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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 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.
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PMID:Cetuximab: an epidermal growth factor receptor chemeric human-murine monoclonal antibody. 1582 83

The epidermal growth factor receptor (EGFR) is a member of the HER family of tyrosine kinase growth factor receptors. Binding to EGFR by its natural ligands, mainly epidermal growth factor (EGF) or transforming growth factor (TGF)-alpha, results in a conformational change in the receptor, which promotes homo- or heterodimerisation or oligomerisation with other EGFR molecules or other HER family members. Dimerisation results in the activation of intracellular tyrosine kinase, autophosphorylation and activation of signal transduction molecules, ultimately leading to cell cycle progression, reduced apoptotic capacity, angiogenesis and the metastatic phenotype. EGFR is expressed on normal human cells and also across a range of malignancies. Tumour EGFR expression correlates with poor prognosis and resistance to therapy. Cetuximab is a chimeric human:murine monoclonal antibody that binds competitively to the EGFR. Binding of the antibody to the EGFR prevents activation of the receptor by endogenous ligands; proliferation is reduced, apoptosis enhanced, and angiogenesis, invasiveness and metastasis reduced. Binding of cetuximab to the receptor also results in internalisation and degradation of the antibody-receptor complex, downregulating EGFR expression. EGFR has been recognised as an important therapeutic target in cancer. Other antibodies are also in development, and small molecular inhibitors of the tyrosine kinase domain are available. Cetuximab adds to the activity of radiotherapy in locoregional head and neck cancer, and when given with platinum-based chemotherapy is active in a proportion of patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck, as is cetuximab monotherapy. When cetuximab is added to cisplatin monotherapy in the first-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck, the objective response rate is significantly improved and the hazard ratio for progression is 0.78. The most commonly reported adverse event associated with cetuximab treatment is an acneiform rash that occurred in 70 - 80% of patients treated with cetuximab. Presence of the characteristic rash is significantly associated with response and/or survival. It is possible that development of acneiform rash may become an important clinical prognostic marker. Serious cetuximab-related toxicities include hypersensitivity reactions. Thus, cetuximab is biologically active across a range of clinical scenarios in squamous cell carcinoma of the head and neck. Ongoing studies will be important in establishing its role in the routine management of head and neck cancer.
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PMID:The role of cetuximab in the treatment of squamous cell cancer of the head and neck. 1605 Jul 85

Signaling pathways activated by epidermal growth factor receptor (EGFR) are pathogenetically involved in the development of head and neck squamous cell carcinomas (HNSCC). A monoclonal antibody against the EGFR protein blocking the receptor activity (cetuximab - Erbitux - C225) is now available for therapeutic applications. The mechanisms of EGFR protein overexpression are poorly understood. Regulatory pathways, EGFR gene structural changes or its amplification may be involved. The aim of the study was to evaluate expression of the EGFR protein in patients with HNSCC, to identify EGFR gene copy numbers, and to find out whether the protein overexpression is associated with the EGFR gene amplification. In the case of a pathogenetical link of the EGFR gene amplification and the protein overexpression it would be useful to employ both diagnostic approaches to identify patients eligible for cetuximab therapy. We investigated 33 patients with HNSCC. The expression of EGFR protein was evaluated by immunohistochemistry, copy numbers of EGFR gene and the numbers of chromosome 7 centromeric signals were investigated by fluorescence in situ hybridization on interphasic nuclei (I-FISH). Histological sections from formalin fixed and paraffin embedded tissues were used. We observed three types of EGFR protein expression (homogeneous 3+ membrane positivity in 13 patients; membrane positivity varying from 1+ to 3+ in 12 patients; a strong membrane positivity at the periphery of the tumor cell clusters in 5 patients). In two cases the results were difficult to interpret. In one case single tumor cells only were positive. Numerical changes of chromosome 7 were present in 23 patients. We found the EGFR gene amplification in seven patients. The tumor cells with amplification of the EGFR gene were generally infrequent and were localized in small clusters, or they were randomly dispersed between the tumor cell population without the gene amplification. We did not find any correlation between the EGFR gene amplification and the EGFR protein overexpression. Thus, amplification of the EGFR gene is not pathogenetically involved in the EGFR protein overexpression. From the diagnostic aspect a standardized immunohistochemical assessment of the EGFR protein expression appears sufficient for detection of the EGFR status. Criteria for cetuximab treatment in patients with HNSCC may differ from those already used for patients with colorectal carcinomas and should take different patterns of the EGFR protein overexpression into consideration.
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PMID:Epidermal growth factor receptor--its expression and copy numbers of EGFR gene in patients with head and neck squamous cell carcinomas. 1605 52

