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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epidermal growth factor receptor (EGFR) is a promising target for cancer therapy and a number of EGFR-targeted agents have been developed. Those most advanced in development are the EGFR tyrosine kinase inhibitors gefitinib ('Iressa', ZD1839) and erlotinib ('Tarceva', OSI-774), and the monoclonal antibody cetuximab ('Erbitux', IMC-C225). This review provides a clinical overview of these agents, highlighting their antitumour activities in different tumour types. Epidermal growth factor receptor-targeted agents are generally well tolerated and are not typically associated with the severe adverse events often seen with cytotoxic chemotherapy. Gefitinib is the agent with the most extensive clinical experience, particularly in non-small-cell lung cancer (NSCLC). Recently, gefitinib became the first-approved EGFR-targeted agent, for use in patients with previously treated advanced NSCLC in Japan, the USA and other countries. Further studies are required to explore the full potential of these novel agents either as monotherapy or combination therapy.
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PMID:Gefitinib ('Iressa', ZD1839) and new epidermal growth factor receptor inhibitors. 1476 Mar 65

ZD-6474, one of a series of inhibitors of vascular endothelial growth factor receptor tyrosine kinase, which also has activity against the epidermal growth factor receptor tyrosine kinase, is under development by AstraZeneca for the potential treatment of solid tumors. Phase II trials in non-small-cell lung cancer, small-cell lung cancer and myeloma were ongoing in January 2003.
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PMID:ZD-6474. AstraZeneca. 1476 34

Lung cancer is very frequent and associated with a high mortality. In the last 25 years therapeutic progress have been limited and do not allow a 5 year global survival rate exceeding to 13-14%. Tumor biology permits a better comprehension of cancerization mechanisms and offers hope of new treatments with targeted therapies which would be specific of cancer cells and so more efficient and less toxic. Epidermal growth factor (EGF) pathway and its receptor (EGFR) expressed by most lung cancer cells is the most successfully completed example. The bond of EGF with its receptor stimulates tyrosine kinase domain of EGFR and allows transduction of an activating signal. Inhibition of this signaling pathway stops tumor growth. Several agents are in development, from preclinical studies to phase III trials. It is a matter of humanized monoclonal antibodies, such as C225 (cetuximab), targeted against EGFR, or small molecules inhibiting tyrosine kinase activity of EGFR including ZD1839 (Iressa), OS1774 (Tarceva) or CI1033, and last antisense oligonucleotides. Antibodies and small molecules are well tolerated and are responsible for limited amount of side effects, mostly cutaneous toxicity and diarrhoea. Antitumor activity has been observed in monotherapy reaching up to 25% of clinical responses in the best series. EGFR inhibition seems to be also promising in combination with chemotherapy according to the synergy observed in preclinical studies and response rate up to 50% have been reported. But phase III studies have been disappointing and additional studies are warranted before consideration for a current daily practice, mostly that severe secondary effects were reported with pulmonary toxicities. In particular it remains to explain why clinical responses do not appear correlated with EGFR expression.
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PMID:[Therapeutic implications of epidermal growth factor receptor in lung cancer]. 1476 45

Combination chemotherapy regimens have emerged as the standard approach in advanced non-small-cell lung cancer. Meta-analyses have demonstrated a 2-month increase in median survival after platinum-based therapy vs. best supportive care, and an absolute 10% improvement in the 1-year survival rate. Just as importantly, cytotoxic therapy has produced benefits in symptom control and quality of life. Newer agents, including the taxanes, vinorelbine, gemcitabine, and irinotecan, have expanded our therapeutic options in the treatment of advanced non-small-cell lung cancer. Despite their contributions, we have reached a therapeutic plateau, with response rates seldom exceeding 30-40% in cooperative group studies and 1-year survival rates stable between 30% and 40%. It is doubtful that substituting one agent for another in various combinations will lead to any further improvement in these rates. The thrust of current research has focused on targeted therapy, and epidermal growth factor receptor inhibition is one of the most promising clinical strategies. Epidermal growth factor receptor inhibitors currently under investigation include the small molecules gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774), as well as monoclonal antibodies such as cetuximab (IMC-225, Erbitux). Agents that have only begun to undergo clinical evaluation include CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, and PKI166 and GW572016, both examples of dual kinase inhibitors (inhibiting epidermal growth factor receptor and Her2). Preclinical models have demonstrated synergy for all these agents in combination with either chemotherapy or radiotherapy, leading to great enthusiasm regarding their ultimate contribution to lung cancer therapy. However, serious clinical challenges persist. These include the identification of the optimal dose(s); the proper integration of these agents into popular, established cytotoxic regimens; and the selection of the optimal setting(s) in which to test these compounds. Both gefitinib and erlotinib have shown clinical activity in pretreated, advanced non-small-cell lung cancer, but placebo-controlled randomized Phase III studies evaluating gefitinib in combination with standard cytotoxic therapy, to our chagrin, have failed to demonstrate a survival advantage compared with chemotherapy alone.
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PMID:Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. 1496 61

