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)

The main aim of this study was to compare the prognostic impact of different histologic grading systems, the expression of the cell cycle-associated antigen DNA-topoisomerase-II-alpha (Ki-S1) and the expression of cell cycle regulators in malignant fibrous histiocytomas (MFH) using multivariate analyses. Paraffin-embedded tissue of 161 cases of MFH were studied immunohistochemically for the expression of the proliferation marker Ki-S1, cell cycle regulators (p53, MDM2, waf-1, pRb, p16) and the oncoprotein EGFR. The percentage of immunolabelled tumor cells (index) was assessed. The histologic grade was determined by the two-level grading systems of Costa, Tsujimoto and Pezzi, by the three-level grading systems of Coindre and Van Unnik and by the grading system presented here. Univariate analyses using the LOG rank test showed that all of the applied grading systems produce highly significant differences in survival between the grades of malignancy. Multivariate analyses with COX regression demonstrated that only the grading system presented here, based on the parameters necroses, mitoses and cellularity, had independent prognostic relevance. Moreover, the inclusion of the proposed grading system, the Ki-S1-index and a prognostic index primarily based on the expression of cell cycle regulators into the COX regression was suited for predicting survival in MFH. The grading system presented shows considerable advantages over the grading systems compared in this study for use in the routine pathology of MFH. The prognostic power of the proposed grading system can be enhanced by the combined study of cell cycle regulators and Ki-S1.
...
PMID:Prognostic relevance of histologic grading, the cell cycle-associated antigen Ki-S1 and cell cycle regulators in malignant fibrous histiocytomas: a multivariate analysis. 1009 40

Stable transfected human p53 (mt/mt) B lymphoma Namalwa variant lines showing differential expression of the Bax-alpha protein were derived under hygromycin selection. Overexpression of Bax-alpha in these variant cells accelerates cell death induced by short or continuous treatments with various concentrations of camptothecin, etoposide, vinblastine and shows no accelerating cell death activity in cis-platinum and paclitaxel-treated cells. Activation of apoptosis and oligonucleosome-sized DNA fragmentation was observed in the variant lines with more pronounced effect in cells containing high level of Bax-alpha protein. These results suggest that increased cell death mediated by anticancer drugs correlates with Bax-alpha level of expression and that Bax-alpha sensitizes Namalwa cells treated at low drug concentrations. The extent of DNA synthesis inhibition following DNA topoisomerase inhibitor treatments was similar in control and all transfected Namalwa cells suggesting that Bax-alpha acts downstream of DNA topoisomerase-mediated DNA strand breaks. To define further the relation between Bax-alpha expression and apoptosis activation, kinetics of caspase activation was measured in drug-treated cells. Caspase activities were measured using specific fluorogenic peptide derivatives DABCYL-YVADAPV-EDANS and Ac-DEVD-AMC, substrates of the caspase 1-like and caspase 3-like families, respectively. In control and Bax-alpha transfected Namalwa cells no increase in caspase 1-like activity was detected following camptothecin and etoposide treatments. In contrast, a significant difference in Ac-DEVD-AMC hydrolysis activity was observed in Bax-alpha transfected Namalwa cells compared to that of control Namalwa cells after camptothecin and etoposide treatment. Increased caspase 3-like activity correlated also with poly(ADPribosyl) polymerase cleavage. Taken together, these results suggest that Bax-alpha sensitize B lymphoma cells to series of anticancer drugs and accelerates the activation of apoptotic protease cascade.
...
PMID:Bax-alpha promotes apoptosis induced by cancer chemotherapy and accelerates the activation of caspase 3-like cysteine proteases in p53 double mutant B lymphoma Namalwa cells. 1020 May 2