The most significant recent advances in the application of monoclonal antibodies (mAbs) to oncology have been the introduction and approval of bevacizumab (Avastin), an anti-vascular endothelial growth factor antibody, and of cetuximab (Erbitux), an anti-epidermal growth factor antibody. In combination with standard chemotherapy regimens, bevacizumab significantly prolongs the survival of patients with metastatic cancers of the colorectum, breast and lung. Cetuximab, used alone or with salvage chemotherapy, produces clinically meaningful anti-tumor responses in patients with chemotherapy-refractory cancers of the colon and rectum. In addition, the anti-HER2/neu antibody trastuzumab (Herceptin), in combination with standard adjuvant chemotherapy, has been shown to reduce relapses and prolong disease-free and overall survival in high-risk patients after definitive local therapy for breast cancer. These exciting recent results provide optimism for the development of mAbs that bind novel targets, exploit novel mechanisms of action or possess improved tumor targeting. Progress in the clinical use of radioimmunoconjugates remains hindered by complexity of administration, toxicity concerns and insufficiently selective tumor targeting.
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PMID:Monoclonal antibody therapy of cancer. 1615 8

Strategies for the treatment of metastatic colorectal cancer must take into account the contribution of monoclonal antibodies. A group of new efficient tools in oncology, these drugs target tumor antigens. Bevacizumab recognizes VEGF. Vascular endothelial growth factor (VEGF) is a key mediator in angiogenesis. This antibody combined with chemotherapy increases the survival of patients treated for metastatic colorectal cancer. Median survival of patients treated with antibodies and chemotherapy is 20 months, compared with only 15 months for patients treated with chemotherapy alone. Cetuximab is a monoclonal antibody that binds competitively and with high affinity to the EGF receptor. Cetuximab is currently approved for use in patients with pretreated colorectal cancer. EGF is a major cell growth factor. The side effects of these new biotherapies are different from chemotherapy: bevacizumab affects vascular elements and the most common side effect of anti-EGFR treatment is acneiform skin rash.
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PMID:[Biotherapy in colorectal cancer]. 1629 7

This study aimed to assess the effect of cetuximab (C225, Erbitux, a chimeric anti-epidermal growth factor receptor (EGFR) monoclonal antibody) in combination with oxaliplatin in vitro and in vivo on four colon cancer cell lines (HCT-8; HT-29, SW620, HCT-116) expressing different levels of EGFR. In vitro, cetuximab combined with oxaliplatin significantly decreased the IC50 values of oxaliplatin in HCT-8 (EGF-R moderate) and HT-29 (EGF-R weak) cell lines, while SW620 (EGF-R negative) and HCT-116 (EGFR strong) cell lines remained unresponsive. This combination was synergistic in HCT-8 and HT-29 cell lines while cetuximab induced no major modification of the IC50 of oxaliplatin in HCT-116 or SW620 cell lines. We then determined the effect of cetuximab on the EGF-induced EGFR phosphorylation and we highlight a correlation between the basal level of phospho-EGFR and the response to the combination. In vivo, the combination of cetuximab plus oxaliplatin significantly inhibited tumor growth of HCT-8 and HT-29 (tumor delay or Td = 21.6+/-2.9 and 18.0+/-2.9 days respectively, synergistic effect) compared to either oxaliplatin (Td=12.6+/-2.3 and 14.4+/-3.2 days respectively) or cetuximab (Td=13.4+/-2.9 and 14.5+/-2.4 days, respectively) alone in xenograft models. The combination had no effect on HCT-116 and SW-620 cell lines. The observed responses are strictly dependent on the cell type, and are not correlated with the level of EGFR expression but related to the basal level of phospho-EGFR. This study provides promising preclinical results for a possible clinical investigation of the combination of oxaliplatin plus cetuximab in chemorefractory colorectal tumors.
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PMID:In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR. 1632 55

