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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ecteinascidin-743 (ET-743), an anti-tumor agent derived from the marine tunicate, Ecteinascidia turbinata, is active against various solid tumor cell lines, including soft tissue sarcoma, breast, ovarian, non-small-cell lung and prostate cancers and melanoma, and has a broad spectrum of anti-cancer activity in vivo. For reasons as yet unclear, sarcoma cell lines are exquisitely sensitive to ET-743. The drug has a unique mechanism of action that makes it a novel anti-tumor agent. ET-743 is a DNA-binding agent that covalently interacts with the minor groove of the DNA double helix to bend the molecule towards the major groove. Defects in DNA repair pathways have paradoxical effects on the anti-tumor activity of ET-743: loss of mismatch repair does not affect its toxicity; loss of DNA-dependent protein kinase activity enhances its toxicity; defects in transcription-coupled nucleotide excision repair confer resistance to ET-743. As a DNA repair capability appears to be necessary for at least one mechanism of ET-743-mediated cytotoxicity, the drug may interact with the DNA repair machinery to induce lethal strand breaks. One of the most novel aspects of ET-743 is its effect on RNA polymerase II-mediated gene transcription. ET-743 selectively inhibits activation of the multidrug resistance gene, while leaving constitutive gene expression relatively unaffected. Preliminary studies of other genes and transcriptional inducers indicate that ET-743 may be a more general inhibitor of activated, but not basal, transcription.
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PMID:ET-743: more than an innovative mechanism of action. 1217 91

Expression of genes such as cytokeratin 19 (CK19), cytokeratin 20 (CK20) and epidermal growth factor receptor (EGFR) has been investigated at mRNA level in peripheral blood of carcinoma patients to detect the presence of circulating tumor cells (CTC). We performed this study because recent literature emphasizes that the importance of CK19, 20 and EGFR mRNAs in CTC as prognostic factors remains unclear especially for breast, head and neck and colon cancer patients. Reverse transcriptase polymerase chain reaction (RT-PCR) followed by Southern blot hybridization was performed in blood samples from 47 subjects (12 colorectal, 15 head and neck and 20 breast carcinoma patients), as well as in 35 healthy donors. The CK19 expression was found in 36/47 patients (9 colorectal, 9 head and neck and 18 breast cancer), two patients (one affected by colorectal and one by head and neck cancer) were positive for CK20 whereas EGFR was found expressed in 9 patients (3 colorectal, 5 head and neck and one breast cancer). Seven of 35 and 4/35 healthy donors displayed positivity for the expression of CK19 and CK20 genes respectively, whereas no EGFR mRNA was found in this group. The correlation of the detection of CTC in peripheral blood with progression of the disease in a follow-up period of 40 months did not show any prognostic value to the presence of mRNAs of these biomarkers in blood. We believe that research should be addressed, at least for breast cancer, to the identification of occult metastases in sentinel lymph nodes, such as recently performed in melanoma patients.
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PMID:Detection of CK19, CK20 and EGFR mRNAs in peripheral blood of carcinoma patients: correlation with clinical stage of disease. 1246 72

Autotaxin (ATX), originally isolated from human melanoma cells, is a novel metastasis-enhancing motogen and angiogenesis factor. In the present study, we compared the expression level of ATX mRNA between normal and breast cancer tissues and found that the expression of ATX mRNA was closely linked to invasiveness of cancer cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical analysis showed higher cellular ATX mRNA expression in the cancer than normal breast tissues. MDA-MB-435S breast cancer cells, expressing higher amount of ATX mRNA, showed greater relative invasiveness to fibroblast-conditioned medium (FCM) than MCF7, MDA-MB-231, and HBL-100 breast cancer cells. Furthermore, ATX-transfected MCF7 cells showed increased motility and invasiveness than vector-transfected MCF7 cells. Collectively, our results suggest that the expression of ATX is closely linked to the invasiveness of breast cancer cells.
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PMID:Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells. 1249 89

Cutaneous melanomas have been found to express several immunogenic differentiation melanoma-associated antigens (MAAs) that have been suggested to play an important role in disease outcome. Adaptive host immunity to MAAs has shown some level of control on melanoma progression. To date, there has been no definitive report correlating the level of differentiated MAAs gene expression in melanomas with overall disease outcome. Metastasis of melanoma to distant visceral organ sites usually indicates a survival of less than 1 year; however, a subset of patients who undergo cytoreductive surgery of distant metastases survive for a longer period. We hypothesized that the gene expression level of differentiation MAAs in metastatic melanoma (AJCC stage IV) lesions would be predictive of survival. We focused on three known differentiation MAAs: tyrosinase (TYR), TYR-related protein 2 (TRP-2), and melanoma antigen recognized by T cells 1 (MART-1); all three of them are known to induce immune responses in melanoma patients and are frequently expressed in melanomas. A quantitative reverse-transcriptase RealTime PCR (qRT) assay was developed for these MAAs to assess mRNA expression in metastatic melanoma tumors obtained from cytoreductive surgery of AJCC stage IV melanoma patients (n = 35). Patients were followed up for over 60 months. There was a variation in mRNA copy levels for individual MAAs in melanoma tumors. Elevated MAA mRNA copy levels of TYR and TRP-2 significantly (P < 0.03 and < 0.009, respectively) correlated with improved overall survival. Patients having at least one MAA expressed in their tumors had a significantly (P = 0.01) better overall survival (median 16 months). These studies demonstrate that levels of differentiated MAA mRNA expression of advanced-stage metastatic melanomas can be used as molecular predictive factors of disease outcome. The studies also imply that an assessment of melanoma tumor MAAs may provide a stratification factor targeted for active-specific immunotherapy.
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PMID:Expression of differentiation melanoma-associated antigen genes is associated with favorable disease outcome in advanced-stage melanomas. 1254

