Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth of the EGF receptor-expressing non-small-cell lung carcinoma cell line H125 seems to be at least partially driven by autocrine activation of the resident EGF receptors. Thus, the possibility of an EGF receptor-directed antiproliferative treatment was investigated in vitro using a monoclonal antibody (alpha EGFR ior egf/r3) against the human EGF receptor and gangliosides which are known to possess antiproliferative and anti-tyrosine kinase activity. The moderate growth-inhibitory effect of alpha EGFR ior egf/r3 was strongly potentiated by the addition of monosialoganglioside GM3. Likewise, the combination of alpha EGFR ior egf/r3 and GM3 inhibited EGF receptor autophosphorylation activity in H125 cells more strongly than either agent alone. A synergistic inhibition of EGF receptor autophosphorylation by alpha EGFR ior egf/r3 and GM3 was also observed in the human epidermoid carcinoma cell line A431. In both cell lines, the inhibition of EGF receptor autophosphorylation by GM3 was prevented by pretreatment of the cells with pervanadate, a potent inhibitor of protein tyrosine phosphatases (PTPases). Also, GM3 accelerated EGF receptor dephosphorylation in isolated A431 cell membranes. These findings indicate that GM3 has the capacity to activate EGF receptor-directed PTPase activity and suggest a novel possible mechanism for the regulation of cellular PTPases.
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PMID:Growth inhibition of human lung adenocarcinoma cells by antibodies against epidermal growth factor receptor and by ganglioside GM3: involvement of receptor-directed protein tyrosine phosphatase(s). 901 29

104 surgery cases of non-small cell (NSLC) and small cell lung carcinoma (SLC) are studied. Oncoprotein bcl-2 is found in 49 out of 104 (47%) cases, more frequently in SLC (71%) than in NSLC (44%) and this correlated with carcinoma morphological malignancy. L-myc oncoprotein and EGFR were expressed practically in all cases, oncoprotein of the p53 mutated gene in 57% cases. The highest content of p53 was in SLC, large cell and poorly differentiated squamous cell carcinoma. Percentage of cells with mutated p53 statistically correlated with morphological malignancy of lung carcinoma. Oncoprotein of Rb gene was revealed in 51%, most frequently in squamous cell carcinoma (71%) and particularly in its well differentiated types. IGFII was found in 74% NSLC and in 100% SLC with cytoplasmic location in tumor cells; the level of expression was higher in SLC. IGFII 2 and 5 were more frequently observed in the foci of keratinization of squamous cell carcinoma. For the first time IGFP B3 was found not only in the cytoplasm but in the nuclei of tumor cells as well. There was a significant positive correlation between the content of IGFIBP3 in the nuclei of tumor cells and morphological malignancy (poor tumor cell differentiation, larger size and metastases). The mean number of proliferating Ki-67 positive cells was 24% but this figure was much higher (47%) in SLC. Squamous cell carcinoma is characterized by a more frequent and stronger expression of CD44 types 5 and 6 in the cytolemma and this may be considered as a marker of squamous cell differentiation of lung carcinoma.
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PMID:[Immunohistochemistry of biomolecular markers of lung cancer]. 948 14

Investigators and clinicians have recently called attention not only to the clinical and morphological parameters, but to the parameters characterizing the biological activity of nonsmall-cell carcinoma of the lung (NSCCL) from biochemical and molecular biological points of view. These include production of epidermal growth factor (EGF) receptors (EGFR) and their ligands which are important auto/paracrine regulation of lung tissue formation in health and tumor growth. Active studies of EGFR and EGF-like peptides (mainly, EGF and alpha-TGF) have failed to gain an insight into their role in the pathogenesis of NSCCL. Most authors suppose that tumor EGFR production increases as cell atypical features enhance and tumors show EGFR hyperexpression as compared with intact lung tissue. The expression of EGF and alpha-TGF is associated with poor prognosis in NSCCL. Attempts at designing and clinically testing the agents that block the transmission of EGFR ligands within the tumor cell are well-known, which open up new possibilities for antitumor therapy of patients with NSCCL.
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PMID:[Epidermal growth factor receptors and their ligands in non-small-cell lung carcinoma]. 966 99

