Gene/Protein Disease Symptom Drug Enzyme Compound
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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) signaling pathway plays an important role in a number of processes that are key to tumor progression, including cell proliferation, angiogenesis, metastatic spread, and inhibition of apoptosis. EGFR is expressed or overexpressed in non-small-cell lung cancer (NSCLC), and EGFR-mediated growth has been associated with advanced disease and poor prognosis in NSCLC patients. ZD1839 (Iressa) is an orally active, selective EGFR-tyrosine kinase inhibitor that blocks EGFR signal transduction. In preclinical studies using NSCLC cell lines, ZD1839 has been shown to inhibit tumor cell growth. In addition, ZD1839, as monotherapy and in combination with commonly used cytotoxic agents, has produced growth delay in NSCLC human xenografts. Preliminary results from phase I trials in patients with advanced disease have shown that ZD1839 has excellent bioavailability, an acceptable tolerability profile, and promising clinical activity in patients with a variety of tumor types, particularly in NSCLC. ZD1839 is currently in phase III clinical development for the treatment of advanced NSCLC.
Clin Lung Cancer 2001 Aug
PMID:ZD1839 (Iressa) in non-small-cell lung cancer. 1465 86

Traditionally, the efficacy of an anticancer agent has been measured by response rate. With the development of biological molecular-targeted agents, which have a different mechanism of action from conventional agents, it may be appropriate to consider alternative criteria that reflect the positive effect of these biological agents on disease control, palliation, symptom improvement and quality of life. One such targeted agent is the orally active epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ("Iressa", ZD1839). This article reviews the clinical experience of patients with advanced/metastatic non-small-cell lung cancer, who have received gefitinib as part of a clinical trial or through the "Iressa" Expanded Access Programme. Disease-control rates of approximately 50% were observed in some Expanded Access Programme series, comparable with results obtained from Phase II trials. Symptom improvement was also reported. Information that will help identify those patients most likely to respond to treatment will become increasingly important. Therefore, the possible role of prognostic markers and the relationship between epidermal growth factor receptor status and response to gefitinib has been investigated. No clear association between epidermal growth factor receptor expression and response was observed. Future studies of other biomarkers in the epidermal growth factor receptor pathway should help to identify which patients are likely to benefit most from gefitinib.
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PMID:Extensive experience of disease control with gefitinib and the role of prognostic markers. 1466 Oct 46

Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, has recently been approved in several countries for use in advanced or metastatic non-small-cell lung cancer (NSCLC). In contrast to chemotherapies, which are generally used at or near their maximum-tolerated dose (MTD), gefitinib is used at an optimal biological dose (250 mg day(-1)), which is substantially below its MTD, minimising the risk of adverse events without compromising efficacy. Tolerability data from the compassionate use of gefitinib in the "Iressa" Expanded Access Programme support the favourable safety profile of the agent reported in Phase I and II trials. In both settings, the majority of adverse drug reactions were mild/moderate and consisted mainly of grade 1/2 diarrhoea and skin rash. Although skin rash has been suggested to predict response to gefitinib, available data do not support this hypothesis. Overall, these tolerability data demonstrate that gefitinib has a relatively benign side-effect profile and is a well-tolerated treatment option for patients with previously treated NCSLC, who currently have few alternatives.
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PMID:Tolerability of gefitinib in patients receiving treatment in everyday clinical practice. 1466 Oct 47

We present a series of cases that illustrate potential benefits of the targeted agent gefitinib for patients with advanced and heavily pretreated non-small-cell lung cancer (NSCLC). In 2 phase II clinical trials, 250 mg/day of gefitinib produced objective tumor response rates of 18% and 11%, with excellent tolerance in patients with advanced NSCLC who had previously received standard chemotherapy. Treatment with gefitinib also led to improvements in disease-related symptoms in approximately 40% of cases. Gefitinib is one of a class of agents that selectively inhibit the epidermal growth factor receptor-tyrosine kinase, which is aberrantly activated in many human solid tumors. Gefitinib treatment resulted in objective radiographic regressions of tumor and symptom improvement in patients with advanced, heavily pretreated NSCLC in clinical trials and in the Expanded Access Program. This series illustrates that the benefits of gefitinib are not limited to patients selected for clinical trial participation but can be generalized to the broader population of patients with NSCLC.
Clin Lung Cancer 2003 Nov
PMID:Antitumor activity and tolerability of gefitinib in patients with non-small-cell lung cancer treated in an expanded access program. 1466 75

