Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

DNA fragments amplified in a stomach cancer-derived cell line, KATO-III, were previously identified by the in-gel DNA renaturation method, and a 0.2-kilobase-pair fragment of the amplified sequence was subsequently cloned. By genomic walking, a portion of the exon of the gene flanking this 0.2-kilobase-pair fragment was cloned, and the gene was designated as K-sam (KATO-III cell-derived stomach cancer amplified gene). The K-sam cDNAs, corresponding to the 3.5-kilobase K-sam mRNA, were cloned from the KATO-III cells. Sequence analysis revealed that this gene coded for 682 amino acid residues that satisfied the characteristics of the receptor tyrosine kinase. The K-sam gene had significant homologies with bek, FLG, and chicken basic fibroblast growth factor receptor gene. The K-sam gene was amplified in KATO-III cells with the major transcript of 3.5-kilobases in size. This gene was also expressed in some other stomach cancer cells, a small cell lung cancer, and germ cell tumors.
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PMID:K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes. 237 25

We describe here the properties of tert-butyloxycarbonyl-Trp-Leu-Asp-Phe-NHNH2 (A-57696), a C-terminal hydrazide analogue of tert-butyloxycarbonyl-CCK4 (Boc-Trp-Met-Asp-Phe-NH2), at four cholecystokinin (CCK) receptor-bearing tissues, the guinea pig pancreas and gall bladder (Type A), guinea pig cortex (Type B), and NCI-H345 cells, a human small cell lung cancer cell line that expresses CCK-B/gastrin receptors. Using 125I-Bolton-Hunter-cholecystokinin octapeptide (26-33) (125I-Bolton-Hunter-CCK8) as the radioligand, A-57696 was found to be selective for cortical CCK-B receptors (IC50 = 25 nM), compared with pancreatic CCK-A receptors (IC50 = 15 microM). A-57696 behaved as a competitive antagonist in reversing CCK8-stimulated pancreatic amylase secretion and phosphoinositide breakdown. By Schild analysis, its Kd was determined to be 4.7 and 6.8 microM in amylase and phosphoinositide assays, respectively. A-57696 (100 microM) did not elicit gall bladder contraction, and it inhibited contractions induced by CCK8. The Kd of A-57696 at gall bladder CCK-A receptors was 19 microM. In contrast, A-57696 behaved as a partial agonist (80% of maximal CCK8 response) in stimulating calcium mobilization at CCK-B/gastrin receptors on NCI-H345 cells. A-57696 and CCK8 inhibited each other in calcium mobilization experiments utilizing the fluorescent dye Indo-1. Stimulatory actions of CCK8 and A-57696 were reversed by the CCK-B-selective (R)-L-365,260 (100 nM), whereas at the same concentration, the CCK-A-selective (S)-L-365,260 was ineffective. Binding studies using 125I-Bolton-Hunter-CCK8 and 125I-gastrin indicated that binding sites labeled by these two ligands displayed similar affinities for CCK8, desulfated CCK8, gastrin, A-57696, and both enantiomers of L-365,260. A-57696 represents a new class of CCK-A peptide antagonist at guinea pig pancreas a new class of CCK-A peptide antagonist at guinea pig pancreas and gall bladder. Its contrasting functional activities at guinea pig CCK-A and CCK-B/gastrin receptors in a human tumor cell demonstrate that, in addition to the previously described differences in binding specificity for selective agonists and antagonists, CCK-A receptors and CCK-B/gastrin receptors have different requirements for activation.
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PMID:Distinct requirements for activation at CCK-A and CCK-B/gastrin receptors: studies with a C-terminal hydrazide analogue of cholecystokinin tetrapeptide (30-33). 260 85

