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

The Erb-B family of receptors plays an important role in lung carcinogenesis and tumor development, and EGFR and HER2 are highly expressed in bronchial preneoplasia. In invasive tumors, EGFR are expressed in 50-90%, and mostly in squamous cell carcinomas, but also in adenocarcinomas and large cell carcinomas, while HER2 is less frequently expressed (20-30%) and mostly expressed in adenocarcinomas. Bronchioloalveolar cell carcinomas may present a distinct EGFR profile compared to the other NSCLCs and evidence and consequences are discussed. The genetic mechanisms responsible for overexpression of EGFR and HER2 proteins might be numerous, including gene dosage (overrepresentation or amplification) as well as translational and post-translational mechanisms. However, for EGFR and HER2 there is a positive correlation between gene copy numbers and level of protein expression demonstrated by fluorescence in situ hybridization analysis and immunochemistry. Gene amplification for EGFR and HER2 is demonstrated in only 5-10% of the tumors. The treatment status and therapeutic limitation with trastuzumab (Herceptin) in lung cancer compared to breast cancer is discussed.
Lung Cancer 2003 Aug
PMID:Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. 1286 60

ZD1839 ('Iressa') is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that inhibits EGFR signaling. Emerging evidence indicates that ZD1839 has clinical potential in lung cancer, but very little is known about the molecular characteristics of lung cancers that may determine sensitivity to ZD1839. We examined a panel of 19 lung cancer cell lines to investigate possible association between ZD1839 sensitivity and histological type, expression level and constitutive phosphorylation of EGFR and K-ras gene status. Our results indicate that neither expression level nor constitutive activation status of EGFR seems to predict sensitivity to ZD1839. In addition, ZD1839 sensitivity was not associated with expression of human epidermal growth factor receptor-2 (HER-2), another member of this tyrosine kinase receptor family nor with co-expression of EGFR and HER-2. Finally, no correlation was found between the presence of activating mutations of the K-ras gene, an important downstream mediator of the EGFR-transduced signals and the relative resistance to ZD1839. These findings warrant future study to clarify how ZD1839 inhibits lung cancer cell growth and to find a useful marker for prediction of sensitivity to this novel and promising agent for the treatment of lung cancers.
Lung Cancer 2003 Oct
PMID:The sensitivity of lung cancer cell lines to the EGFR-selective tyrosine kinase inhibitor ZD1839 ('Iressa') is not related to the expression of EGFR or HER-2 or to K-ras gene status. 1451 85

Aberrations in cell cycle progression occur in the majority of human malignancies. The main pathway affected is the retinoblastoma (Rb) pathway. The tumor suppressor gene Rb is an important component in the G(1)/S transition and its function is abnormal in most human neoplasms. Loss in Rb function occurs by the hyperactivation of the cyclin-dependent kinases (cdk's). Therefore, modulation of cdk's may have an important use for the therapy and prevention of human neoplasms. Efforts to obtain small-molecule cdk modulators yielded two classes of modulators: direct and indirect modulators. Direct cdk modulators are small molecules that specifically target the ATP binding site of cdk's. Examples for this group include flavopiridol, roscovitine and BMS-387032. In contrast, indirect cdk modulators affect cdk function due to modulation of upstream pathways required for cdk activation. Some examples include perifosine, lovastatin, and UCN-01. The first example of a direct small-molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. Clinical trials with this agent were performed with at least three different schedules of administration: 1-, 24- and 72-h infusions. The main toxicities for infusions >/=24-h are secretory diarrhea and proinflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. A phase II trial of patients with advanced non-small-cell lung carcinoma using the 72-h infusion every 2 weeks was recently completed. The median overall survival for the 20 patients who received treatment was 7.5 months, a survival similar to that obtained in a randomized trial of four chemotherapy regimens containing platinum analogues in combination with taxanes or gemcitabine, or with gefitinib, a recently approved EGFR inhibitor for the treatment of advanced lung cancer. Based on these encouraging results, a phase III trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small-molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca(2+)-dependent PKCs, promotes apoptosis, arrests cell cycle progression at G(1)/S, and abrogates checkpoints upon DNA damage. The first phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72-h continuous infusion every 4 weeks (in second and subsequent cycles UCN-01 is administered as a 36-h infusion). Other shorter schedules (i.e. 3 h) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia, and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, phase I trials with two novel small-molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. In summary, novel small-molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies.
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PMID:Small-molecule cyclin-dependent kinase modulators. 1452 86