Malignant melanoma is one of the most rapidly increasing cancer types, and patients with metastatic disease have a very poor prognosis. Detection of metastatic melanoma cells in circulation may aid the clinician in assessing tumor progression, metastatic potential, and response to therapy. Tyrosinase is a key enzyme in melanin biosynthesis. The gene is actively expressed in melanocytes and melanoma cells. Melan A is a differentiation antigen that is expressed in melanocytes. The presence of these molecules in blood is considered a marker for circulating melanoma cells. In this study, we analyzed the usefulness of this marker combination in evaluating the response to therapy in the blood of 30 patients with malignant melanoma. Circulating cells were detected by a reverse-transcriptase-polymerase-chain reaction. The tyrosinase expression was observed in 9 (30%) patients and Melan A in 19 (63.3%) patients before therapy. Following treatment, the tyrosinase mRNA was detected in only one patient, while Melan A transcripts were still present in 14 patients. We suggest that this molecular assay can identify circulating melanoma cells that express melanoma-associated antigens and may provide an early indication of therapy effectiveness.
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PMID:Detection of circulating melanoma cells by a two-marker polymerase chain reaction assay in relation to therapy. 1268 15

Vascular endothelial growth factor-A (VEGF-A) is an important mediator of angiogenesis in normal and neoplastic tissues. Total VEGF-A levels have been associated with melanoma progression, but the relative contributions of each isoform is unknown. To determine whether differences in the production of any or all of the major VEGF-A isoforms are related to stage of progression, we compared message levels for the three major isoforms of VEGF in melanoma specimens from different stages of progression.Primary melanomas (N = 18), primary recurrences (N = 5), regional dermal metastases (N = 11), nodal metastases (N = 12), normal lymph nodes (N = 18), and distant metastases (N = 9) were prospectively collected. Samples from the horizontal and vertical growth phases of primary tumors were also collected from five additional patients. Message levels for the three major VEGF-A isoforms were measured using real-time quantitative reverse-transcriptase polymerase chain reaction and normalized to beta-actin mRNA levels. There was a marked increase in the expression of all three VEGF-A isoforms from the vertical growth phase tissue as compared with the horizontal growth phase tissue. Primary tumors, local recurrences, regional dermal metastases, nodal metastases, and distant metastases all produced more VEGF(121) and VEGF(165) than negative nodes. Nodal metastases produced the highest level of these two isoforms, higher even than distant metastases. There was no significant difference in VEGF(189) message among the groups. Melanomas in the vertical growth phase produce more VEGF-A (all isoforms) than in the horizontal growth phase. Nodal metastases produce the highest levels of VEGF(121) and VEGF(165), but not VEGF(189) as compared with other stages of progression. These data suggest that the soluble forms of VEGF-A might be an important factor in melanoma metastasis to regional lymph nodes.
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PMID:Differential expression of vascular endothelial growth factor-A isoforms at different stages of melanoma progression. 1294 96

The migratory responses of four human melanoma cell lines (A-2058, DEMEL, HTB-63, and HTB-72), using chemotaxis (CTX) and haptotaxis (HPTX) assays, were studied. The attractants were three extracellular matrix components (EMCs), fibronectin, laminin, and collagen type IV. The conditioned media (CM) of each cell line were used to study autocrine and paracrine responses. A screening and sensitive CTX assay was performed, using pertussis toxin (PTX)- treated A-2058 as responder cells; the other melanoma cells and normal cells were used as secretory cells. Autotaxin (ATX), a purified autocrine motility factor, was also used as a chemoattractant. Reverse transcriptase-polymerase chain reaction was used to detect the expression of ATX by all cell lines. The secretion of ATX was determined by Western blot. The invasive capacity of the cell lines was evaluated using Matrigel and ATX as attractant. Chemotaxis responses to EMCs varied. Except for the A-2058 cells, HPTX migration was low. Autocrine and paracrine responses also varied. The migration of PTX-treated A-2058 cells to ATX and to their own CM was abolished. All the melanoma cells expressed ATX, and except for the HTB-72 and normal cells, all secreted ATX. Matrigel was invaded by all the melanoma cell lines except the HTB-72 and normal cells. The migratory properties of human melanoma cells in vitro suggest that they could correlate to their metastatic potential in vivo.
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PMID:Characterization of human melanoma cell lines according to their migratory properties in vitro. 1469 28

