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

Small-cell lung cancer (SCLC) is an aggressive, malignant neoplasm with a 5-year survival of less than 10%. This poor survival rate is related to a high propensity for recurrence and a high rate of metastases. Metastases initially occur in the lymph nodes and thereafter in other organs such as the lung itself, liver, adrenal glands, brain, bone, and bone marrow. The mechanisms of metastases have been better understood recently and are described in this review. Receptor tyrosine kinases (RTKs) have been identified as important therapeutic targets in non-small-cell lung cancer (such as the EGF-receptor). We have begun to identify RTKs in SCLC and have shown that c-Kit and c-Met are expressed and functional in SCLC. RTKs have also been shown to be important in the metastasis of cancer cells. The roles of RTKs in the mechanism of metastasis are detailed in this review, with special emphasis on downstream signal transduction from RTK signaling.
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PMID:Mechanisms of metastasis as related to receptor tyrosine kinases in small-cell lung cancer. 1452 91

Malignant pleural mesothelioma is an aggressive malignancy with no known single curative modality. Most patients are candidates for chemotherapy at some point in their treatment, but no standard regimen has been established. Several phase II single-agent and combination chemotherapy studies have been performed over the past 2 decades. Although the true impact of chemotherapy in mesothelioma remains to be determined, agents with consistent antitumor activity include doxorubicin, platinum agents, and antimetabolites. Combination chemotherapy is associated with higher response rates, but not necessarily longer median survivals. Large randomized trials, which are currently ongoing or have been performed in the past few years, will yield important answers in regard to the role of chemotherapy and the efficacy of various single and combination chemotherapy agents. Furthermore, the biologic and genetic studies of mesothelioma have identified several receptor tyrosine kinases that are aberrantly expressed in these tumors. Orally available small molecule inhibitors of several receptor tyrosine kinases have been developed and are now being evaluated in clinical trials.
Clin Lung Cancer 2003 Sep
PMID:Chemotherapy for malignant pleural mesothelioma. 1459 92

The ErbB family of receptor tyrosine kinases, of which the epidermal growth factor receptor (EGFR) is the prototype, is associated with the formation and malignant progression of most of the common solid tumors. These molecules play a key role in a complex network of signal transduction pathways that function in normal development as well as in neoplastic transformation. The EGFR and other family members are therefore promising targets for new anticancer therapies. In normal tissues, EGFR-tyrosine kinase (TK) activity is strictly controlled. However, in tumor cells, there are multiple mechanisms that can lead to increased or inappropriate EGFR-TK activity, including altered expression of EGFR, its ligand, or interacting molecules; decreased deactivation through phosphatases or downregulation; or mutation of the EGFR protein. Novel therapeutic approaches aimed at inhibiting increased EGFR-TK activity include antibodies that block the extracellular ligand-binding site, antibody or ligand fusion proteins that specifically target toxins to the tumor cells, or small-molecule TK inhibitors (TKIs) that act intracellularly to block downstream signal transduction from EGFR. Studies have shown that such blockade can lead to reduced cellular proliferation, inhibition of survival signals, and inhibition of tumor metastasis and angiogenesis. Additionally, some agents, including EGFR antibodies and TKIs such as gefitinib have been demonstrated to be effective against various human solid tumors in preclinical models and have shown activity in advanced non-small-cell lung cancer and other solid tumors.
Clin Lung Cancer 2003 Sep
PMID:The impact of gefitinib on epidermal growth factor receptor signaling pathways in cancer. 1464 88

Chemotherapy is the standard of care for patients with advanced non-small cell lung cancer (NSCLC). Over the past 20 years, advances in chemotherapy have shown minimal incremental improvement in the survival outcomes of patients with advanced NSCLC. With the identification of molecular and genetic alterations in lung cancer, several new potential rationally designed therapeutic targets have emerged. One of these is the epidermal growth factor receptor (EGFR) and member of the ErbB family of receptor tyrosine kinases. Several inhibitors, both antibodies directed at the extra-cellular portion of the receptor, and small molecule inhibitors directed at the tyrosine kinase domain of EGFR are in clinical development in lung cancer. This article will review the pre-clinical rationale and the clinical studies of EGFR inhibitors alone and/or in combination with chemotherapy that have been performed to date in advanced NSCLC.
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PMID:The role of epidermal growth factor receptor in advanced non-small cell lung carcinoma. 1464 27

Despite advances in chemotherapy, radiation therapy, and surgery, the overall survival for patients with lung cancer remains poor. Thus, novel therapeutic approaches are warranted. As knowledge of the molecular abnormalities and dysregulated cellular processes contributing to the pathogenesis and progression of lung cancer has been acquired, intense interest has been directed at developing agents that target these abnormalities. New agents targeting aberrant receptor tyrosine kinases, the Ras oncoprotein, mediators of metastases and angiogenesis, and the tumor suppressor gene p53 have, among other agents, shown promise in preclinical studies. Early clinical trials with these agents in patients with advanced malignancies suggest preliminary evidence of clinical activity and possible applications in non-small-cell lung cancer (NSCLC). Ongoing clinical trials will help clarify the settings in which these agents are of greatest therapeutic value, the optimal schedule of administration, toxicities associated with chronic administration, and hopefully, provide additional insight into the biology of lung cancer. Selected clinical trials will be presented to highlight the use of rationally designed, targeted therapies for patients with NSCLC.
Clin Lung Cancer 2002 Sep
PMID:Promising developments in targeted therapies for non-small-cell lung cancer. 1465 69

