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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung cancer is one of the leading types of cancer with an associated high mortality. Currently, treatment with conventional cytotoxic agents remains suboptimal. Inhibition of the epidermal growth factor receptor (EGFR) with monoclonal antibodies or small-molecule inhibitors of the tyrosine kinase (TK) domain of the receptor have demonstrated modest, albeit significant, antitumor activities in patients with non-small-cell lung cancer (NSCLC). The goal of any targeted therapy is to direct treatment to those patients who are more likely to derive benefit from such a treatment. Two interventions may improve the predicted sensitivity to these agents: (1) the use of a real predictor before treatment, represented by pharmacodiagnostic tests, and (2) studying the relationship between an early event after treatment and outcome, represented by pharmacodynamic tests. Pharmacodiagnostic factors that have been studied include the clinical features and histologic subtype of the tumor, the presence of somatic mutations in the TK domain of the EGFR, the expression of the receptor itself, and the activation of the receptor signaling pathway. Pharmacodynamic events associated with improved outcome include drug-induced rash and regulation of the receptor expression. Currently, the best established determinant of response to small-molecule inhibitors of the EGFR is the presence of activating mutations in the receptor TK domain. However, it is not known whether these functional mutations are involved in the response of NSCLC to monoclonal antibodies. Further investigation is needed to better predict patients who are more likely to benefit from these drugs.
Clin Lung Cancer 2004 Dec
PMID:Predictors of sensitivity and resistance to epidermal growth factor receptor inhibitors. 1563 55

The recent identification of somatic mutations in the epidermal growth factor receptor (EGFR)-tyrosine kinase (TK) domain of tumor samples from patients with non-small-cell lung cancer (NSCLC) that portend robust response to small-molecule inhibitors of EGFR TK is a watershed event in the fields of lung cancer genetics and therapeutic agents. In addition to paralleling what is already known about c-kit mutations that drive the proliferation of gastrointestinal stromal tumors and their response to imatinib, and providing the possibility of prospectively selecting patients with NSCLC who have a high probability of responding to EGFR TK inhibitors, these reports will likely have much broader implications with regard to the optimal and most expeditious means to develop rationally designed, target-based therapeutic agents--first establishing proof of principle in patients whose malignancies are dependent or driven by aberrations of the therapeutic's target. These new findings will undoubtedly lead to a greater understanding of the biology of EGFR-mutant NSCLC and the mechanism of action of EGFR TK inhibitors. This further validates EGFR as a target for anticancer therapy, particularly in tumors with activating mutations of the target, which lead to sequencing of genes that govern other relevant proteins that are currently being targeted with novel therapeutic agents. The result should be more efficient and scientifically founded clinical development strategies for rationally designed target-based therapeutic agents.
Clin Lung Cancer 2004 Dec
PMID:Effect of epidermal growth factor receptor mutations on the response to epidermal growth factor receptor tyrosine kinase inhibitors: target-based populations for target-based drugs. 1563 56

Bronchoalveolar carcinoma (BAC) is a previously uncommon subset of non-small-cell lung cancer (NSCLC) with unique epidemiology, pathology, clinical features, and natural history compared with other NSCLC subtypes. Recent data indicate that the incidence of BAC is increasing. Although many studies have reported that patients with BAC have prolonged survival, advanced BAC remains incurable, with most patients eventually dying of respiratory failure from progressive pulmonary involvement or intercurrent illness. Previous limited data suggest that chemotherapy for BAC provides modest benefit; however, anecdotal reports of swift and durable responses after treatment with tyrosine kinase (TK) inhibitors of the epidermal growth factor receptor (EGFR) in patients with BAC have prompted further investigation in this subset of patients. Two trials using the EGFR TK inhibitors gefitinib and/or erlotinib have demonstrated encouraging results, and have prompted further enthusiasm for this approach. Furthermore, recent insights into mechanisms of drug sensitivity should impact future clinical trial design.
Clin Lung Cancer 2004 Dec
PMID:Role of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of bronchoalveolar carcinoma. 1563 57