Fifteen% or fewer of patients with non-small cell lung cancer (NSCLC) survive 5 years. The current standard of care for patients with locally advanced or metastatic NSCLC is systemic chemotherapy with a two-drug combination regimen that includes a platinum agent. Although systemic chemotherapy reduces the rate of death attributable to lung cancer, disease progression is inevitable and dose-limiting toxicities restrict their use. New molecularly targeted therapies aim to inhibit specific pathways and key molecules implicated in tumor growth and progression while sparing normal cells. Several therapies, which target signal transduction pathways involved in angiogenesis, metastasis, and apoptosis, are in clinical development to treat lung cancer. Among these targeted therapies are the oral, small-molecule epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitors gefitinib and erlotinib. Both therapies have been validated preclinically as new treatment approaches for NSCLC and have shown single-agent activity against advanced, chemorefractory NSCLC in clinical trials. This article focuses on the biology of the EGFR-TK signal transduction pathway, its role in the proliferation of solid tumors, and the rationale for the clinical development of EGFR-TK inhibitors. We also review clinical trials with EGFR-TK inhibitors in NSCLC and future directions of investigation with these targeted agents.
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PMID:Targeting the epidermal growth factor receptor in non-small cell lung cancer. 1467 1

Erlotinib (Tarceva) is an orally available selective small-molecule inhibitor of HER1/EGFR tyrosine kinase with a 50% inhibitory concentration of 2 nM for purified tyrosine kinase. This agent has been shown to produce stasis or regression of tumor growth in human cancer xenograft models, including non-small-cell lung cancer models. Ongoing preclinical investigations indicate that inhibition of the MAPK and Atk signaling pathways downstream of HER1/EGFR may be required for optimal antitumor effects. Erlotinib exhibits inhibition of MAPK and Atk kinases at concentrations higher than those required for HER1/EGFR tyrosine kinase inhibition; such findings suggest that maximal inhibition of HER1/EGFR, requiring high erlotinib doses, is necessary for optimum antitumor activity. These considerations are supported by tumor models, including non-small-cell lung cancer models, showing dose-related antitumor effects up to high doses of erlotinib. Erlotinib exhibits additive antitumor effects when combined with chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel, gemcitabine [Gemzar], and capecitabine [Xeloda]), radiation therapy, and other targeted agents (e.g., bevacizumab [Avastin]). Recent studies indicate that erlotinib inhibits the EGFRvIII mutant at concentrations higher than those required for inhibition of wild-type receptor. Ongoing investigation will help to determine optimal dosing and dose frequency of erlotinib in various cancers in the clinical setting.
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PMID:Erlotinib: preclinical investigations. 1468 18

One year has passed since the launch of a new molecular targeted agent, Iressa (generic name: Gefitinib), in Japan ahead of other countries in the world. Gefitinib is the first selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor. Gefitinib was investigated clinically by a single dose ascending study and 3-day multiple dosing study in male volunteers in the UK initially. On confirmation of tolerability by those studies, 4 Phase I studies were conducted in patients with solid tumours generally known to over-express EGFR, with a result of 250 mg or 500 mg (oral administration) decided to be chosen as the recommended dose for Phase II studies. A Phase II study was then conducted in 9 countries including European countries, Australia, and Japan, using once daily oral dosing regimen. In this study gefitinib demonstrated response rate of 18.4% (19/103), and disease control rate of 54.4% (56/103) in advanced non-small cell lung cancer patients (with 1 or 2 previous chemotherapy regimens) at a dose level of 250 mg/day. Symptom improvement rate, which was determined using lung cancer sub-scale (LCS) for QOL assessment, was 40.3% (27/67), and median time to symptom improvement was 8 days (on the initial assessment). In 3 months after the launch, 39 lung injury deaths of patients were reported including deaths attributed to interstitial pneumonia, which was covered broadly by mass media. It is, however, considered that development of Iressa, the first EGFR tyrosine kinase inhibitor showing effects on solid tumours, for clinical use through assiduous researches on molecular targeted agents has truly great significance. This paper gives an overview covering development history to date, clinical study results, and post-launch safety reports.
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PMID:[Development of novel molecular targeted drug, "Iressa", for the treatment of malignant diseases--its basic and clinical studies]. 1471 82