In cancer cells, aberrant signaling through the epidermal growth factor receptor (EGFR) activates pathways that stimulate many of the properties associated with neoplasia, including proliferation, migration, stromal invasion, tumor angiogenesis, and resistance to cell death-inducing signals. Because of the frequency of abnormalities in receptor signaling in human cancers, the EGFR is an attractive target for therapeutic development. Monoclonal antibodies and small molecule tyrosine kinase inhibitors are the two classes of agents that are the furthest advanced in clinical development. Although pharmacologic and mechanistic differences exist between the two classes, the results of preclinical studies suggest that both inhibit proliferation, have little normal tissue toxicity, and are additive/synergistic with standard therapies. The results from early clinical trials have indicated that both classes of agents are well tolerated and have antitumor activity. However, the first Phase III studies to be completed have not shown an improvement in survival with the addition of the monoclonal antibody C225 to cisplatin in patients with head-and-neck carcinoma or the addition of the kinase inhibitor ZD1839 to chemotherapy in patients with advanced lung cancer. Ongoing and future studies must address issues related to the selection of patients for study, dose and schedule of administration, monotherapy vs. combination treatment, and combinations with standard and investigational agents.
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PMID:Epidermal growth factor receptor inhibitors in clinical development. 1496 62

Overexpression of the epidermal growth factor receptor is commonly seen in a variety of epithelial tumors including lung cancer, and it is particularly common in the non-small cell histologic variant. Despite intense research efforts, therapeutic advances to date have failed to result in a significant survival benefit for patients with advanced disease. The lack of overall survival benefit and high toxicity associated with cytotoxic chemotherapy indicates the need for novel therapies that have a favorable effect on survival with minimal toxicity. Greater understanding of molecular biology and the intricate cellular pathways has resulted in the development of a new field of targeted therapeutics that will arrest dysregulated cell growth in malignant cells. Tyrosine kinases represent an important category of signaling proteins that catalyze phosphorylation of tyrosine residues leading to reactions ultimately resulting in cell growth, differentiation, proliferation, and death. Inhibition of tyrosine kinase activity represents a logical targeted approach in malignancies with overexpression of tyrosine kinase. Several small-molecule epidermal growth factor receptor tyrosine kinase inhibitors have been developed and are currently undergoing clinical trials. This article will review several of these agents as well as their role in the treatment of non-small cell lung cancer.
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PMID:A review of small-molecule epidermal growth factor receptor-specific tyrosine kinase inhibitors in development for non-small cell lung cancer. 1498 85

Despite treatment advances over the past decade, long-term survival for patients with non-small cell lung cancer (NSCLC) remains poor, and treatment options available after second-line therapy are limited. Increased understanding of cancer biology has led to the identification of several potential targets for treatment. The epidermal growth factor receptor (EGFR) belongs to a family of plasma membrane receptor tyrosine kinases that controls many important cellular functions, from growth and proliferation to cell death. This receptor is a particularly promising therapeutic target because it often is overexpressed in patients with NSCLC and has been implicated in the pathogenesis as well as the proliferation, invasion, and metastasis of lung cancer and other malignancies. New agents developed to inhibit EGFR function include small-molecule tyrosine kinase inhibitors, monoclonal antibodies to EGFR, and pan-EGFR inhibitors. Completed and ongoing clinical trials have shown that EGFR inhibitors have remarkable efficacy for patients with relapsed NSCLC. Among these, two phase 2 trials have shown that ZD1839 is effective when used as monotherapy. The response rates are comparable with those for docetaxel given in the second-line setting. Another phase 2 trial has shown that OSI-774 is effective in the same setting. Data from phase 3 trials indicate that adding an EGFR tyrosine kinase inhibitor to chemotherapy does not provide an additional survival benefit, as compared with standard chemotherapy alone for first-line treatment of NSCLC. It appears that EGFR tyrosine kinase inhibitors are safe and well tolerated by patients with cancer. Further studies will elucidate how these new agents can best be used for NSCLC and other tumor types.
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PMID:Epidermal growth factor receptor tyrosine kinase inhibitors: application in non-small cell lung cancer. 1502 9

