Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the epidermal growth factor receptor (EGFR) and its increased tyrosine kinase activity are implicated in colorectal cancer (CRC) development and malignant progression. The C57BL/6J-Min/+ (Min/+) mouse is a model for CRC and develops numerous intestinal adenomas. We analyzed the normal mucosa of Min/+ and Apc+/+ (WT) littermate mice together with Apc-null adenomas to gain insight into the roles of Egfr in these intestinal tissues. Protein analyses showed that Egfr activity was highest in the tumors, and also up-regulated in Min/+ relative to WT enterocytes. Expression of ubiquitylated Egfr (Egfr-Ub) was increased in Min/+ enterocytes and tumors. Tumors exhibited increased association of Egfr with clathrin heavy chain (CHC), Gab1, and p85alpha, the regulatory subunit of phosphoinositide 3-kinase (PI3K), and tumors also overexpressed c-Src, PDK1, and Akt. Immunohistochemistry for Akt-p-Ser473 revealed a low level of this active kinase in Min/+ and WT enterocytes and its strong presence in tumors. Prostaglandin E2 (PGE2) is a product of cyclooxygenase-2 (Cox-2) activity that is up-regulated in Min/+ tumors and transactivates Egfr. PGE2 expression was significantly higher in untreated Min/+ tumors and reduced by treatment with the Cox-2 inhibitor, celecoxib. Dietary administration of this NSAID also inhibited Egfr activity in tumors. Increased activation of the EGFR-PI3K-Akt signaling pathway in tumors relative to Apc+/+ and ApcMin/+ enterocytes provides potential opportunities for therapeutic interventions to differentially suppress tumor formation, promotion, progression, and/or recurrence.
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PMID:Apc deficiency is associated with increased Egfr activity in the intestinal enterocytes and adenomas of C57BL/6J-Min/+ mice. 1529 12

Metastatic disease is present at diagnosis in 30% of the patients with colorectal cancer (CRC), and approximately half of early-stage patients with CRC will eventually present with metastatic disease. Until recently, few chemotherapy options were available to treat metastatic colorectal carcinoma (MCRC). Fluorouracil (5-FU) with leucovorin (LV) modulation has a marginal but positive effect on survival in those patients. The recent incorporation of irinotecan (CPT-11) and oxaliplatin for the management of advanced CRC has generated further improvement in survival. The development of oral fluoropyrimidines, mimicking continuous infusion 5-FU, is convenient to use. Recently completed or ongoing clinical trials to study novel targeting agents have initiated a new era of drug development. Anti-angiogenesis drugs, tyrosine kinase inhibitors, and epidermal growth factor blockers are among the new generation of agents.
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PMID:Meta-analysis of new treatment strategies for metastatic colorectal cancer. 1914 83

Angiogenesis, the formation of blood vessels, is a vital process in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a potential target for antiangiogenic therapy because its overexpression has been associated with tumor vascularity, poor prognosis, and aggressive disease in many malignancies, including colorectal cancer (CRC). Bevacizumab is a recombinant humanized monoclonal antibody against VEGF. It is the first angiogenesis inhibitor to show significant activity in patients and, when combined with chemotherapy, leads to a significant survival benefit in CRC. This monoclonal antibody has been approved for first-line therapy in combination with intravenous 5-fluorouracil-containing regimens in patients with metastatic CRC. Vatalanib (PTK787/ZK222584) is an oral antiangiogenic tyrosine kinase inhibitor of the VEGF receptor. Currently, it is being evaluated in combination with FOLFOX (5-fluorouracil/leucovorin/oxaliplatin) in metastatic CRC. This article reviews the process of angiogenesis and the successful translation of antiangiogenic agents into the clinic. Specifically, studies evaluating VEGF-targeted agents in combination with oxaliplatin-containing regimens in CRC are discussed.
Clin Colorectal Cancer 2004 Oct
PMID:Combining anti-VEGF approaches with oxaliplatin in advanced colorectal cancer. 1547 83

