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

Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.
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PMID:EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. 1573 72

Chemical transformation of the SV-40 immortalized bronchial epithelial cell line BEAS2-B induces alterations in molecules involved in cell cycle control, including up-regulation of EGFR and cyclin E [Oncogene 13 (1996) 1983; Clin Cancer Res 8 (2002) 54]. The finding that these changes also occur in vivo, in both pre-invasive and invasive lung cancer [Cancer Res 55 (1995) 1365; Cancer Res 59 (1999) 2470], proves this to be a suitable model to study lung carcinogenesis. The current study tested the hypothesis that chemical treatment of BEAS2-B with Cigarette Smoke Condensate (CSC) may affect levels of gene products involved in cell adhesion and tissue remodeling. To this end, we studied the extent of changes in osteonectin (ON) protein levels induced in BEAS 2 B-cells by CSC treatment and its timing to changes occurring in the anchorage independent cloning efficiency. ON, a multimodular protein component of the extra-cellular matrix, has been implicated in tissue remodeling occurring in neoplastic and non-neoplastic conditions, but its role in lung carcinogenesis is incompletely characterized. To validate the in vitro findings, as in our previous reports, we studied resected lung tissue, to assess whether ON expression in neoplastic lung tissue differs from normal, and to determine its cellular localization. We found that CSC treatment of BEAS2-B cells results in a 7-16-fold increase in ON protein levels, that is associated with increased colony forming efficiency. ON is absent in normal lung; in contrast it is present in the majority (39/52) of non-small cell lung cancer (NSCLC). Here, its expression is restricted to peritumoral fibroblasts in squamous cell carcinoma and adenocarcinoma. In contrast, it is localized to tumor cells in pulmonary sarcomatoid carcinoma (8/10). Thus, up-regulated ON is linked in vitro to cell transformation and in vivo, it is frequently expressed in tumor-associated fibrosis, compatible with its proposed role in tissue remodelling. Increased ON expression by tumor cells appears to represent a marker of sarcomatoid NSCLC.
Lung Cancer 2004 Aug
PMID:Increased osteonectin expression is associated with malignant transformation and tumor associated fibrosis in the lung. 1524 91

The role of biomarkers in disease prognosis continues to be an important investigation in many cancer studies. In order for these biomarkers to have practical application in clinical decision making regarding patient treatment and follow-up, it is common to dichotomize patients into those with low vs. high expression levels. In this study, receiver operating characteristic (ROC) curves, area under the curve (AUC) of the ROC, sensitivity, specificity, as well as likelihood ratios were calculated to determine levels of growth factor biomarkers that best differentiate lung cancer cases versus control subjects. Selected cut-off points for p185(erbB-2) and EGFR membrane appear to have good discriminating power to differentiate control tissues versus uninvolved tissues from patients with lung cancer (AUC = 89% and 90%, respectively); while AUC increased to at least 90% for selected cut-off points for p185(erbB-2) membrane, EGFR membrane, and FASE when comparing between control versus carcinoma tissues from lung cancer cases. Using data from control subjects compared to patients with lung cancer, we presented a simple and intuitive approach to determine dichotomized levels of biomarkers and validated the value of these biomarkers as surrogate endpoints for cancer outcome.
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PMID:Receiver operating characteristic (ROC) to determine cut-off points of biomarkers in lung cancer patients. 1525 28