Lung cancer is the leading cause of cancer death in the world. Therapeutic improvements caused by recent cytotoxic agents seem to have reached a plateau. New therapeutic strategies are, therefore, necessary to improve the cure rate. These include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, cyclooxygenase-2 (COX-2) inhibitors, gene therapy and vaccines. The antiepidermal growth factor receptor (EGFR) group includes compounds acting on the extracellular domain of EGFR, such as IMC-C225 and trastuzumab; small molecules inhibiting EGFR phosphorylation, such as ZD 1839 and OSI-774; or compounds that interfere with one of the downstream steps, such as mitogen-activated protein kinase kinase (MEK) inhibitors. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumour activity. Antiangiogenesis inhibitors include matrix metalloprotease inhibitors (MMPIs), suchs as marimastat, AG3340, BAY 12-9566, BMS-275291 and Col-3. Antiangiogenic agents offer great potential for the treatment of lung cancer, as shown in preclinical models, whereas emerging data suggest that there are limits to their use as monotherapy in advanced disease. Molecules targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) also seem to control tumour progression and may prolong survival. COX-2 inhibitors are another class of agents currently under evaluation in clinical trials for their chemoprevention role in subjects at high lung cancer risk, and also in patients with non-small cell lung cancer (NSCLC) in combination with standard chemotherapeutics. Genetic and immunologic therapies represent two additional promising modalities. All of these therapies are in different phases of clinical testing and have shown encouraging activity alone or in combination with chemotherapy drugs.
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PMID:Emerging drugs for non-small cell lung cancer. 1461 Sep 20

Resveratrol (3,4',5-trihydroxystilbene) is a phytoalexin found in grapes and other food products that can prevent cancer. We studied the in vitro biological activity of this compound by examining its effect on proliferation and inducing apoptosis in three lung cancer cell lines (A549, EBC-1, Lu65). Resveratrol inhibited the growth of A549, EBC-1 and Lu65 lung cancer cells by 50% (ED50) at concentrations between 5-10 microM. We also examined the combined effects in these cells of resveratrol and paclitaxel, an essential chemotherapeutic agent against lung cancer. Although simultaneous exposure to resveratrol plus paclitaxel did not result in significant synergy, resveratrol (10 microM, 3 days) significantly enhanced the subsequent antiproliferative effect of paclitaxel. In addition, resveratrol as well as paclitaxel induced apoptosis in EBC-1 and Lu65 cells, as measured by TUNEL and caspase assays, as well as flow cytometry. Resveratrol (10 microM, 3 days) similarly enhanced the subsequent apoptotic effects of paclitaxel. We examined the effects of resveratrol and paclitaxel on levels of p21waf1, p27kip1, E-cadherin, EGFR and Bcl-2 in EBC-1 cells. Resveratrol (10 microM, 3 days) prior to paclitaxel induced p21waf1 expression approximately 4-fold. These results suggest that resveratrol may be a promising alternative therapy for lung cancer and that lung cancer cells exposed to resveratrol have a lowered threshold for killing by paclitaxel.
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PMID:Combined effects of resveratrol and paclitaxel on lung cancer cells. 1466 16

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

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

Lung cancer is the leading cause of death worldwide. Current treatment modalities, including chemotherapy, radiotherapy and surgery, provide only limited improvement in the natural course of this disease. Therefore, the development of new therapeutic strategies is highly awaited. This review focuses on recent achievements on a novel class of anticancer drugs targeting the EGFR (Epidermal Growth Factor Receptor). The EGFR family is a group of four structurally similar growth factor receptors with tyrosine-kinase activity (EGFR, HER2/neu, ErbB-3, ErbB-4), which dimerize upon binding with a number of ligands, including EGF (Epidermal Growth Factor) and TGF (Transforming Growth Factor), allowing downstream transduction of mitogenic signals. Overexpression of EGFR and HER2 is frequently found in non-small-cell lung cancer (NSCLC), which accounts for over 80% of all malignant lung tumors, and has been associated with a worse clinical outcome. New agents developed to inhibit EGFR function include monoclonal antibodies and small-molecule receptor tyrosine-kinase inhibitors. In this review, results of most recent clinical with EGFR inhibitors including monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839 (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016), are summarized. In particular, final results of phase II (IDEAL 1 and 2) and III (INTACT 1 and 2) studies of ZD1839 are reported. In IDEAL trials (ZD1839 single agent in patients pre-treated with chemotherapy) there was clear evidence of tumor regression, symptoms improvement and overall clinical benefit, whereas in the two INTACT trials (ZD1839 in combination with standard platinum-based chemotherapy in chemo-naive patients) ZD1839 did not improve either survival or other clinical endpoints. Possible explanations for these contradictory results and future perspectives are discussed.
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PMID:Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer. 1503 19

The incidence of lung cancer is increasing throughout the world and is the most common cause of cancer-related death. Early detection followed by surgery has a reasonable, curative potential, but 30-50% of patients experience relapses. The immunohistochemical expressions of HER-2, EGFR and COX-2 were investigated in 53 resected non-small cell lung carcinomas and correlated to microvessel density and clinical data. HER-2, EGFR and COX-2 overexpressions were demonstrated in 15%, 30% and 40% of the tumours, respectively. In adenocarcinomas, HER-2 and COX-2 overexpression were more common, whereas in squamous cell carcinomas, EGFR overexpression was more common. COX-2 expression correlated with HER-2 expression (p = 0.002), and demonstrated a trend towards a correlation with microvessel density (p = 0.10). None of the markers alone had any impact on survival. However, HER-2+/EGFR- tumours proved to have a poor prognosis. In conclusion, adjuvant treatment with HER-2 antagonists might be a future treatment option in resected non-small cell lung cancer patients, especially when HER-2 is overexpressed without a concomitant overexpression of EGFR.
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PMID:HER-2, EGFR, COX-2 expression status correlated to microvessel density and survival in resected non-small cell lung cancer. 1506 24


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