This study represents an attempt of showing own author's example of using basic research data as an inspiration for the clinical studies. The project evaluates the role of gastrin in colorectal carcinogenesis as well as the differences of its action in proximal and distal colon. Colonocytes were isolated from Fischer-344 rats and incubated for 2 minutes with gastrin (10(-8)M). This treatment resulted with 60-70% rise in tyrosine kinase (Tyr-k) and 150-200% - in phospholipase C activity as regards to basal levels. In vivo infusion of gastrin for 5 days to Fischer-344 rats resulted with 90-150% increase in distal but not proximal colonic mucosal proliferative activity as well as tyrosine phosphorylation of several colonic mucosal proteins. In clinical study, the mean fasting gastrin level in the control group was significantly lower (p<0.01) than in patients with colorectal cancer before surgery. Mean plasma gastrin level in patients with distal tumor yielded 105,31 +/- 12,5 microU/l and was significantly higher than in patients with the proximal tumor site (42, 2 +/- 3,1 microU/l) (p<0,001). We conclude, that Tyr-k is involved in the mechanism of the trophic action of gastrin, particularly in distal colon. The differences in gastrin concentration in patients with distal and proximal tumors may probably contribute to the distinct pathogenesis and biological properties of those cancers.
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PMID:Experimental studies as an inspiration for clinical investigation. 1560 68

An international meeting on 'New Drugs in Cancer Therapy' was held at the National Tumor Institute of Naples, on 17-18 June 2004. The first session of the meeting focused on analogs of conventional anti-cancer drugs, such as taxanes, platinum compounds, anthracyclines and topoisomerase I inhibitors. The data of a phase II trial of BMS-247550, an epothilone B analog, in patients with renal cell carcinoma were reported. Data were also presented on BBR-3464, a trinucleate platinum analog which was developed on the grounds of greater potency, a more rapid rate of DNA binding and the ability to induce apoptosis regardless of the p53 status of the cell. Pegylated-coated liposomal formulation doxorubicin (Caelyx) has shown efficacy in metastatic breast cancer and in advanced ovarian cancer; sabarubicin is a third-generation anthracycline with equal or superior potency to doxorubicin or idarubicin in a variety of human tumor cell lines of different histotypes. The main mechanisms of resistance to topoisomerase I inhibitors were discussed; data on diflomotecan were reported, showing a narrow therapeutic index of the drug. The second session of the meeting focused on the ErbB family as a target for anti-cancer therapy. Recent evidence of a correlation between epidermal growth factor receptor (EGFR) mutations at exons 18-21 and clinical response of advanced non-small cell lung cancer to gefitinib therapy was commented on. The issue of the association between ErbB2 expression and gefitinib activity was addressed, while clinical data of a phase II study of gefitinib in advanced breast cancer were presented. Monoclonal antibodies targeting EGFR represent another worthwhile way to interfere with EGFR-driven signal transduction. Cetuximab is reaching market registration in advanced colorectal cancer; in particular, due to the results of the BOND study. The recently presented results of the Bonner study strongly support the activity of this drug in head and neck cancer. A step forward in the research on anti-EGFR monoclonal antibodies may be represented by humanized monoclonal antibodies, such as EMD 72000 and ABX-EGF. Imatinib mesylate is probably the most outstanding example of an effective targeted therapy--its activity in gastrointestinal stromal tumors was so exciting that the drug reached the market without undergoing phase III evaluation. The third session of the meeting was on angiogenesis inhibitors. Drugs may interfere with the angiogenic process via different mechanisms and there is a sound rationale for combining anti-angiogenic agents with chemotherapy or multiple anti-angiogenic strategies. Clinical results obtained with direct anti-angiogenic agents have been negative up to now, but some exciting results have been seen with bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF). A few VEGF-tyrosine kinase inhibiting small molecules, such as ZD6474, AZD2171 and PTK/ZK, are undergoing clinical trials. The fourth session of the meeting was on interference with intracellular signal transduction. Farnesyl transferase inhibitors exert their action by interfering with either pro-Ras or RhoB farnesylation. Several clinical studies of different phases with compounds belonging to this class have been carried out, either alone or in combination with chemotherapy; unfortunately, all of them have turned out to be negative. Cell cycle inhibitors, such as CYC-202 and BMS-387032, represent a class of interesting compounds which are in the early phase of development and whose clinical results are eagerly awaited. Another strategy to achieve cell cycle inhibition is to target heat shock protein 90, a molecular chaperone required for protein folding. Clinical data on depsipeptide, a histone deacetylase (HDAC) inhibitor with activity in T cell lymphoma, were presented. Suberoylanilide hydroxamic acid is another small molecular weight inhibitor of HDAC activity. Phase I/II clinical trials have shown low toxicity and evidence of anti-tumor activity; on the other hand, this compound has potential for synergism with radiotherapy, chemotherapy and biologicals.
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PMID:New drugs in cancer therapy, National Tumor Institute, Naples, 17-18 June 2004. 1565 20