Molecular inhibition of epidermal growth factor receptor (EGFR/HER1) signaling is under active investigation as a promising cancer treatment strategy. We examined the potency of EGFR inhibition achieved by combining anti-EGFR monoclonal antibody and tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively. We specifically studied the combination of cetuximab (Erbitux, C225; ImClone Systems, New York, NY) with either gefitinib (Iressa, ZD1839; AstraZeneca, Macclesfield, UK) or erlotinib (Tarceva, OSI-774; Genentech, South San Francisco, CA) across a variety of human cancer cells. The combination of cetuximab plus gefitinib or erlotinib enhanced growth inhibition over that observed with either agent alone. As measured by immunostaining, inhibition of EGFR phosphorylation with the combination of cetuximab plus gefitinib or erlotinib was augmented over that obtained with single-agent therapy in head and neck (H&N) cancer cell lines. Phosphorylation inhibition of downstream effector molecules [mitogen-activated protein kinase (MAPK) and AKT] also was enhanced in tumor cells treated with the combination of cetuximab plus gefitinib or erlotinib. Flow cytometry and immunoblot analysis demonstrated that treatment of H&N tumor cells with cetuximab in combination with either gefitinib or erlotinib amplified the induction of apoptosis. Following establishment of cetuximab-resistant cell lines, we observed that gefitinib or erlotinib retained the capacity to inhibit growth of lung and H&N tumor cells that were highly resistant to cetuximab. Treatment with gefitinib or erlotinib, but not cetuximab, also could further inhibit the activation of downstream effectors of EGFR signaling in cetuximab-resistant cells, including MAPK and AKT. These data suggest that tyrosine kinase inhibitors may further modulate intracellular signaling that is not fully blocked by extracellular anti-EGFR antibody treatment. Finally, animal studies confirmed that single EGFR inhibitor treatment resulted in partial and transient tumor regression in human lung cancer xenografts. In contrast, more profound tumor regression and regrowth delay were observed in mice treated with the combination of cetuximab and gefitinib or erlotinib. Immunohistochemical staining, which demonstrated significant reduction of the proliferative marker proliferating cell nuclear antigen in mice treated with dual EGFR inhibitors, further supported this in vivo observation. Together, these data suggest that combined treatment with distinct EGFR inhibitory agents can augment the potency of EGFR signaling inhibition. This approach suggests potential new strategies to maximize effective target inhibition, which may improve the therapeutic ratio for anti-EGFR-targeted therapies in developing clinical trials.
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PMID:Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. 1528 42

beta-Hydroxyisovalerylshikonin (beta-HIVS), a compound isolated from the traditional oriental medicinal herb Lithospermum radix, is an ATP non-competitive inhibitor of protein-tyrosine kinases, such as v-Src and EGFR, and it induces apoptosis in various lines of human tumor cells. However, the way in which beta-HIVS induces apoptosis remains to be clarified. In this study, we performed cDNA array analysis and found that beta-HIVS suppressed the expression of the gene for tumor necrosis factor receptor-associated protein 1 (TRAP1), which is a member of the heat-shock family of proteins. When human leukemia HL60 cells and human lung cancer DMS114 cells were treated with beta-HIVS, the amount of TRAP1 in mitochondria decreased in a time-dependent manner during apoptosis. A similar reduction in the level of TRAP1 was also observed upon exposure of cells to VP16. Treatment of DMS114 cells with TRAP1-specific siRNA sensitized the cells to beta-HIVS-induced apoptosis. Moreover, the reduction in the level of expression of TRAP1 by TRAP1-specific siRNA enhanced the release of cytochrome c from mitochondria when DMS114 cells were treated with either beta-HIVS or VP16. The suppression of the level of TRAP1 by either beta-HIVS or VP16 was blocked by N-acetyl-cysteine, indicating the involvement of reactive oxygen species (ROS) in the regulation of the expression of TRAP1. These results suggest that suppression of the expression of TRAP1 in mitochondria might play an important role in the induction of apoptosis caused via formation of ROS.
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PMID:Involvement of tumor necrosis factor receptor-associated protein 1 (TRAP1) in apoptosis induced by beta-hydroxyisovalerylshikonin. 1529 18

HER gene family (HER1-HER4) encodes structurally similar transmembrane proteins (EGFR, HER2, ErB-3, and ErB-4) with tyrosine kinase activity. Dimerised on binding with a number of ligands, including epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha), these proteins stimulate epithelial cell proliferation. HER2 and EGFR overexpression is detected in the cells of many tumours, mainly in breast, lung and oral cancer and may be connected with HER2 gene amplification or point mutations as well as with the presence of overactive polymorphic forms of HER1 gene. The first medication of a proved efficacy in breast cancer treatment was trastuzumab (Herceptin)--monoclonal antibody against HER2 protein. Trastuzumab was effective only in the case of patients with high HER2 expression evaluated by immunohistochemical methods and with gene amplification ascertained by fluorescence in situ hybridisation assays. In non-small-cell lung cancer (NSCLC), HER2 overexpression was detected only in a few cases. Therefore, trastuzumab treatment seems to be problematic in NSCLC patients. A small molecule quinazoline (erlotinib, Tarceva) is a promising therapeutic agent selectively blocking EGFR. Phase III Tarceva clinical trail in NSCLC patients showed that their survival is prolonged and that the medication acts together with other chemotherapeutic agents like cisplatin and gemcitabine.
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PMID:Anti-HER therapeutic agents in the treatment of non-small-cell lung cancer. 1531 69