Traditional cytotoxic anticancer therapies do not differentiate between tumour and host cells, and research efforts have been focused on finding new agents that target tumour tissue. Gefitinib ('Iressa', ZD1839) is an orally active epidermal growth factor receptor tyrosine kinase inhibitor that blocks signal pathways implicated in solid tumour growth and metastasis. In phase II trials, gefitinib 250 mg/day demonstrated efficacy in the control of advanced non-small-cell lung cancer (NSCLC) in patients who had undergone prior chemotherapy. Response rates were 18.4 and 11.8%, and disease control rates were 54.4 and 42.2%, at 250 mg/day in two multicentre trials - IDEAL 1 and 2. Gefitinib also caused rapid relief from the symptoms of NSCLC in approximately 40% of patients, while displaying a generally good tolerability profile that most commonly included mild, reversible gastrointestinal and skin adverse events. Gefitinib 250 mg/day has been approved for use in advanced, previously treated NSCLC in several countries including the USA, Japan and Australia. As a monotherapy and combination therapy, it is being investigated for the treatment of several common tumour types in addition to NSCLC. The pharmacokinetics of gefitinib have shown it to be suitable for once daily dosing, with a terminal half-life of approximately 48 h in patients with cancer. Steady-state exposure is achieved after 10 days dosing, and exposure is dose proportional up to 250 mg/day. Gefitinib is cleared principally by the biliary route and in part by metabolism. This review summarizes relevant data from studies of gefitinib that inform its clinical administration.
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PMID:Gefitinib, a novel, orally administered agent for the treatment of cancer. 1506 98

Gefitinib (Iressa, ZD1839), a quinazoline tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR), is approved for patients with advanced non-small cell lung cancer (NSCLC) in several countries including Japan. However, the mechanism of drug sensitivity to gefitinib is not fully understood. In this study, we examined the molecular basis of sensitivity to gefitinib using nine human lung cancer cell lines derived from NSCLC. PC9 was the most sensitive to gefitinib of the nine NSCLC cell lines when assayed either by colony formation or MTS assays. The various cell lines expressed different levels of EGFR, HER2, HER3, and HER4, but there was no correlation between levels of EGFR and/or HER2 expression and drug sensitivity. Phosphorylation of EGFR, protein kinase B/AKT (Akt), and extracellular signal-regulated kinase (ERK) 1/2 was inhibited by much lower concentration of gefitinib in PC9 cells than in the other eight cell lines under exponential growing conditions. About 80% of cell surface EGFR in PC-9 was internalized within 10 min, whereas only about 30-50% of the cell surface EGFR was internalized in more drug-resistant cell lines in 15-60 min. The present study is the first to demonstrate that sensitivity to growth inhibition by gefitinib in NSCLC cell lines under basal growth condition is associated with dependence on Akt and ERK1/2 activation in response to EGFR signaling for survival and proliferation and also that drug sensitivity may be related to the extent of EGF-induced down-regulation of cell surface EGFR.
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PMID:Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. 1507 90

Non-small-cell lung cancer (NSCLC) is a common and frequently incurable disease. Patients with advanced Stage IIIB and Stage IV disease, although not candidates for curative resection, can benefit from receiving treatment (chemotherapy and radiation therapy) that prolongs survival, alleviates symptoms, and/or reduces complications. However, these therapies are often associated with significant adverse events. Treatments have recently been developed to selectively target cancer-specific molecules and signaling pathways. By acting preferentially on tumor cells, these drugs leave normal cells relatively undisturbed, thereby limiting toxic effects and preserving the patient's quality of life. ZD1839 is one of a new class of targeted anticancer agents known as tyrosine kinase inhibitors that has demonstrated activity in the treatment of NSCLC. In clinical trials, ZD1839 produced responses in patients with relapsed or refractory NSCLC, reduced disease-related symptoms, and was associated with an improvement in quality of life. Results from pivotal trials with single-agent ZD1839 are reviewed in this article, with an emphasis on its effects on quality of life and symptom improvement.
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PMID:Epidermal growth factor receptor-targeted therapy with ZD1839: symptom improvement in non-small-cell lung cancer. 1514 33


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