Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human tissue factor pathway inhibitor-2 (hTFPI-2) is a 32-kDa serine protease inhibitor that is associated with the extracellular matrix. hTFPI-2 inhibits several extracellular matrix-degrading serine proteases and may play a role in tumor invasion and metastasis. To study the signal transduction pathway that leads to the activation of the hTFPI-2, we cloned the potential promoter region of this gene adjacent to a heterologous luciferase reporter gene. Phorbol 12-myristate 13-acetate (PMA) induced the luciferase reporter gene in HEK293 cells and other epithelial cell lines, such as the human lung carcinoma A549 cells, the breast carcinoma MCF7 cells, and the cervical HeLa cells. This PMA induction was blocked with the MEK inhibitor UO126, suggesting that the PMA-induced activation of the hTFPI-2 promoter is mediated through MEK. Furthermore, epidermal growth factor induced the luciferase reporter gene in HeLa cells. Cotransfection of the luciferase construct with constitutively active components of the Ras/Raf/MEK/ERK pathway in EcR-293 cells lead to a 7- to 92-fold induction of the luciferase reporter gene, indicating that regulation of hTFPI-2 is mediated through this pathway. A series of luciferase reporter gene constructs with progressive deletions of the 5'-flanking region suggested that the minimal basal promoter activity is located between nucleotide positions -89 and -384, whereas the minimal inducible promoter activity is between -89 and -222. We have used the computer program TFSEARCH and mutagenesis to analyze potential transcription factor binding sites. We identified an AP-1 binding site at nucleotide position -156 (inducible activity) and a Sp1 site at position -134 (basal activity) as potential cis-acting elements in the promoter region of the hTFPI-2.
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PMID:The ERK/MAPK pathway regulates the activity of the human tissue factor pathway inhibitor-2 promoter. 1244 83

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

Two receptors, neuropilin 1 (NP1) and neuropilin 2 (NP2), bind class 3 semaphorins, axon guidance molecules including SEMA3F, the gene for which was isolated from a 3p21.3 deletion in lung cancer. In addition, they bind VEGF (vascular endothelial growth factor), enhancing the effects of VEGF binding to KDR/Flk-1. Elevated VEGF levels are associated with the loss and cytoplasmic delocalization of SEMA3F in lung cancer, suggesting competition for their NP1 and NP2 receptors. To determine the timing of these events, we compared by immunohistochemistry VEGF, SEMA3F, NP1 and NP2 expression in 50 preneoplastic lesions and 112 lung tumours. In preneoplastic lesions, VEGF increased from low-grade to high-grade dysplasia (p=0.001) whereas SEMA3F levels remained low. NP1 and NP2 levels increased from dysplasia to microinvasive carcinoma (p=0.0001) and correlated with VEGF expression (p=0.04 and 0.0002, respectively). Non-small cell lung carcinoma overexpressed VEGF and NP1 and NP2 significantly more often than neuroendocrine tumours including small cell lung carcinoma. SEMA3F loss or delocalization correlated with advanced tumour stage. Migrating cells overexpressed VEGF, SEMA3F, NP1 and NP2 with cytoplasmic delocalization of NP1 as demonstrated in an in vitro wound assay. These results demonstrate early alteration of the VEGF/SEMA3F/NP pathway in lung cancer progression.
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PMID:Expression of VEGF, semaphorin SEMA3F, and their common receptors neuropilins NP1 and NP2 in preinvasive bronchial lesions, lung tumours, and cell lines. 1284 30

In oncology, the term 'targeted therapy' is used to describe drugs that target only the cancer cells and spare normal cells thereby reducing host toxicity while simultaneously increasing the eradication of cancer. Trastuzumab and imatinib are well known examples of successful targeted therapy. Newer agents like gefitinib and cetuximab offer hope that targeted therapy also may yield therapeutic benefit for such refractory malignancies as lung and colon cancers. One of many remaining challenges is to identify markers, molecular or clinical, that predict for responsiveness to a specific targeted therapy (e.g. HER2/neu positivity and trastuzumab responsiveness). However, using emerging technologies such as gene or protein profiling, it may be possible to predict a tumor's responsiveness to a particular targeted therapy based on its molecular signature. If true, clinicians might then possess the ability to predict a tumor's clinical behavior and shape its density through specific, targeted interventions.
Lung Cancer 2003 Aug
PMID:Targeted therapy in non-small cell lung cancer: myth or reality. 1286 56