Although chemotherapy remains the standard of care for lung cancer, new less toxic drugs are urgently needed. Targeted agents represent a new era in cancer therapy, and non-small-cell lung cancer (NSCLC) is at the forefront of many development programs. An exciting target is the human epidermal growth factor receptor (EGFR, ie, HER1), and agents targeting this receptor, including gefitinib, cetuximab, and erlotinib (OSI-774; Tarceva), are being investigated. These agents have antitumor activity and are less toxic than most therapies. Based on phase II data, gefitinib received US approval for third-line treatment of patients with locally advanced or metastatic NSCLC. Cetuximab is licensed in the United States for patients with metastatic colorectal carcinoma. However, erlotinib, recently approved in the United States for second- and third-line treatment of patients with locally advanced or metastatic NSCLC, is the only agent of this class to improve survival as monotherapy in patients with advanced, refractory NSCLC, as shown in a phase III placebo-controlled trial. Phase III trials of erlotinib and gefitinib combined with chemotherapy were disappointing, which could be the result of drug scheduling, chemotherapy combinations, or other factors. Patient characteristics may also affect outcome, and research is ongoing to identify predictive markers of response to enable patient selection and improve outcome. Recently identified mutations within the HER1/EGFR tyrosine kinase (TK) domain may provide insight into why some patients respond rapidly to HER1/EGFR tyrosine kinase inhibitors. Surrogate markers of efficacy are also being investigated, including rash, which could be used to monitor and optimize antitumor activity. Therefore, although more work is required, data indicate that HER1/EGFR inhibitors will play an important role in treating patients with NSCLC.
Clin Lung Cancer 2004 Dec
PMID:Overview of the current status of human epidermal growth factor receptor inhibitors in lung cancer. 1563 59

Epidermal growth factor receptor (EGFR) has become an important target in the treatment of cancer. Multiple epithelial cancers have been found to overexpress the receptor including head and neck, breast, colon, lung, prostate, kidney, ovary, brain, pancreas, and bladder. Strategies to block EGFR include development of monoclonal antibodies to EGFR, tyrosine kinase inhibitors, ligand-linked toxins, and antisense approaches. The inhibition of EGFR may lead to suppression of tumor proliferation and improve overall clinical outcome, as overexpression of the receptor has been associated with a poorer prognosis in patients with cancer. This article will focus on the monoclonal antibody cetuximab and its applications in the treatment of non-small-cell lung cancer.
Clin Lung Cancer 2004 Dec
PMID:Cetuximab as a single agent or in combination with chemotherapy in lung cancer. 1563 64

N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC(50) value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRalpha and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.
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PMID:Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas. 1574 79

The epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor gefitinib (Iressa, ZD1839) has shown promising activity preclinically and clinically. Because comparative investigations of drug-resistant sublines with their parental cells are useful approaches to identifying the mechanism of gefitinib resistance and select factors that determine sensitivity to gefitinib, we established a human non-small cell lung carcinoma subline (PC-9/ZD) that is resistant to gefitinib. PC-9/ZD cells are approximately 180-fold more resistant to gefitinib than their parental PC-9 cells and PC-9/ZD cells do not exhibit cross-resistance to conventional anticancer agents or other tyrosine kinase inhibitors, except AG-1478, a specific inhibitor of EGFR. PC-9/ZD cells also display significant resistance to gefitinib in a tumor-bearing animal model. To elucidate the mechanism of resistance, we characterized PC-9/ZD cells. The basal level of EGFR in PC-9 and PC-9/ZD cells was comparable. A deletion mutation was identified within the kinase domain of EGFR in both PC-9 and PC-9/ZD, but no difference in the sequence of EGFR cDNA was detected in either cell line. Increased EGFR/HER2 (and EGFR/HER3) heterodimer formations were demonstrated in PC-9/ZD cells by chemical cross-linking and immunoprecipitation analysis in cells unexposed to gefitinib. Exposure to gefitinib increased heterodimer formation in PC-9 cells, but not in PC-9/ZD cells. Gefitinib inhibits EGFR autophosphorylation in a dose-dependent manner in PC-9 cells but not in PC-9/ZD cells. A marked difference in inhibition of site-specific phosphorylation of EGFR was observed at Tyr1068 compared to other tyrosine residues (Tyr845, 992 and 1045). To elucidate the downstream signaling in the PC9/ZD cellular machinery, complex formation between EGFR and its adaptor proteins GRB2, SOS, and Shc was examined. A marked reduction in the GRB2-EGFR complex and absence of SOS-EGFR were observed in PC-9/ZD cells, even though the protein levels of GRB2 and SOS in PC-9 and PC-9/ZD cells were comparable. Expression of phosphorylated AKT was increased in PC-9 cells and inhibited by 0.02 microM gefitinib. But the inhibition was not significant in PC-9/ZD cells. These results suggest that alterations of adaptor-protein-mediated signal transduction from EGFR to AKT is a possible mechanism of the resistance to gefitinib in PC-9/ZD cells. These phenotypes including EGFR-SOS complex and heterodimer formation of HER family members are potential biomarkers for predicting resistance to gefitinib.
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PMID:Establishment of a human non-small cell lung cancer cell line resistant to gefitinib. 1576 68