When compared with best supportive care alone, the second-line treatment of non-small cell lung cancer (NSCLC) with 75 mg/m(2) docetaxel significantly improved the 1-year survival rate (37 vs. 12%) and lengthened time to disease progression (median 12.3 vs. 7.0 weeks) in study TAX 317. Quality of life was superior with docetaxel and the need for tumor-related therapy was reduced. Docetaxel 75 mg/m(2) in this setting is safe, and offers clinically meaningful benefit to patients. These findings are supported by data from study TAX 320 in which a heavily pre-treated population of advanced NSCLC patients was randomized to receive docetaxel 100 mg/m(2), docetaxel 75 mg/m(2) or a comparator arm of either vinorelbine or ifosfamide. Treatment with either dose of docetaxel significantly increased the proportion of patients without disease progression at 26 weeks. By intent to treat analysis, 1-year survival was 32% in patients randomized to docetaxel 75 mg/m(2). This was significantly greater than the 19% 1-year survival rate in the comparator arm. Prior exposure to paclitaxel did not lessen the response rate or survival advantage of docetaxel in this second-line setting. Future development is likely to lie in the combination of docetaxel with novel molecular-targeted agents such as EGFR tyrosine kinase inhibitors.
Lung Cancer 2002 Dec
PMID:Second line chemotherapy for NSCLC: establishing a gold standard. 1248 Jan 89

In advanced non-small cell lung cancer (NSCLC), monotherapy with gemcitabine improves quality of life when compared to best supportive care alone, while single-agent taxanes and vinorelbine also improve survival. Platinum-based combinations achieve benefits in response rate, time to progression and survival compared to single-agent cisplatin. With the introduction of combinations of newer agents, 2-year survival rates of 10-20% are being seen in co-operative group trials. Until recently, the various doublets that have been subjected to randomized comparison appear to have achieved similar rates of response and survival, though toxicities differ considerably depending on the choice of drugs used. However, study TAX 326, the largest trial yet conducted in advanced NSCLC, has now demonstrated that the combination of docetaxel with cisplatin is superior to that of vinorelbine and cisplatin. Controlled trials of platinum-containing vs. non-platinum combinations have yet to demonstrate any superiority of one over the other. Hopes for further improvement in survival are focused on the combination of cytotoxic agents with novel molecularly-targeted drugs such as the anti-angiogenics and EGFR inhibitors.
Lung Cancer 2002 Dec
PMID:First-line chemotherapy for NSCLC: an overview of relevant trials. 1248 Jan 90

Detection of genomic differences predictive of drug response or resistance in individual patients may allow therapy to be customized to the characteristics of particular tumors. Preliminary findings are that non-small cell lung cancer patients overexpressing ERCC1 mRNA have lower response to cisplatin chemotherapy, while those overexpressing ribonucleotide reductase mRNA have limited benefit from gemcitabine. In addition, overexpression of beta-tubulin III and stathmin can influence the sensitivity to microtubule interacting drugs, like vinorelbine and paclitaxel. The introduction of biological agents which target highly specific intracellular pathways offers the promise of enhancing the efficacy of cytotoxic chemotherapy. Among many promising biological agents is the monoclonal antibody C225, which blocks the EGFR receptor. The addition of C225 appears to induce responses in a proportion of colon cancer patients refractory to 5-FU or irinotecan, supporting pre-clinical evidence of synergistic activity. It also appears from xenograft data that C225 enhances the sensitivity of tumors to radiation and docetaxel or the combination.
Lung Cancer 2002 Dec
PMID:Molecular markers and targeted therapy with novel agents: prospects in the treatment of non-small cell lung cancer. 1248 Jan 94

EGFR and Her-2 are overexpressed in lung cancers and have, therefore, been chosen as preferred targets for novel therapies. Recent results on Iressa trials show only a moderate response to the agent, even in cases where it is documented that EGFR is over-expressed. These findings prompted us to re-visit the oncogenic pathways, which play a role in lung cancers, with special emphasis on the way EGFR/Her-2 signaling cooperates with other signaling pathways.
Lung Cancer 2003 Aug
PMID:EGF receptor as a therapeutic target. 1286 57

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


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