Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin E is a critical G(1)-S cell cycle regulator aberrantly expressed in bronchial premalignancy and lung cancer. Cyclin E expression negatively affects lung cancer prognosis. Its role in lung carcinogenesis was explored. Retroviral cyclin E transduction promoted pulmonary epithelial cell growth, and small interfering RNA targeting of cyclin E repressed this growth. Murine transgenic lines were engineered to mimic aberrant cyclin E expression in the lung. Wild-type and proteasome degradation-resistant human cyclin E transgenic lines were independently driven by the human surfactant C (SP-C) promoter. Chromosome instability (CIN), pulmonary dysplasia, sonic hedgehog (Shh) pathway activation, adenocarcinomas, and metastases occurred. Notably, high expression of degradation-resistant cyclin E frequently caused dysplasia and multiple lung adenocarcinomas. Thus, recapitulation of aberrant cyclin E expression as seen in human premalignant and malignant lung lesions reproduces in the mouse frequent features of lung carcinogenesis, including CIN, Shh pathway activation, dysplasia, single or multiple lung cancers, or presence of metastases. This article reports unique mouse lung cancer models that replicate many carcinogenic changes found in patients. These models provide insights into the carcinogenesis process and implicate cyclin E as a therapeutic target in the lung.
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PMID:Transgenic cyclin E triggers dysplasia and multiple pulmonary adenocarcinomas. 1736 Apr 82

One subclass of antiestrogens, the selective estrogen receptor down-regulators (SERDs), have received considerable attention of late as they competitively inhibit estrogen binding and induce a rapid, proteasome-dependent degradation of the receptor. Contained within this class of molecules is the steroidal antiestrogen ICI182,780 (faslodex), recently approved for the treatment of metastatic cancer, and GW5638/DPC974, a SERD that is currently being evaluated in the clinic. Given that mechanistic differences between different selective estrogen receptor modulators have been translated into important clinical profiles, it was of interest to determine if the SERD subclass of ligands were likewise functionally or mechanistically distinguishable. In this study, we show that although the steroidal and nonsteroidal SERDs target ERalpha for degradation, the underlying mechanism(s) are different. Of note was the identification of a specific protein-protein interaction surface presented on ERalpha in the presence of the ICI182,780-activated receptor which is required for degradation. Interestingly, this surface is also presented on ERalpha in the presence of RU58,668, a SERD that is chemically distinct from ICI182,780. This surface is not required for GW5638-mediated degradation, and thus, this SERD seems to affect ERalpha down-regulation by a different mechanism. These data suggest that sequencing of therapies using drugs of this class is likely to be possible. Finally, because of the unmet need for orally active SERDS that function similarly to ICI182,780, we have used the insights from these mechanistic studies to develop and validate a high-throughput screen for compounds of this class with improved pharmaceutical properties.
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PMID:Definition of functionally important mechanistic differences among selective estrogen receptor down-regulators. 1790 66

Renal cell carcinoma (RCC) accounts for approximately 2.6% of all cancers in the United States. While early stage disease is curable by surgery, the median survival of metastatic disease is only 13 months. In the last decade, there has been considerable progress in understanding the genetics of RCC. The VHL tumor suppressor gene is inactivated in the majority of RCC cases. The VHL protein (pVHL) acts as an E3 ligase that targets HIF-1, the hypoxia inducible transcription factor, for degradation by the ubiquitin proteasome system (UPS). In RCC cases with mutant pVHL, HIF-1 is stabilized and aberrantly expressed in normoxia, leading to the activation of pro-survival genes such as vascular endothelial growth factor (VEGF). This review will focus on the defect in the UPS that underlies RCC and describe the development of novel therapies that target the UPS. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
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PMID:Role of the ubiquitin proteasome system in renal cell carcinoma. 1804 41

Uveal melanoma is the most common primary intra-ocular malignancy in adults. Overall mortality rate remains high because of the development of metastatic disease, which is highly resistant to systemic therapy. Improved understanding of the molecular pathogenesis of cancers has led to a new generation of therapeutic agents that interfere with a specific pathway critical in tumor development or progression. Although no specific genes have been linked to the pathogenesis of uveal melanoma, which differs from that of cutaneous melanoma, progress has been made in identifying potential targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and angiogenesis. This review focuses on the prospects for improving the systemic therapy of uveal melanoma using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials. Preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. Clinical trials of some of these approaches have been initiated in patients with metastatic uveal melanoma as well as in the adjuvant setting after primary therapy.
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PMID:Targeted therapy for uveal melanoma. 1822 59

Proteasome antibodies were detected by enzyme-linked immunosorbent assay in two of the 45 (4.4%) patients with lung cancer, 0 of the 39 patients with breast cancer and six of the 51 (11.8%) patients with ovarian cancer. Six of the 47 (12.8%) patients with relapsing remitting multiple sclerosis had proteasome antibodies, as well as two of the 100 (2%) blood donors. Significant higher odds ratios compared to the blood donors were found for the patients with ovarian cancer (OR: 6.4; 95% CI: 1.1-68) and multiple sclerosis (OR: 7.1; 95% CI: 1.2-74). There was no association between proteasome antibodies and metastases or onconeural antibodies. The antibodies showed reactivity to 23, 25 and 27 kD proteins of the 20S proteasome using Western blot. The increased prevalence of proteasome antibodies in patients with ovarian cancer or multiple sclerosis may reflect cellular damage and release of intracellular antigens. Whether the antibodies take part in the clearance of released proteasomes and thus participate in the pathogenesis of cancer or autoimmune disease is not known.
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PMID:Proteasome antibodies in patients with cancer or multiple sclerosis. 1826 96