Gefitinib (Iressa, ZD1839) is an orally active inhibitor selective for the epidermal growth factor receptor tyrosine kinase and has shown promise in the treatment of non-small cell lung cancer (NSCLC). There has been no report to date of the effect of gefitinib treatment in patients with small-cell lung cancer (SCLC). Here we report a case of metastatic SCLC that was successfully treated with gefitinib. This case is the first reported of objective clinical response after gefitinib treatment in a patient with SCLC. Our report suggests that treatment with gefitinib is a novel option for a subset of patients with SCLC.
Lung Cancer 2005 Apr
PMID:Efficacy of the tyrosine kinase inhibitor gefitinib in a patient with metastatic small cell lung cancer. 1577 82

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has a response rate of 10% to 20% in refractory non-small cell lung carcinoma. Although female gender, adenocarcinoma, and never having smoked are possible markers of a favorable response, mutations of the EGFR gene have also been reported to be highly significant predictors of response. Seventy patients with relapsed non-small cell lung carcinoma were enrolled in the Expanded Access Program. After the drug became available commercially, 28 more patients were treated with gefitinib. Response evaluations were feasible in 80 patients. Twenty-seven tumor specimens (8 responders and 19 nonresponders) were available for the sequence analysis of the EGFR gene. The response rate was 25% (20/80) and the disease control rate (remission + stable disease) was 47.5% (38/80). The response rate was significantly higher for adenocarcinoma (41.0%) versus non-adenocarcinoma (9.8%, P = 0.001), in those who never smoked (58.8%) versus smokers (15.9%, P < 0.001), and in females (42.1%) versus males (19.7%, P = 0.049). A deletion or mutation of the EGFR gene was found in six of eight responders. Remission was noted in all patients with a mutation, whereas the response rate was 9.5% (2/21) in patients without a mutation (P < 0.001). The predictors of response showed significant correlations with survival and time to progression. In a multivariate logistic analysis, the independent predictors of response were smoking history and adenocarcinoma. Given that 9.5% of smokers and 6.7% of those with non-adenocarcinoma showed a mutation of the EGFR gene, the genetic profile may replace those variables as an independent predictor of a response.
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PMID:Predictors of the response to gefitinib in refractory non-small cell lung cancer. 1578 73

Sialyl-Lewis x epitopes and MUC5AC protein are known to be overexpressed in mucins secreted by patients suffering from various respiratory diseases. To investigate the mechanisms by which airway inflammatory agents mediate the expression of sialyl-Lewis x epitopes and MUC5AC mucin, we examined the effects of tumor necrosis factor (TNF)-alpha and epidermal growth factor (EGF) in the human lung carcinoma cell line, NCI-H292. Basal expression levels of hST3GalIV, FUT3 and C2/4GnT mRNA, involved in the biosynthesis of sialyl-Lewis x, were higher than those of other glycosyltransferases in NCI-H292 cells. TNF-alpha induced expression of hST3GalIV, FUT3, C2/4GnT and MUC5AC mRNAs in NCI-H292 cells. When cells were pretreated with U73122, a phosphatidylinositol-phospholipase C (PI-PLC) inhibitor, the expression of these glycosyltransferase mRNAs was suppressed. Treating cells with EGF induced the down-regulation of these glycosyltransferase mRNAs and sialyl-Lewis x epitopes, while inducing an increase in expression of MUC5AC mRNA. These EGF-mediated effects on the glycosyltransferase and MUC5AC mRNAs were blocked when cells were first exposed to AG1478, an EGF receptor tyrosine kinase inhibitor. These findings suggest that the expression of sialyl-Lewis x epitopes, which is regulated separately from the expression of MUC5AC protein, may be controlled through pathways such as the EGF receptor tyrosine kinase and PI-PLC signaling cascades in NCI-H292 cells.
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PMID:Regulation of sialyl-Lewis x epitope expression by TNF-alpha and EGF in an airway carcinoma cell line. 1586 35


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