The epidermal growth factor receptor (EGFR) provides survival signals and is overexpressed in the majority of colorectal cancers. As more is learned about the molecular details of EGFR signaling, antibodies can be designed to interfere with specific domains of the EGFR molecule. In this review, we analyze preclinical and current clinical data on EGFR-targeting molecules and their potential role in the treatment of colorectal cancer. Cetuximab binds to domain III of EGFR and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment. Panitumumab is another widely studied anti-EGFR antibody with similar properties. Bispecific antibodies are modified immunoglobulin molecules containing 2 different binding specificities. These antibodies can redirect the immune response against tumor cells by tethering effector cells such as CD3e-expressing T cells or CD16-expressing natural killer cells and granulocytes to the surface of cancer cells. Tyrosine kinase inhibitors are quinazoline-derived, low molecular weight synthetic molecules that can block the intracellular tyrosine kinase domain of several receptors, including EGFR, Erb2, and vascular endothelial growth factor receptor, and thereby inhibit ligand-induced receptor phosphorylation and abrogate the biologic effect of EGFR signaling. The presence of skin rash and EGFR gene amplification have been advanced as possible predictors of clinical effectiveness of targeted anti-EGFR therapies.
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PMID:Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer. 1633 52

Extensive treatment-related morbidities and stagnant survival rates over the past few decades for patients with squamous cell cancer of the head and neck (SCCHN) emphasize the need for novel diagnostics and therapeutics based on the molecular characteristics of the tumor. The development of an early detection test remains largely preliminary. Much attention has recently been given to saliva-based early detection assays that use accepted tumor markers such as p53 and DNA methylation. Most of these studies have focused on feasibility as opposed to prospective clinical trials. To date, early detection saliva assays have failed to yield a high enough sensitivity and specificity for broad population-based screening. The use of saliva as a noninvasive, inexpensive, and accessible diagnostic substrate remains desirable. Unlike SCCHN diagnostics, molecular-targeted therapies for SCCHN will soon be a reality, with many more compounds in the pipeline. The most promising of these drugs target the epidermal growth factor receptor (EGFR), which is known to be overexpressed in squamous cell carcinomas. Cetuximab, a monoclonal EGFR antibody, has shown efficacy in combination with radiotherapy in advanced SCCHN in a recent phase III trial and is currently being petitioned for US Food and Drug Administration approval. Likewise, erlotinib, an EGFR tyrosine kinase inhibitor, has shown favorable results in phase II trials as monotherapy and in combination with chemotherapy. Gefitinib, another EGFR tyrosine kinase inhibitor, has shown efficacy as monotherapy, in combination with chemotherapy, and with chemoradiotherapy. At least two phase III trials of gefitinib in patients with advanced SCCHN are ongoing. Such low-toxicity, tumor-specific targeting strategies will soon be available for patients with head and neck cancer. The challenge is to establish assays to determine which patients are most likely to benefit from these agents.
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PMID:Advances in molecular diagnostics and therapeutics in head and neck cancer. 1634 64