Radiolabeled cell-surface peptide receptor-binding molecules are emerging as an important class of radiopharmaceuticals. Their binding to specific cell membrane receptors allows for noninvasive assessment of regional receptor proteomics in vivo. Information thus obtained can be used for diagnostic purposes and for predicting and monitoring response to treatment. This paradigm also applies to pulmonary diseases. In this review, available radiopharmaceuticals of great potential or already in clinical use for imaging of lung cancer, lung inflammation and infection and pulmonary embolism are discussed. In lung cancer, somatostatin receptor imaging by means of technetium-99m (99mTc)-octreotide scintigraphy has proven useful for characterizing malignancy in solitary pulmonary nodules. Additionally, several radiopharmaceuticals targeting tyrosine-kinase, e.g. 99mTc labeled epidermal growth factor and indium-111 (111In)-diethylene triamine penta-acetic acid-trastuzumab, or G-protein coupled receptors, e.g. 99mTc-bombesin, iodine-123-vasoactive intestinal peptide and 111In-tetraazacyclododecane tetra-acetic acid (DOTA)-cholecystokinine-B, are being explored for their diagnostic as well as treatment monitoring potential. With the purpose of better evaluating the source of pulmonary embolism, as well as to differentiate acute from chronic deep venous thrombosis, several radiolabeled peptides targeting the glycoprotein IIb/IIIa fibrinogen receptor found on activated platelets have been developed. Out of these, 99mTc-P280 is now approved by the US Food and Drug Administration for scintigraphic imaging of suspected acute venous thrombosis in the lower extremities of patients. In the field of lung inflammation and infection, non-specific 111In and 99mTc-human polyclonal immunoglobulins have been successfully used to identify the presence and extent of Pneumocystis carinii, cytomegalovirus, Mycobaterium avium and fungal infections in patients with HIV infection. The clinical role of other radiopharmaceuticals such as 99mTc-J001X, a nonpyrogenic acylated polygalactoside isolated from Klebsiella pneumoniae and binding with high affinity to CD11b and CD14 lipopolysaccharide receptors expressed on monocytes/macrophages, and 111In-octreotide, binding to up-regulated somatostatin receptors on activated lymphocytes needs to be further defined.
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PMID:Peptide receptor imaging: advances in the diagnosis of pulmonary diseases. 1472 55

Growth-stimulating pathways activated independently of their normal tissue environment are critical to the carcinogenesis and progression of lung cancer. These pathways are comprised of extracellular growth factors; their specific receptors on the cellular membrane; signal transduction cascades in the cytosol; and target molecules, including cytoskeletal proteins, metabolic regulators, and transcription factors in the nucleus. Growth factors can be divided into two groups based on their receptors: G-protein-coupled receptors and receptor tyrosine kinases. Growth factors induce clonal expansion of lung cancer cells by autocrine and/or paracrine mechanisms. Signal transduction cascades form an extremely large and complicated network with cross-talk connections. Ras, phosphatidylinositol-3-OH kinase, and phospholipase C are three key regulators involved in the network. Recent progress in our understanding of the oncoproteins functioning in the pathways has led to the development of novel therapeutic agents. Some of the most exciting results have been obtained with inhibitors of receptor tyrosine kinases. Phase I studies of epidermal growth factor-receptor inhibitors demonstrate objective responses without severe toxicity as single agents in patients with non-small-cell lung cancer refractory to conventional chemotherapy. This new strategy might lead to breakthroughs in the treatment of lung cancer with distant metastases not curable by conventional chemotherapy alone.
Clin Lung Cancer 2001 May
PMID:Growth-stimulating pathways in lung cancer: implications for targets of therapy. 1472 Mar 64

Antagonists of human growth hormone-releasing hormone (hGHRH) with increased potency and improved enzymatic and chemical stability are needed for potential clinical applications. We synthesized 21 antagonistic analogs of hGHRH(1-29)NH(2), substituted at positions 8, 9, and 10 of the common core sequence [phenylacetyl-Tyr(1), d-Arg(2,28), para-chloro-phenylalanine 6, Arg(9)/homoarginine 9, Tyr(10)/O-methyltyrosine 10, alpha-aminobutyric acid 15, norleucine 27, Har(29)] hGHRH(1-29)NH(2). Inhibitory effects on hGHRH-induced GH release were evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinities of the peptides to pituitary GHRH receptors were also determined. Introduction of para-amidinophenylalanine 10 yielded antagonists JV-1-62 and -63 with the highest activities in vitro and lowest receptor dissociation constants (K(i) = 0.057-0.062 nM). Antagonists JV-1-62 and -63 also exhibited the strongest effect in vivo, significantly (P < 0.05-0.001) inhibiting hGHRH-induced GH release for at least 1 h. Para-aminophenylalanine 10 and O-ethyltyrosine 10 substitutions yielded antagonists potent in vitro, but His(10), 3,3'-diphenylalanine 10, 2-naphthylalanine 10, and cyclohexylalanine 10 modifications were detrimental. Antagonists containing citrulline 9 (in MZ-J-7-72), amidinophenylalanine 9 (in JV-1-65), His(9), d-Arg(9), citrulline 8, Ala(8), d-Ala(8), or alpha-aminobutyric acid 8 substituents also had high activity and receptor affinity in vitro. However, in vitro potencies of analogs with substitution in position 9 correlated poorly with acute endocrine effects in vivo, as exemplified by the weak and/or short inhibitory actions of antagonists JV-1-65 and MZ-J-7-72 on GH release in vivo. Nevertheless, antagonist JV-1-65 was more potent than JV-1-63 in tests on inhibition of the growth of human prostatic and lung cancer lines xenografted into nude mice. This indicates that oncological activity may be based on several mechanisms. hGHRH antagonists with improved efficacy could be useful for treatment of cancers that depend on insulin-like growth factors or GHRH.
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PMID:Increased activity of antagonists of growth hormone-releasing hormone substituted at positions 8, 9, and 10. 1475 56

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


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