Epidermal growth factor receptor (EGFR) belongs to a family of receptors known as the ErbB family (ErbB tyrosine kinase receptors) which comprises four proteins encoded by the c-erbB proto-oncogene. EGFR is known to activate a cascade of multiple signaling pathways that facilitate tumor growth process. EGFR has been shown to be overexpressed in colorectal cancer patient populations but its prognostic value in colorectal cancer progression remains unclear. The development of a panel of EGFR inhibitors could reduce the proliferation of tumor cells when used alone or in combination with cytotoxic drugs or radiation. This review focuses on the potential role of EGFR signaling in the survival of colorectal tumor cells and the possible modulation of such signaling pathways by EGFR inhibitors so as to increase tumor control or render tumor cells more sensitive to conventional therapy.
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PMID:Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives. 1566 69

The epidermal growth factor receptor (EGFR) plays an important role in cell growth, differentiation, and survival. Targeting EGFR in patients with colorectal cancer has become an important therapeutic tool. Recently, a monoclonal antibody against the extracellular domain of the receptor (cetuximab [Erbitux]) has been approved for the treatment of patients with EGFR-positive metastatic disease refractory to irinotecan (Camptosar)-based therapy. The role of other targeted agents against EGFR, including other monoclonal antibodies as well as inhibitors of the intracellular tyrosine kinase domain, will also be discussed.
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PMID:Epidermal growth factor receptor inhibitors and colorectal cancer. 1568 32

Considerable progress has been achieved in the treatment of colorectal cancer over the last few years, but it remains a major cause of cancer death in the United States. Among the most important recent developments is the understanding that angiogenesis is a fundamental requirement of early tumor growth and metastasis and therefore is an important target for therapy. The recent positive results obtained by adding bevacizumab to a standard regimen of chemotherapy highlight the potential impact of angiogenesis. Although not the final answer to the problem of advanced colorectal cancer, the success obtained with bevacizumab should encourage the development of even more effective and less toxic molecular targeted agents and regimens. The tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) is in the final stages of clinical development, and several other promising compounds will be available for clinical development in the near future. Agents already commercially available, such as the monoclonal antibody cetuximab, may have some antiangiogenic properties as well. However, the greatest benefit from antiangiogenic therapies may come from their combined use, not only with conventional chemotherapy but also with other molecular targeted agents, radiotherapy, and surgery in a true multidisciplinary approach.
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PMID:Future directions in the use of antiangiogenic agents in patients with colorectal cancer. 1569 26

The epidermal growth factor receptor (EGFR) is the prototypical member of the erbB receptor family. The EGFR axis is activated by a variety of ligands that are crucial in the formation and propagation of many tumors, including colorectal cancer, through their effects on cell signaling pathways, cellular proliferation, control of apoptosis, and angiogenesis. The importance of the EGFR axis in tumorigenesis and tumor progression makes it an attractive target for the development of anticancer therapies. A variety of targeting strategies to exploit the role of EGFR in tumors have been employed. The most highly developed of these anti-EGFR approaches are the monoclonal antibodies and the tyrosine kinase inhibitors (TKIs). Clinical evaluations of these compounds have yielded some promising results. The role of the EGFR axis in colorectal cancer formation and progression is reviewed and the clinical development of these anticancer EGFR-targeted drugs is reviewed and updated.
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PMID:The epidermal growth factor receptor as a target for colorectal cancer therapy. 1572 6

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


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