Drug costs and reimbursement issues for targeted therapies for lung cancer and how they affect pharmacy practice are discussed. Lung cancer is the most frequent cause of cancer death in the western world. Despite improvements in treatment results, less than 15% of patients survive five years after their primary diagnosis. Major advances in the understanding of cancer biology have led to the identification of several potential targets for cancer treatment. In non-small cell lung cancer (NSCLC) one of the most promising new targets has been the epidermal growth factor receptor (EGFR), which is overexpressed in most squamous cell subtypes and > or = 65% of adenocarcinomas and large cell subtypes. Gefitinib is an orally available small-molecule tyrosine kinase inhibitor that targets the intracellular domain of the EGFR. It has demonstrated activity and tolerable toxicity in patients with NSCLC. Because of its daily oral route of administration, patient compliance and education are of paramount importance, and the pharmacist plays an increasingly important role in patient management.
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PMID:Pharmacy practice issues with targeted therapy for lung cancer. 1471 23

Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and high mortality. The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau. The main categories of targeted therapeutics applicable for NSCLC include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, gene therapy, and vaccines. Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC. The anti-epidermal growth factor receptor (EGFR) group contains trastuzumab and IMC-C225, monoclonal antibodies against EGFRs that are overexpressed in many cancers. OSI-774 and ZD1839 are inhibitors of EGFR tyrosine kinase, a key enzyme of the signaling pathway. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumor activity. Antiangiogenesis agents that have shown promise include TNP-470, recombinant endostatin, and angiostatin. Antibodies to vascular endothelial growth factor (VEGF) also seem to control tumor progression and may prolong survival. LY317615, an inhibitor of protein kinase Cb, augmented the tumor growth delay produced by cytotoxic drugs. All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs. These new agents are more target specific, less toxic, easier to administer, and may lead to enhanced safety and survival for patients with advanced NSCLC.
Clin Lung Cancer 2002 Mar
PMID:Targeted therapy using novel agents in the treatment of non-small-cell lung cancer. 1472 Mar 53

Patients with locally advanced or metastatic non-small-cell lung cancer (stage III and IV) who are not candidates for surgery and exhibit good performance status are typically treated with concurrent radiation and platinum-based chemotherapy for disease palliation. Platinum-based chemotherapies, used alone or with radiation therapy, offer a small but significant survival benefit compared with supportive care. The incorporation of first-line agents such as gemcitabine (Gemzar), vinorelbine (Navelbine), and paclitaxel, as well as second-line agents such as docetaxel (Taxotere), in doublet and triplet combinations has had a further significant therapeutic impact. Randomized trials have shown that cisplatin-based therapy in combination with new agents results in improved 1- and 2-year survival rates in patients with adequate performance status. The 1-year survival benefit has significantly improved, with greater symptom relief and improved quality of life in these patients. Thus, delaying disease progression with combination chemotherapy appears both beneficial and cost-effective in patients with advanced non-small-cell lung cancer. Newer approaches--including targeting critical signaling pathways, such as tyrosine kinase receptors, angiogenesis, and downstream signal transduction mechanisms--may provide novel agents with an improved toxicity profile and the potential for better disease management.
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PMID:State-of-the-art treatment for advanced non-small-cell lung cancer. 1472 2


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