The erbB family of receptor tyrosine kinases plays critical roles in human cancers, including pancreatic cancer. Discovering a specific agent, which targets multiple members of the erbB family, would be important in pancreatic cancer therapy. Recently, we isolated a novel negative regulator of epidermal growth factor receptor (EGFR), termed EGFR-related protein (ERRP), whose expression attenuates EGFR activation. In the current study, we examined the effects of recombinant ERRP on the growth and ligand-induced activation of multiple members of erbB family in three pancreatic cancer cell lines that express varying levels of EGFR and other member(s) of its family, specifically HER-2. Additionally, we compared the growth inhibitory effect of ERRP with that of Erbitux or Herceptin. Our results showed that ERRP is most effective in inhibiting proliferation of BxPC-3, HPAC, and PANC-1 pancreatic cancer cells. ERRP also inhibited ligand-induced activation of EGFR, HER-2, and HER-3 (ErbB3). In contrast, Erbitux and Herceptin only partially or modestly inhibited activation of EGFR, HER-2, and HER-3. Most importantly, ERRP was found to inhibit pancreatic tumor growth in a severe combined immunodeficient mouse xenograft model. The antitumor activity of ERRP correlates well with tumor differentiation and down-regulation of nuclear factor-kappaB activity. In summary, our results suggest that ERRP is an effective pan-erbB inhibitor, which could be a potential therapeutic agent for pancreatic cancers expressing different levels and subclasses of erbB family of proteins.
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PMID:Antitumor activity of epidermal growth factor receptor-related protein is mediated by inactivation of ErbB receptors and nuclear factor-kappaB in pancreatic cancer. 3021 87

We have constructed a drug delivery vehicle that targets the epidermal growth factor receptor (EGFR) and its mutant isoform EGFRvIII. The monoclonal antibody, cetuximab, previously known as C225, which binds to both EGFR and EGFRvIII, was covalently linked via its Fc region to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. As measured by mass spectrometry and UV/vis spectroscopy, the resulting bioconjugate, designated C225-G5-MTX, contained 12.6 molecules of methotrexate per unit of dendrimer. Specific binding and cytotoxicity of the bioconjugate was evaluated against the EGFR-expressing rat glioma cell line F98(EGFR). Using a competitive binding assay, it was shown that the bioconjugate retained its affinity for F98(EGFR) cells, with a 0.8 log unit reduction in its EC(50). Only cetuximab completely inhibited binding of the bioconjugate, which was unaffected by methotrexate or dendrimer. Cetuximab alone was not cytotoxic to F98(EGFR) cells at the concentration tested, whereas the IC(50) of the bioconjugate was 220 nmol/L, which was a 2.7 log unit decrease in toxicity over that of free methotrexate. The biodistribution of C225-G5-MTX in rats bearing i.c. implants of either F98(EGFR) or F98(WT) gliomas was determined 24 hours following convection enhanced delivery of (125)I-labeled bioconjugate. At this time, 62.9 +/- 14.7% ID/g tumor was localized in rats bearing F98(EGFR) gliomas versus 11.3 +/- 3.6% ID/g tumor in animals bearing F98(WT) gliomas, thereby showing specific molecular targeting of the tumor. The corresponding radioactivity of normal brain from the F98(EGFR) tumor-bearing right and non-tumor-bearing left cerebral hemisphere were 5.8 +/- 3.4% and 0.8 +/- 0.6% ID/g, respectively. Based on these results, therapy studies were initiated in F98(EGFR) glioma-bearing rats. Animals that received C225-G5-MTX, cetuximab, or free methotrexate had median survival times of 15, 17, and 19.5 days, respectively, which were not statistically different from each other or untreated control animals. Our results, which are both positive and negative, show that specific molecular targeting is but one of several requirements that must be fulfilled if an antibody-drug bioconjugate will be therapeutically useful.
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PMID:Targeted delivery of methotrexate to epidermal growth factor receptor-positive brain tumors by means of cetuximab (IMC-C225) dendrimer bioconjugates. 1643 62


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