Most tumors grow in immunocompetent hosts despite expressing NKG2D ligands (NKG2DLs) such as the MHC class I chain-related genes A and B (MICA/B). However, their participation in tumor cell evasion is still not completely understood. Here we demonstrate that several human melanomas (cell lines and freshly isolated metastases) do not express MICA on the cell surface but have intracellular deposits of this NKG2DL. Susceptibility to NK cell-mediated cytotoxicity correlated with the ratio of NKG2DLs to HLA class I molecules but not with the amounts of MICA on the cell surface of tumor cells. Transfection-mediated overexpression of MICA restored cell surface expression and resulted in an increased in vitro cytotoxicity and IFN-gamma secretion by human NK cells. In xenografted nude mice, these melanomas exhibited a delayed growth and extensive in vivo apoptosis. Retardation of tumor growth was due to NK cell-mediated antitumor activity against MICA-transfected tumors, given that this effect was not observed in NK cell-depleted mice. Also, mouse NK cells killed MICA-overexpressing melanomas in vitro. A mechanistic analysis revealed the retention of MICA in the endoplasmic reticulum, an effect that was associated with accumulation of endoH-sensitive (immature) forms of MICA, retrograde transport to the cytoplasm, and degradation by the proteasome. Our study identifies a novel strategy developed by melanoma cells to evade NK cell-mediated immune surveillance based on the intracellular sequestration of immature forms of MICA in the endoplasmic reticulum. Furthermore, this tumor immune escape strategy can be overcome by gene therapy approaches aimed at overexpressing MICA on tumor cells.
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PMID:Intracellular retention of the NKG2D ligand MHC class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity. 1835 83

Pancreatic cancer is a deadly malignancy with still high mortality and poor survival despite the significant advances in understanding, diagnosis, and access to conventional and novel treatments. Though cytotoxic chemotherapy based on the purine analogue gemcitabine remains the standard approach in adjuvant and palliative setting the need for novel agents aiming at the main pathophysiological abnormalities and molecular pathways involved remains soaring. So far, evidence of clinical benefit, though small, exists only from the addition of the targeted agent erlotinib on the standard gemcitabine chemotherapy. Apart from the popular monoclonal antibodies and small molecules tyrosine kinase inhibitors, other novel compounds being tested in preclinical and clinical studies target mTOR, NF-kappaB, proteasome and histone deacetylase. These new drugs along with gene therapy and immunotherapy, which are also under clinical evaluation, may alter the unfavorable natural course of this disease. In this review we present the main pathophysiological alterations met in pancreatic cancer and the results of the florid preclinical and clinical research with regards to the targeted therapy associated to these abnormalities.
Cancer Metastasis Rev 2008 Sep
PMID:Pancreatic cancer: from molecular pathogenesis to targeted therapy. 1842 34

The major approach to the development of anticancer drugs involves searching for new compounds, efficient against malignancies, which are not, as yet, used clinically. This strategy is time-consuming and expensive. Recent studies have disclosed a surprising, but mechanistically consistent, anticancer activity of disulfiram (antabuse), a drug used for about 50 years in the treatment of alcoholism. Disulfiram has been successfully used to suppress hepatic metastases originating from ocular melanoma. The pharmacokinetics of disulfiram and its pharmacological profile in cancer cell lines and in cancer cells obtained from patients is well known. Disulfiram is a readily available and inexpensive substance whose adverse effects are negligible, compared to classical cancerostatics. In addition, the inhibitory potency of disulfiram against the proteasome conforms to current anticancer strategies and represents a new, promising approach to proteasome inhibition.
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PMID:The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor? 1857 31

The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.
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PMID:An EORTC phase I study of Bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer. 1880 14

Metastasis is a lethal attribute of a cancer and presents a continuing therapeutic challenge. Metastasis is a highly complex process and more knowledge about the mechanisms behind metastasis is highly desirable. Isogenic CMT cell lines were selected from a spontaneous mouse lung adenocarcinoma and characterized in vivo to have different metastatic potential. In this study, the comprehensive protein expression profiles of three of these CMT cell lines at passage 5, 15 and 35 were analyzed by 2-DE separation followed by MS identification. As a result, 82 and 40 unique proteins were found to be significantly up- or down-regulated between cell lines with different metastatic potential at passages 5 and 15, respectively. These proteins were identified by MS and most of them have previously been reported to be related to cancer development and/or metastasis. Bioinformatics analysis indicated that several of the proteins were involved in proteasome, cell-cycle and cell-communication pathways. Among them, some keratins, 14-3-3 proteins and 26S proteasome proteins were identified and their aberrant expression may be directly or indirectly involved in cancer development and metastasis. In conclusion, our comprehensive 2-DE-based proteomics studies revealed some candidate proteins, protein families and signaling pathways, which might be important in cancer development and metastasis.
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PMID:Comparative proteome analysis of three mouse lung adenocarcinoma CMT cell lines with different metastatic potential by two-dimensional gel electrophoresis and mass spectrometry. 1900 61


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