Treatment of solid tumors with chemotherapy regimens commonly is associated with debilitating or life-threatening side effects. Careful patient management, appropriate and prompt management of side effects, and interruption of therapy frequently are required for patients receiving chemotherapy. Furthermore, the systemic toxicity associated with chemotherapy may result in irreversible and incapacitating side effects, such as peripheral neuropathy, that lead to poor quality of life in patients. Gefitinib (Iressa, ZD1839, AstraZeneca Pharmaceuticals LP, Wilmington, DE) is a biologically based, molecular targeted therapy with a novel mechanism of action: selective inhibition of the epidermal growth factor receptortyrosine kinase (EGFR-TK) activity. Once-daily oral treatment with gefitinib is well tolerated. In clinical trials, treatment with gefitinib resulted in durable tumor responses and improvement in lung cancer-related symptoms in patients with advanced non-small cell lung cancer who had received prior chemotherapy. Trials are under way to explore the full potential of gefitinib and additional EGFR-TK inhibitors for other solid tumors and in other treatment settings, including prevention. Biologically based, molecular-targeted therapies such as gefitinib are providing new treatment options for patients and adding a new dimension to clinical practice for oncology nurses.
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PMID:New directions in oncology nursing care: focus on gefitinib in patients with lung cancer. 1535 25

Identification of biomarkers is one of the most promising approaches for the detection of early malignant or even premalignant lesions with the chance of diagnosing early stages of non-small cell lung cancer that could be treated curatively. Alterations of chromosomes (3p, 5q, 9p), genes (Rb, C-myc, C-mos, hTERT), proteins (p16, p53, K-ras, hnRNP A2/B1, MCM2, EGFR, erbB-2, erbB-3, erbB-4) and others can be found in lung cancer. Some of these occur at early stages of the disease and few could serve as potential screening markers. The actual literature is reviewed and the relevance of the different biomarkers for early lung cancer detection is discussed.
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PMID:Biomarkers in non-small cell lung cancer prevention. 1545 56

Purine bases and their bioisosteric analogs are widely used as building blocks in combinatorial chemistry. Recently a great number of fused pyrimidine derivatives became known as potential drug molecules against various types of proliferative diseases, caused by over-expression of protein kinases. One of the most important compound families are quinazolines : e.g. the best inhibitor of EGFR tyrosine kinase is PD153035 (6,7-dimethoxy-4-(3'-bromophenyl)amino-quinazoline) and IRESSA (gefitinib, ZD1839), developed from this compound family, is presently the only one approved and granted drug by the FDA for the treatment of advanced non-small-cell lung cancer (NSCLC). KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]-quinazoline-2-thione dihydrochloride) from this group, showed significantly higher inhibitory activity on cyclic GMP-specific phosphodiesterase compared with those of sildenafil (Viagra). The synthetic procedures of the example compounds are based on imidoyl chloride intermediates that were prepared from the appropriate 3H-quinazoline-4-ones. Although the key intermediates, quinazoline-4-ones, have been known since more than hundred years, their synthetic procedures have been improved much only in the past ten years. In this paper we reviewed the efficient synthetic methods of quinazolin-4-ones, and presented a novel, reliable method for their synthesis. There was no considerable effect of microwave-, or traditional thermal activation on the yield and compound purity.
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PMID:Improved, high yield synthesis of 3H-quinazolin-4-ones, the key intermediates of recently developed drugs. 1554 62

Molecular targeting is a promising option to increase the radiation response of tumours and to decrease normal tissue reactions, i.e. to achieve therapeutic gain. Molecular targeting substances in themselves are not curative while radiation is a highly efficient cytotoxic agent, with local recurrences often occurring from only few surviving clonogenic cells. High-dose radiotherapy therefore offers optimal conditions to evaluate the potential of specific biology-driven drugs for oncology. This review summarises the current status of preclinical and clinical research on combined radiation with examples of molecular targeting substances relevant for the treatment of NSCLC (EGFR, COX-2, VEGFR, KGF, TGF-beta, BBI).
Lung Cancer 2004 Aug
PMID:Molecular targeting in radiotherapy of lung cancer. 1555 99


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