted therapy for gastrointestinal cancer

Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.     

Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer

Treatment of metastatic colorectal disease has evolved over the last decade. Two epidermal growth factor receptor (EGFR) monoclonal antibodies--cetuximab and panitumumab--have been developed in an effort to provide yet another therapeutic option. The EGFR is a transmembrane glycoprotein, expressed constitutively throughout the body and found on many epithelial tissues. The monoclonal antibodies bind to and inhibit the activation of the receptor in the body. This inhibition prevents tumor cell growth, angiogenesis, invasion, and metastasis, and induces apoptosis. Cetuximab and panitumumab exhibit nonlinear pharmacokinetics. Both monoclonal antibodies are approved for the treatment of refractory metastatic colorectal cancer. Cetuximab in combination with irinotecan has significantly better response rates and progression-free survival compared with those of cetuximab or irinotecan alone. Cetuximab and panitumumab as monotherapy have shown significantly better response rates and progression-free survival compared with best supportive care in patients refractory to irinotecan and oxaliplatin. In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, treatment-na?ve patients received cetuximab in combination with the chemotherapy regimen infusional leucovorin, fluorouracil, and irinotecan (FOLFIRI) or FOLFIRI alone; the difference in progression-free survival was statistically significant but suggested only a modest benefit over FOLFIRI alone (8.9 vs 8 mo, p=0.036). Results of a preplanned analysis of the first 231 events in the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial favored the control group (chemotherapy regimen with folinic acid [leucovorin], fluorouracil, and oxaliplatin [FOLFOX] plus bevacizumab) instead of the control group plus panitumumab. For clinical consideration, many trials have shown that the intensity or absence of EGFR expression is not a clinically significant predictor of outcomes. Development and intensity of a rash are suggested to be a positive predictor of outcomes in patients. The most common adverse events of EGFR monoclonal antibody therapy are rash, diarrhea, and hypomagnesemia. Other serious but not common adverse events include hypersensitivity reactions and pulmonary toxicity. The availability of EGFR monoclonal antibodies has provided another weapon in the arsenal to treat refractory metastatic colorectal cancer. They have shown safety and efficacy in combination with other chemotherapy regimens and as monotherapy; however, their use as metastatic colorectal cancer therapy needs to be further explored.     

尼妥珠单抗联合FOLFIRI化疗治疗术后复发转移性结直肠癌的临床观察

目的：观察和评价表皮生长因子受体（EGFR）的单克隆抗体尼妥珠单抗（nimotuzumab）联合FOLFIRI化疗治疗术后复发转移性结直肠癌的近期疗效和不良反应。方法：入组患者为经手术治疗后复发转移性结直肠癌患者17例,应用尼妥珠单抗联合伊立替康＋亚叶酸钙＋氟尿嘧啶两周方案（FOLFIRI）,尼妥珠单抗剂量200mg·m-1,每2周（200mg·m-1）1次维持。治疗4个周期后评价疗效。结果：全组17例完全缓解1例,部分缓解7例,稳定7例,进展2例,总有效率47．1％。不良反应主要是恶心呕吐、骨髓抑制、迟发性腹泻、胆碱能综合征等。结论：尼妥珠单抗联合FOLFIRI化疗治疗术后复发转移性结直肠癌疗效肯定,不良反应可耐受,可供临床安全使用。     

Cetuximab: in the treatment of metastatic colorectal cancer

Cetuximab is a chimeric monoclonal antibody highly selective for the epidermal growth factor receptor (EGFR), which is over-expressed by 25-80% of colorectal cancer tumours and associated with advanced disease. Cetuximab induces a broad range of cellular responses in tumours expressing EGFR, enhancing sensitivity to radiotherapy and chemotherapeutic agents. In a large, randomised, open-label, multicentre study in adult patients with irinotecan-refractory, metastatic colorectal cancer expressing EGFR, cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 weekly plus irinotecan (various doses) produced a greater rate of partial response and disease control (partial response plus stable disease), and increased time to disease progression, compared with cetuximab monotherapy; survival was similar in both groups. The same dosage of cetuximab combined with irinotecan, fluorouracil and folinic acid (various regimens) produced partial responses in 43-58% of patients, a complete response in 5% of patients (one study only) and stable disease in 32-52% of patients with treatment-naive metastatic colorectal cancer expressing EGFR in three small, open-label trials. The most common grade 3/4 adverse events associated with cetuximab monotherapy were acne-like rash, asthenia, abdominal pain and nausea/vomiting. In patients receiving cetuximab plus irinotecan, these were diarrhoea, asthenia, leucopenia and neutropenia.     

Cetuximab, its clinical use and future perspectives

Increase in the expression of epidermal growth factor receptors (EGFRs) has been observed in many tumours. EGFR overexpression usually correlates with a more advanced stage of the disease, a poorer prognosis and a worse chemotherapy response. For all the aforementioned reasons, EGFR inhibition can be considered an attractive approach in cancer treatment. One strategy has been extracellular domain receptor inhibition, using monoclonal antibodies. In this review, we summarize the current status as well as what is likely to be the future use of monoclonal antibodies directed against EGFR. We have focussed on cetuximab being the most developed one. It has been mainly studied in colorectal cancer, and the major portion of this review will focus on all the research that has been carried out on this tumour. Clinical development of cetuximab is also important in head and neck cancer and in lung cancer. Interesting studies have been carried out in pancreatic, gastric, oesophageal and ovarian tumours, as well as in malignant gliomas.     

EGFR-targeted immunoliposomes derived from the monoclonal antibody EMD72000 mediate specific and efficient drug delivery to a variety of colorectal cancer cells

We hypothesized that immunoliposomes (ILs) constructed using Fab' from the humanized anti-EGFR monoclonal antibody, EMD72000, can provide efficient intracellular drug delivery in EGFR-overexpressing colorectal tumor cells.ILs were constructed modularly with various MAb fragments, including Fab' from EMD72000 (matuzumab) or C225 (cetuximab, Erbitux) covalently linked to stabilized liposomes containing chemotherapeutic drugs or probes. Immunoliposome preparation was optimized, including Fab' reduction and linkage, and evaluated for specific binding and cytotoxicity in epidermal growth factor receptor (EGFR)--overexpressing colorectal cancer cell lines in vitro. Flow cytometry showed that EGFR-targeted ILs, but not non-targeted liposomes or irrelevant ILs, were efficiently bound and internalized by a variety of EGFR-overexpressing colorectal cancer cells. Linkage of the Fab' to a longer PEG chain (Mal-PEG3400-DSPE) resulted in an increased uptake of immunoliposomal constructs when compared to previously used materials (Mal-PEG2000-DSPE). ILs derived from EMD72000-Fab' were used to deliver doxorubicin to EGFR-overexpressing target cells in vitro. Immunoliposomal doxorubicin was significantly more cytotoxic than the corresponding non-targeted liposomal drug in target cells, such as HCT116, while equivalent in cells lacking EGFR-overexpression, such as Colo205. We conclude that EGFR-targeted ILs derived from the humanized MAb EMD72000 provide efficient and targeted delivery of anticancer drugs in colorectal cancer cells overexpressing EGFR.