Small cell lung cancer requires aggressive combination chemotherapy. The three active agents, doxorubicin (A) 45 mg/m2 i.v. day 1, cyclophosphamide (C) 1.0 mg/m2 i.v. day 1 and VP16-213 (E) 50 mg/m2/day i.v. days 1-5 were given together. The combination (ACE) was given every 21 days without chest irradiation. One hundred and seventy-four patients have been stratified for extent of disease and randomized on three sequential studies testing ACE vs ACE + MER immunotherapy (38 patients), or ACE vs ACE alternating with CCNU, methotrexate, vincristine and procarbazine (109 patients), or ACE vs ACE II (ACE with continuous VP16-213 - 100 mg/m2/day X 5 days - 27 patients - ongoing). The immunotherapy and the alternating non-cross resistant combination have not proven beneficial with respect to response or survival. The ACE combination, regardless of additional treatments, has produced greater than 90% response overall. In limited disease the complete response (CR) frequency is 65%. The median survival for limited disease overall is 14 months and 18 months for patients achieving CR. In extensive disease the CR frequency is 40% with a median survival of 9 months overall and 13 months for patients achieving CR. Response frequency and survival are identical in the first two studies and 20-30% of patients with limited disease are long-term survivors with one late relapse (greater than 3 years). Patients who achieved CR had a significantly longer survival regardless of other factors such as performance status or extent of disease. Prophylactic cranial irradiation was demonstrated to be useful in prevention or delaying CNS metastases in patients who achieved CR. The third generation study of high-dose VP16-213 infusion seeks to increase the CR frequency. ACE chemotherapy without chest irradiation is a highly effective treatment for all patients with small cell lung cancer and compares favorably with all other studies with or without adjuvant radiotherapy.
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PMID:Doxorubicin, Cyclophosphamide and VP16-213 (ACE) in the treatment of small cell lung cancer. 628 82

Neutral endopeptidase (NEP; CALLA, CD10, EC 3.4.24.11) is a cell surface endopeptidase that hydrolyses bioactive peptides, including the bombesin-like peptides, as well as other neuropeptides. Bombesin-like peptides and other neuropeptides are autocrine growth factors for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Low expression of NEP has been reported in SCLC and NSCLC cell lines. NEP inhibition has been shown to increase proliferation in one cell line. To date, NEP expression has not been quantitatively evaluated in normal adult lung, SCLC or NSCLC tumors, paired uninvolved lung from the same patient, or in other pulmonary neoplasms such as mesotheliomas and carcinoids. We examined the expression of NEP in these tissues and human cell lines using immunohistochemistry, flow cytometry, enzyme activity, ELISA, Western blot, and reverse transcription (RT)-PCR. Uninvolved lung tissue from different individuals displayed considerable variation in NEP activity and protein. By immunohistochemistry, NEP expression was detectable in alveolar and airway epithelium, fibroblasts of normal lung, and in mesotheliomas, whereas it was undetectable in most SCLC, adenocarcinoma, squamous cell carcinoma, and carcinoid tumors of the lung. NEP activity and protein levels were lower in all SCLC and adenocarcinoma tumors when compared to adjacent uninvolved lung, often at levels consistent with expression derived from contaminating stroma. NEP expression and activity were reduced or undetectable in most SCLC and lung adenocarcinoma cell lines. NEP mRNA by RT-PCR was not expressed or was in low abundance in the majority of lung cancer cell lines. The majority of lung tumors did not express NEP by RT-PCR as compared with normal adjacent lung. In addition, recombinant NEP abolished, whereas an NEP inhibitor potentiated, the calcium flux generated by neuropeptides in some lung cancer cell lines, demonstrating potential physiological significance for low NEP expression. NEP, therefore, is a signal transduction and possibly a growth modulator for both SCLC and NSCLC, emphasizing the role of neuropeptides in the pathogenesis of the major histological forms of lung cancer.
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PMID:Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux. 863 Oct 21

In 1989, we reorganized acute and rehabilitation cares for patients operated for non small cell lung cancer (NSCLC) in order to decrease costs by setting up a specialised intermediate care unit (SICU). This report deals with the postoperative complications and the total cost of these cares (SICU, acute and rehabilitation cares) as well as their cost/benefit. From 1990 to 1994, we performed 95 thoracotomies, 7 exploratory and 88 with lung resection (24 pneumonectomies, 8 bilobectomies, 48 lobectomies and 8 segmentectomies or wedge resections). The postoperative staging was I in 52, II in 17, III a in 15, S III b in 2, IV in 2. Patients 30-days postoperative mortality was 2/95 (2.1%). We had in 11 patients respiratory complications (12%; 3 bronchopleural fistulas, 3 pneumonias, 3 pneumothorax > 7 days, 1 empyema, 1 chronic hypoxemia), in 15 patients cardiac arrhythmias which were easily controlled by medication and in 2 general complications (1 hemiplegia, 1 transitory stupor state). The total duration of hospital stay, including SICU, acute and rehabilitative cares, was 32 +/- 10 (3-70) days with a mean total cost of 14,722 Sfr. per case. In conclusion, surgery for NSCLC can be safely performed in intermediate cares without intensive care unit at low costs and with a low morbidity and mortality provided they are staffed by a specialised and well trained team.
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PMID:[Thoracic surgery for non-small cell lung cancer. Cost-benefit of its management in specialized intermediate care]. 865 76

