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

---

Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the HER2/neu oncogene is associated with tumorigenicity and drug resistance in many types of cancer. Three different human Ewing's sarcoma cell lines (TC71, RD, and A4573) were found to express high levels of the HER2/neu protein. Transduction of TC71 cells with the E1A gene using an adenoviral vector (Ad-E1A) down-regulated HER2/neu overexpression in those cells and increased cytostasis. E1A-induced apoptosis was demonstrated by both flow cytometric analysis and Western blot analysis using a poly(ADP-ribose) polymerase antibody. After transduction of the E1A gene into these cells, the sensitivity of these cells to VP-16 (etoposide) was enhanced 18-fold and to Adriamycin 5-fold. However, no change was seen in cisplatin sensitivity. E1A also significantly increased topoisomerase IIalpha protein expression, indicating that the up-regulation of topoisomerase IIalpha may be one of the mechanisms by which E1A enhanced the sensitivity to topoisomerase II-targeting anticancer drugs, such as VP-16 and Adriamycin, but not cisplatin. In summary, these studies demonstrated that Ad-E1A can down-regulate HER2/neu overexpression and up-regulate topoisomerase IIalpha expression in human Ewing's sarcoma cells, increasing their apoptosis rate and enhancing their sensitivity to VP-16 and ADRIAMYCIN:
...
PMID:E1A sensitizes HER2/neu-overexpressing Ewing's sarcoma cells to topoisomerase II-targeting anticancer drugs. 1130 98

Hybridization with cDNA arrays was used to obtain expression profiles of 214 protein-tyrosine kinase, protein-tyrosine phosphatase, dual-specific phosphatase, and other genes for kidney carcinomas (KC) and normal kidney tissues of 34 patients and for seven carcinoma cell lines. Computer analysis revealed three clusters of genes coexpressed in KC. A proliferating-cell gene cluster included MET, VIM, MYC, TOP2A, PCNA, etc. A neoangiogenesis and blood-cell gene cluster included LCK, HCK, FGR, MMP9, CSFR1, VEGF, FLT1, and KDR. A cluster corresponding to normal, differentiated kidney cells included ERBB2 (HER2) for receptor protein-tyrosine kinase, several phosphatase genes (PTPRE, PTPRB, DUSP9), and EGF. The results suggested that MET, DUSP9, PCNA, TOP2A, and VIM may serve as diagnostic and prognostic markers in KC. Tubulin and topoisomerase II were assumed to be promising targets for cell proliferation inhibitors in KC.
...
PMID:[Molecular portrait of human kidney carcinomas: the gene expression profiling of protein-tyrosine kinases and tyrosine phosphatases which controlled regulatory signals in the cells]. 1206 34

Fewer than 20% of patients with pancreatic cancer present with disease macroscopically confined to the pancreas, and approximately 40% already have locally advanced disease. Based on data from the Gastrointestinal Tumor Study Group, adjuvant therapy with radiation and 5-fluorouracil has become standard practice in the United States; however, in other countries, adjuvant treatment has not been as widely accepted. Other issues include the potential of neoadjuvant therapy and optimal systemic management. The issue of second-line therapy has also been raised in the treatment of pancreatic carcinoma, after the establishment of gemcitabine as a first-line standard treatment approach, in which it achieves a significant clinical benefit response. Other combination partners with gemcitabine under investigation include the antimetabolite 5-fluorouracil, the topoisomerase-I inhibitor irinotecan, the taxane docetaxel, the platinum oxaliplatin, the multitargeted antifolate pemetrexed, the farnesyl transferase inhibitor R-115777, the anti-HER2/neu antibody trastuzumab, and the epidermal growth factor inhibitor cetuximab. Combined-modality approaches with gemcitabine and radiation are also under active investigation.
...
PMID:Future directions in the treatment of pancreatic cancer. 1257 31

A significant proportion of breast cancers with HER2 amplification have simultaneous amplification of topoisomerase II-alpha (topoII). Amplification of HER2 and topoII was assayed using a novel chromogenic in situ hybridisation (CISH) method. HER2 and topoII amplification status and the response to preoperative doxorubicin chemotherapy were analysed in 67 locally advanced breast cancer patients. Response to chemotherapy was increased in the cases with coamplification of HER2 and topoII (18/19), whereas the response rate was significantly decreased in the cases without HER2 and topoII amplification (17/36). The 12 cases with HER2 amplification alone showed an intermediate response rate (9/12). The findings of the current study indicate that topoII amplification may play a role in determining chemosensitivity of breast cancers to doxorubicin chemotherapy.
...
PMID:Topoisomerase II-alpha (topoII) and HER2 amplification in breast cancers and response to preoperative doxorubicin chemotherapy. 1262 42