The success and further evolution of the sentinel lymph node (SLN) concept decisively depend on histological techniques. Fundamental standards were agreed on by a panel of international experts from various disciplines in 1999 and published as "The Augsburg Consensus" in 2000. Conventional histology (hematoxylin and eosin [H&E]) has to be supplemented by immunohistochemistry (eg, S100 and HMB45) using adequate series of paraffin sections. Melanoma cells in SLNs must be carefully differentiated from capsular and trabecular nevocytes, from immigrated Langerhans cells, from interdigitating dendritic leukocytes, and from nerve sheath cells, which all share S100 positivity in the cytoplasm. The micromorphometric S classification is based on the maximum distance of intranodal melanoma cells from the interior margin of the SLN capsule. It has proven its practicability under routine circumstances, as well as its predictive value regarding further nodal and distant metastases as well as overall survival. This has to be considered in prospective randomized trials dealing with the issues of completion lymphadenectomy and adjuvant therapies of melanoma patients. Reverse-transcriptase polymerase chain reaction (RT-PCR) techniques, when performed as a supplement to histology on the basis of additional paraffin sections, can further enhance the diagnostic sensitivity for detecting melanoma cells in SLNs.
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PMID:Pathology of the sentinel lymph node in melanoma. 1519 Apr 93

Expression of transporter associated with antigen processing (TAP) is often lost in metastatic carcinomas, resulting in defective antigen processing and presentation and escape of the cancer cells from immune surveillance. In this study, the nature of TAP deficiencies in tumors was investigated. By chromatin immunoprecipitation assay, we showed that the recruitment of RNA polymerase II to the TAP-1 gene was impaired in TAP-deficient cells derived from murine melanoma, prostate, and lung carcinomas, compared with TAP-expressing fibroblasts and lymphoma cells. This suggested that the deficiency in TAP-1 expression resulted, at least partially, from a relatively low level of transcription of the TAP-1 gene. Furthermore, levels of TAP-1 promoter activity, as assessed by stable transfections with a reporter construct containing the TAP-1 promoter, were relatively low in TAP-deficient cells. To examine genetic heritability of regulators of TAP-1 promoter activity, TAP- and MHC class I-deficient cells of H-2b origin were fused with wild-type fibroblasts of H-2k origin. Fusion with TAP-expressing cells complemented the low levels of TAP-1 promoter activity in TAP-deficient cells. However, these fused cells exhibited lower levels of TAP-1 mRNA and H-2k than unfused fibroblasts. Further analysis showed that TAP-1 mRNA stability was lower in fused carcinoma fibroblasts than in unfused fibroblasts. Based on these results, we propose that TAP deficiency in many carcinomas is caused by a decrease in activity/expression of trans-acting factors regulating TAP-1 promoter activity, as well as a decrease in TAP-1 mRNA stability. These results have significant implications for understanding immune evasion mechanisms in tumors.
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PMID:Identification of mechanisms underlying transporter associated with antigen processing deficiency in metastatic murine carcinomas. 1610 3

Clear cell sarcoma of soft tissue (malignant melanoma of soft parts) is a soft tissue sarcoma with melanocytic differentiation that typically occurs in the tendons and aponeuroses of young adults. As demonstrated by cytogenetics and reverse-transcriptase polymerase chain reaction, between 70% and over 90% of clear cell sarcomas have a t(12;22) translocation, fusing the EWS and ATF1 genes on chromosomes 22q12 and 12q13, respectively. Identification of this translocation distinguishes clear cell sarcoma from histologic mimics, most importantly conventional malignant melanoma. We report our experience with a commercially available, dual-color, break-apart fluorescence in situ hybridization (FISH) probe, which allows detection of EWS (22q12) gene rearrangement in formalin-fixed, paraffin-embedded tissues. Histologically and immunophenotypically well-characterized cases of clear cell sarcoma (n = 10) and malignant melanoma (n = 32) were evaluated with a 22q12 dual-color, break-apart probe (Vysis, Downer's Grove, IL, USA), which spans the known common breakpoints in the EWS gene on chromosome 22 (introns 7-10). Signals from tumor cell nuclei were counted under a fluorescence microscope and the presence of red-green break-apart signals was recorded. Of the clear cell sarcoma cases, seven of 10 showed evidence of an EWS gene rearrangement with a mean of 81.6% positive cells per sample (range: 60-95%). All cases of malignant melanoma (n = 32) showed virtually absent break-apart signals in the EWS gene (less than 4% cells per case). FISH detects EWS gene rearrangement in a substantial proportion of clear cell sarcomas, with excellent specificity. Importantly, EWS FISH is negative in malignant melanoma, a clinically dissimilar tumor, which may closely mimic clear cell sarcoma histologically and immunohistochemically. As the studied probe can be utilized in routinely processed tissue, FISH provides an excellent alternative to reverse-transcriptase polymerase chain reaction in cases where fresh tissue is unavailable.
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PMID:Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma. 1625


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