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

Inhibition of the vascular endothelial growth factor VEGF-VEGF receptor (VEGF-R) kinase axes in the tumor angiogenic cascade is a promising therapeutic strategy in oncology. CEP-7055 is the fully synthetic orally active N,N-dimethyl glycine ester of CEP-5214, a C3-(isopropylmethoxy) fused pyrrolocarbazole with potent pan-VEGF-R kinase inhibitory activity. CEP-5214 demonstrates IC(50) values of 18 nM, 12 nM, and 17 nM against human VEGF-R2/KDR kinase, VEGF-R1/FLT-1 kinase, and VEGF-R3/FLT-4 kinase, respectively, in biochemical kinase assays. CEP-5214 inhibited VEGF-stimulated VEGF-R2/KDR autophosphorylation in human umbilical vein endothelial cells (HUVECs) with an IC (50) of approximately 10 nM and demonstrated an equivalent inhibition of murine FLK-1 autophosphorylation in transformed SVR endothelial cells. Evaluation of the antiangiogenic activity of CEP-5214 revealed a dose-related inhibition of microvessel growth ex vivo in rat aortic ring explant cultures and in vitro on HUVEC capillary-tube formation on Matrigel at low nanomolar concentrations. The antiangiogenic activity of CEP-5214 in these bioassays was observed in the absence of apparent cytotoxicity. Single-dose p.o. or s.c. administration of CEP-7055 or CEP-5214 to CD-1 mice at 23.8 mg/kg/dose b.i.d. resulted in a reversible inhibition of VEGF-R2/FLK-1 phosphorylation in murine lung tissues. Administration p.o. of CEP-7055 at 2.57 to 23.8 mg/kg/dose b.i.d. resulted in dose-related reductions in neovascularization in vivo in porcine aortic endothelial cell (PAEC)-VEGF/basic fibroblast growth factor-Matrigel implants in nude mice (maximum, 82% inhibition), significant reductions in granuloma formation (30%) and granuloma vascularity (42%) in a murine chronic inflammation-induced angiogenesis model, and significant and sustained (6 h) inhibition of VEGF-induced plasma extravasation in rats, with an ED(50) of 20 mg/kg/dose. Chronic p.o. administration of CEP-7055 at doses of 11.9 to 23.8 mg/kg/dose b.i.d. resulted in significant inhibition (50-90% maximum inhibition relative to controls) in the growth of a variety of established murine and human s.c. tumor xenografts in nude mice, including A375 melanomas, U251MG and U87MG glioblastomas, CALU-6 lung carcinoma, ASPC-1 pancreatic carcinoma, HT-29 and HCT-116 colon carcinomas, MCF-7 breast carcinomas, and SVR angiosarcomas. Significant antitumor efficacy was observed similarly against orthotopically implanted LNCaP human prostate carcinomas in male nude mice and orthotopically implanted renal carcinoma (RENCA) tumors in BALB/c mice, in terms of a significant reduction in the metastatic score and the extent of pulmonary metastases. These antitumor responses were associated with marked increases in tumor apoptosis, and significant reductions in intratumoral microvessel density (CD34 and Factor VIII staining) of 22-38% relative to controls depending on the specific tumor xenograft. The antitumor efficacy of chronic CEP-7055 administration was independent of initial tumor volume (in the ASPC-1 pancreatic carcinoma model) and reversible on withdrawal of treatment. Chronic p.o. administration of CEP-7055 in preclinical efficacy studies for periods of up to 65 days was well tolerated with no apparent toxicity or significant morbidity. Orally administered CEP-7055 has entered Phase I clinical trials in cancer patients.
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PMID:CEP-7055: a novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models. 1452 25


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