The role of HER2 in predicting response to doxorubicin (DXR) therapy in breast cancer was evaluated in vivo in a series of breast carcinomas from 220 patients with tumors larger than 2.5 cm and treated with 3 cycles of DXR (75 mg/m(2)) as neoadjuvant chemotherapy. Patients with HER2-positive tumors were more frequently responsive to DXR treatment compared with HER2-negative patients (p = 0.05; Mantel-Haenszel Chi(2) = 0.009). Progesterone receptor (PgR) negativity, but not mutated p53, was also associated with response to DXR (p = 0.05; Mantel-Haenszel Chi(2) = 0.004). Further analysis of those correlations using breast carcinoma cell lines characterized for different biologic parameters revealed a trend between HER2 positivity/PgR negativity and greater DXR sensitivity, but the strongest direct correlation was found between the proliferation rate and sensitivity to DXR (r = 0.82, p = 0.00009). Neither p53 nor the DXR target molecule topoisomerase-II-alpha was significantly associated with in vitro sensitivity to DXR. Thus, whereas data showed that the major biologic parameter associated with in vitro response to DXR in breast cancer cells appears to be the tumor proliferation rate, HER2 expression together with PgR negativity may serve as the counterpart of the proliferation marker in predicting the in vivo response to DXR.
...
PMID:Role of proliferation in HER2 status predicted response to doxorubicin. 1271 52

MLL rearrangements in acute myeloid leukemia (AML) include translocations and intragenic abnormalities such as internal duplication and breakage induced by topoisomerase II inhibitors. In adult AML, FLT3 internal tandem duplications (ITDs) are more common in cases with MLL intragenic abnormalities (33%) than those with MLL translocation (8%). Mutation/deletion involving FLT3 D835 are found in more than 20% of cases with MLL intragenic abnormalities compared with 10% of AML with MLL translocation and 5% of adult AML with normal MLL status. Real-time quantification of FLT3 in 141 cases of AML showed that all cases with FLT3 D835 express high level transcripts, whereas FLT3-ITD AML can be divided into cases with high-level FLT3 expression, which belong essentially to the monocytic lineage, and those with relatively low-level expression, which predominantly demonstrate PML-RARA and DEK-CAN. FLT3 abnormalities in CBF leukemias with AML1-ETO or CBFbeta-MYH11 were virtually restricted to cases with variant CBFbeta-MYH11 fusion transcripts and/or atypical morphology. These data suggest that the FLT3 and MLL loci demonstrate similar susceptibility to agents that modify chromatin configuration, including topoisomerase II inhibitors and abnormalities involving PML and DEK, with consequent errors in DNA repair. Variant CBFbeta-MYH11 fusions and bcr3 PML-RARA may also be initiated by similar mechanisms.
...
PMID:FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress. 1279 58

We have shown previously that the Epstein-Barr virus nuclear antigen-1 (EBNA1) can act as a transforming suppressor in the HER2/neu-overexpressing ovarian cancer cells. In the present study, by using flow cytometric analysis, we demonstrate that EBNA1 could prolong G(2)/M phase and sensitize to Taxol-induced apoptosis in the EBNA1-expressing ovarian cancer cell stable transfectants. In addition, EBNA1 could also significantly increase topoisomerase IIalpha protein expression, indicating that the up-regulation of topoisomerase IIalpha may be one of the mechanisms by which EBNA1 enhances the sensitivity of ovarian cancer cells to topoisomerase II-targeting anticancer drugs, such as VP-16 and Adriamycin. These data suggest that EBNA1 not only prolongs cell cycle at G(2)/M phase and up-regulates topoisomerase IIalpha expression in HER2/neu-overexpressing ovarian cancer cells, but also increases cellular apoptosis through sensitization of cancer cells to topoisomerase II-directing anticancer drugs.
...
PMID:EBNA1 may prolong G(2)/M phase and sensitize HER2/neu-overexpressing ovarian cancer cells to both topoisomerase II-targeting and paclitaxel drugs. 1289 73