Tumour angiogenesis is an important prognostic factor in non-small cell lung cancer. Recently, EGFR and c-erbB-2 protein was found to regulate cell adhesion and the invasive growth of cancer through its association with the cadherin-catenin complex. The role of c-erbB-2 protein in cell migration has been also reported. In this study we investigate the combined role of tumoral neoangiogenesis and c-erbB-2/EGFR expression in the metastatic behaviour and prognosis of operable non-small cell lung cancer. 107 tumour samples from patients suffering from operable non small cell lung cancer were examined. EGFR and c-erbB-2 were not correlated with each other. C-erbB-2 expression was associated with low angiogenesis, approaching statistical significance in adenocarcinomas (p = 0.08). The absence of expression of both c-erbB-2 and EGFR oncogenes in tumours with high angiogenesis, was most frequently observed in node negative cases (p = 0.04). C-erbB-2 overexpression defined a subgroup of node negative patients with low angiogenesis and prognosis similar to patients with tumours bearing high angiogenesis. These findings support the hypothesis that expression of the erb genes is a mechanism activated in non-small cell lung cancer to enable cancer cell migration. This pathway seems to be activated mainly in tumours with poor vasculature presumably lading to an unfavourable intratumoral nutritional and oxygen ambience.
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PMID:Non-small cell lung cancer: c-erbB-2 overexpression correlates with low angiogenesis and poor prognosis. 904 64

Causative germline missense mutations in the RET proto-oncogene have been associated with over 92% of families with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). MEN 2A is characterized primarily by medullary thyroid carcinoma (MTC) and pheochromocytoma, both tumors of neural crest origin. Parathyroid hyperplasia or adenoma is also seen in MEN 2A, but rarely in MEN 2B, which has additional stigmata, including a marfanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gastrointestinal tract. In familial MTC, MTC is the only lesion present. Somatic RET mutations have also been identified in a subset of sporadic MTCs, pheochromocytomas, and rarely, small cell lung cancer, but not in sporadic parathyroid hyperplasias/adenomas or other neuroendocrine tumors. Glial cell line-derived neurotrophic factor (GDNF) and its receptor molecule GDNFR-alpha, have recently been identified as members of the RET ligand binding complex. Therefore, the genes encoding both GDNF and GDNFR-alpha are excellent candidates for a role in the pathogenesis of those MEN 2 families and sporadic neuroendocrine tumors without RET mutations. No mutations were found in the coding region of GDNF in DNA samples from 9 RET mutation negative MEN 2 individuals (comprising 6 distinct families), 12 sporadic MTCs, 17 sporadic cases of parathyroid adenoma, and 10 small cell lung cancer cell lines. Therefore, we find no evidence that mutation within the coding regions of GDNF plays a role in the genesis of MEN 2 and sporadic neuroendocrine tumors.
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PMID:Mutation analysis of glial cell line-derived neurotrophic factor, a ligand for an RET/coreceptor complex, in multiple endocrine neoplasia type 2 and sporadic neuroendocrine tumors. 928 37