This article attempts to provide the reader with a complete overview of topoisomerase (topo) II alpha as a marker for predicting the efficacy of anthracyclines in patients with breast cancer. In the first section of this article, in vitro data supporting the predictive value of topo II alpha are reviewed. Interestingly, these data suggest that the interaction between HER2 and anthracycline efficacy, which has been hypothesized in several clinical studies performed in the past decade, might depend on the concomitant topo II alpha status. Molecular pathology studies further reinforce the concept that HER2 might not be directly involved in the prediction of response to anthracyclines. They report that topo II alpha gene amplification can be found in 25%-40% of HER2/neu-amplified tumors, while no topo II gene amplification is detected in the absence of HER2/neu gene amplification. In the second part of this article, a series of clinical studies are reviewed and interpreted. These studies have attempted to correlate topo II alpha status with anthracycline efficacy in the adjuvant, neoadjuvant, and metastatic settings. All of the studies evaluating the topo II alpha gene suggest that gene amplification might be associated with an increased efficacy of anthracyclines, and some of the studies evaluating topo II alpha protein find that protein overexpression might correlate with an increased sensitivity to these compounds. Despite these findings, however, the reported studies do not provide the proof of principle needed to authorize the use of topo II alpha as a predictive marker for standard practice. A new generation of research is currently testing the predictive value of topo II alpha. It is hoped that these projects, which are described in the last section of the article, will clarify the role of topo IIa in the prediction of response to anthracyclines.
...
PMID:Topoisomerase II alpha as a marker predicting the efficacy of anthracyclines in breast cancer: are we at the end of the beginning? 1449 10

We have previously reported that XK469 inhibited topoisomerase (topo) IIbeta, in Waldenstrom's macroglobulinemia cell line (WSU-WM) however the inhibition alone is not sufficient to induce apoptosis. In this study, the apoptotic potential of XK469 and its mechanism in WSU-WM cell line was investigated. Exposure of WSU-WM cells to XK469 caused a decrease in viable cell number in a dose-dependent manner. In addition, XK469 caused the activation of caspase 3 resulting in subsequent cleavage of PARP. These events were preceded by the release of cytochrome c from the mitochondria to the cytosol. Simultaneous exposure of cells to cyclosporin A prevented the release of cytochrome c to cytosol and reduced the loss of viability. XK469 caused the activation of p53 with up-regulation of p53-dependent proteins such as Bax, p21, Gadd 45 and cyclin B1 in association with G2M arrest. The addition of ubiquitin carboxyl terminal hydrolase (UCH-L1) inhibitor (NaBH4) inhibited up-regulation of p53 and p53 related molecules by XK469 and reduced the loss of viability. Pre-incubation with NOK-1, a monoclonal antibody that prevents Fas-Fas ligand interaction and is inhibitory to Fas signaling interfered with XK469 induced activation of caspase 8 and also reduced the loss of viability. Simultaneous exposure of all three inhibitors (cyclosporin A, NaBH4 and NOK-1) abrogated the toxicity of XK469 by 95%. These data define multiple sequences of biochemical events that mediate cell death induced by XK469. Our study suggests a complex mechanistic cascade of XK469-mediated apoptosis that involves Fas signaling pathway, ubiquitination, p53 activation and cytochrome c release.
...
PMID:XK469, a topo IIbeta inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways. 1461 35

ERBB2 is one of the most important oncogenes in breast cancer, and its disordered expression is commonly associated with gene amplification. Amplification of at least one gene near ERBB2, topoisomerase IIalpha (TOP2A), has been shown to be clinically significant, but the prevailing patterns of gene amplification in this region of chromosome arm 17q have not been studied systematically in clinical cases of breast cancer. For characterizing this region, a commercial ERBB2-containing contig probe and 7 probes prepared from single overlapping BAC and P1 clones lying telomeric to ERBB2 and including TOP2A were hybridized to 77 ERBB2-amplified archival breast tumor specimens from 75 patients. The 7 single-clone probes covered a region of approximately 650 kb starting 114 kb telomeric to ERBB2. Amplification of the ERBB2 contig target alone was found in 32% of the tumors, whereas all 8 probe targets were amplified in 12% of the tumors, based on an amplification criterion of there being more than or equal to 2 targets per chromosome 17 centromere. When one of the 7 overlapping probes encompassing TOP2A indicated amplification within a specimen, all probes telomeric to that probe usually showed amplification. Only 5 specimens had regions of normal or deleted targets separating 2 amplified targets. Also, tumors that showed deletion of TOP2A usually showed deletion of one or more contiguous targets. The observed patterns of amplification and deletion are consistent with the break-fusion-bridge model for gene amplification. TOP2A was amplified in 25% of all tumor specimens and was deleted in 24%, based on a deletion criterion of there being fewer than or equal to 0.75 targets per chromosome 17 centromere. Considering the relevance of the TOP2A gene product to anthracycline therapy and the wealth of other cancer-associated genes within the ERBB2/TOP2A region, the pattern of amplification and deletion near ERBB2 and TOP2A may have a dramatic effect on the malignant potential of breast carcinomas and their response to therapy.
...
PMID:Gene copy mapping of the ERBB2/TOP2A region in breast cancer. 1503 64


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---