Autocrine and paracrine signaling leading to stimulation of tumor cell growth is a common theme in human cancers. In addition to polypeptide growth factors such as EGF family members which signal through receptor tyrosine kinases, accumulating evidence supports the autocrine and paracrine involvement of specific neuropeptides with defined physiologic actions as neurotransmitters and gut hormones in lung, gastric, colorectal, pancreatic and prostatic cancers. These neuropeptides, including gastrin-releasing peptide, neuromedin B, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric G proteins. Studies with human small cell lung cancer (SCLC) cells support a requirement for balanced signaling through G(q) and G(12/13) proteins leading to intracellular Ca2+ mobilization, PKC activation and regulation of the ERK and JNK MAP kinase pathways. While specific neuropeptide antagonists offer promise for interrupting the single neuropeptide autocrine systems operating in pancreatic and prostatic cancers, SCLC is exemplified by multiple, redundant neuropeptide autocrine systems such that tumor growth cannot be inhibited with a single specific antagonist. However, a novel class of neuropeptide derivatives based on the substance P sequence have been defined that exhibit broad specificity for neuropeptide receptors and induce apoptosis in SCLC by functioning as biased agonists that stimulate discordant signal transduction. Thus, interruption of autocrine and paracrine neuropeptide signaling with specific antagonists or broad-spectrum biased agonists offer promising new therapeutic approaches to the treatment of human cancers.
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PMID:Autocrine and paracrine signaling through neuropeptide receptors in human cancer. 1131 3

Numerous inhibitors of angiogenesis are currently under study in lung cancer. Four trials of adjuvant interferon after chemotherapy for small cell lung cancer (SCLC) were negative. Several metalloproteinase inhibitors (MMPIs) are now in study in SCLC and non-small cell lung cancer (NSCLC). Two large randomized trials have closed recently in which Marimastat 10 mg bid was compared to placebo in responding patients with SCLC. Two randomized studies of Prinomastat versus placebo with combination chemotherapy in advanced NSCLC have also completed accrual. The results of these trials are not yet available, but should be reported in mid-2001. A Phase III trial of BMS-275291, a broad-spectrum MMPI in combination with paclitaxel and carboplatin is open for patients with advanced NSCLC. Neovastat, a standardized shark cartilage extract is under study in inoperable Stage III NSCLC. VEG-F gene expression is increased in many tumors including NSCLC, and may act as a paracrine mediator of growth. A randomized Phase II trial of paclitaxel and carboplatin with or without a recombinant humanized anti-VEG-F has been undertaken in NSCLC. Modestly better response and survival were seen with anti-VEG-F and a large Phase III trial is planned. Numerous receptor tyrosine kinases (TK) have been found to be directly or indirectly involved in angiogenesis including Flk-1, Flt-l, Tie-1 and Tie-2. SU5416 is a small molecular TK inhibitor and potent inhibitor of VEG-F-mediated Flk-1 receptor signaling. Another TK inhibitor SU6668 blocks VEG-F, bFGF and PDGF receptor signaling. It is orally available, and it may be evaluated in lung cancer trials in the near future. ZD4190 is an inhibitor of KDR/Flk-1 that may be evaluated in SCLC. Thalidomide has recently been shown in pre-clinical models to be anti-angiogenic. A randomized trial of paclitaxel/carboplatin and radiation with or without thalidomide is open for patients with Stage IIIB NSCLC in the United States. Numerous other anti-angiogenesis agents are in early clinical trials, but have not been evaluated in lung cancer yet.
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PMID:Angiogenesis inhibitors in the treatment of lung cancer. 1174 Sep 99

Despite intensive treatment efforts, the prognosis for lung cancer is very poor; less than 15% of patients survive 5 years. Trastuzumab, a monoclonal antibody targeting the HER2/neu protein receptor, is effective in the treatment of metastatic breast cancer and may be useful in the treatment of non-small cell lung cancer (NSCLC). Using the HercepTest (Dako; Carpenteria, CA), 25% of NSCLC show 2+ or greater HER2/neu expression, but only 6% to 8% of NSCLC tumors have 3+ overexpression. Positive HER2/neu expression is most often seen in adenocarcinomas compared with squamous cell carcinomas or large cell carcinomas, and is rarely seen in small cell lung cancer. As determined by fluorescence in situ hybridization analysis, the high degree of HER2/neu gene expression and gene amplification seen in breast cancer is lower in NSCLC. Polysomy is the cause of increased HER2/neu expression in most NSCLC. Prospective clinical studies with trastuzumab in lung cancer are ongoing. Future studies in NSCLC need to include immunohistochemistry and fluorescence in situ hybridization analysis to determine the method of choice for evaluating clinically relevant HER2/neu-positive tumors.
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PMID:HER2/neu expression in malignant lung tumors. 1189 14


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