Glutathione peroxidase (GPX) is a primary antioxidant enzyme that scavenges hydrogen peroxide or organic hydroperoxides. We have recently found that GPX is induced by etoposide, a topoisomerase II inhibitor and a p53 activator. In a search for a cis-element that confers potential p53 regulation of GPX, we identified a p53 binding site in the promoter of the GPX gene. This site bound to purified p53 as well as p53 in nuclear extract activated by etoposide. A luciferase reporter driven by a 262-base pair GPX promoter fragment was transcriptionally activated by wild type p53 in a p53 binding site-dependent manner. The same reporter was also activated in a p53 binding site-independent manner by several p53 mutants. The p53 binding and transactivation of the GPX promoter were enhanced by etoposide in p53-positive U2-OS cells. Etoposide-induced transactivation was blocked by a dominant negative p53 mutant, indicating that endogenous wild type p53, upon activation by etoposide, transactivated the GPX promoter. Furthermore, expression of endogenous GPX was induced significantly at both mRNA and enzyme activity levels by etoposide in U2-OS cells but not in p53-negative Saos-2 cells. This is the first report demonstrating that GPX is a novel p53 target gene. The finding links the p53 tumor suppressor to an antioxidant enzyme and will facilitate study of the p53 signaling pathway and antioxidant enzyme regulation.
...
PMID:Transcriptional activation of the human glutathione peroxidase promoter by p53. 1020 30

Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kappaB. It is activated by various stress situations, including oxidative stress, and by DNA-damaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kappaB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kappaB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NF-kappaB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.
...
PMID:The ATM protein is required for sustained activation of NF-kappaB following DNA damage. 1032 72

Malignant melanoma is considered to be a chemotherapy-refractory tumour and the commonly used anticancer drugs do not seem to modify the prognosis of metastatic disease. The cellular resistance mechanisms involved in melanoma chemoresistance have not yet been elucidated. Melanoma-derived cell lines are often markedly chemoresistant. Using the in vitro soft agar culture system to predict tumour cell sensitivity in well-established human melanoma cell lines, a high degree of resistance against all the cytostatic agents studied has been reported, suggesting the presence of intrinsic cellular resistance mechanisms. The relevance of the well-defined resistance mechanisms mediated by P-glycoprotein, multidrug resistance-associated protein (MRP), the glutathione/glutathione S-transferase system and topoisomerase II enzyme are reviewed. Mutated N-Ras oncogene has recently been implicated in melanoma resistance to cisplatin, both in vitro and in vivo, and the role of two other oncogenes, Bcl-2 and p53, which are already involved in the chemoresistance of haematological and solid malignancies, is beginning to be better elucidated. The finding that many chemotherapeutic agents can kill susceptible cells through the apoptosis pathway provides new molecular insight into chemoresistance mechanisms and suggests that apoptosis and/or resistance to apoptosis of melanoma cells should be investigated to better clarify the mechanism of melanoma chemoresistance.
...
PMID:The chemoresistance of human malignant melanoma: an update. 1033 34

We examined the effect of overexpression of p21(waf1) on cytotoxicity of paclitaxel, a microtubule stabilizer, using a tetracycline-inducible expression system in human sarcoma cells (SaOs-2) that lack both functional retinoblastoma protein and p53. Under normal growth conditions, p21(waf1) is not detectable in SaOs-2 cells. Upon p21(waf1) induction by tetracycline withdrawal, we observed a reduced apoptotic response to paclitaxel with a 3- to 6-fold increase in IC50 values compared with that of cells not induced by p21(waf1). We also observed a 5-fold increase in the IC50 value when cytotoxicity to vincristine, another microtubule-disrupting agent, was assessed, whereas we observed a marked decrease in the IC50 value after p21(waf1) induction in response to etoposide, a topoisomerase II inhibitor. After treatment with paclitaxel, less accumulation of G2-M was observed in p21(waf1)-induced cells compared with non-p21(waf1)-induced cells (57% versus 74%). p21(waf1) induction also inhibited the increased cyclin B1-associated kinase activity induced by paclitaxel. Overexpression of p21(waf1) in SaOs-2 cells lacking both p53 and functional retinoblastoma protein may decrease the G2-M arrest induced by paclitaxel due to suppression of the S-G2 checkpoint, resulting in a decreased apoptotic response of cells to paclitaxel.
...
PMID:Overexpression of p21(waf1) decreases G2-M arrest and apoptosis induced by paclitaxel in human sarcoma cells lacking both p53 and functional Rb protein. 1034 52

Cyclin-dependent kinase inhibitors are potent suppressors of cell growth and have been proposed as targets for gene replacement therapy in cancer. Expression of either p16INK4a or p21WAF1 protected cells from the cytotoxic effects of the topoisomerase II inhibitor, etoposide. A lower level of p53 was induced in CDK inhibitor-expressing etoposide-exposed cells suggesting that protection may be due to lower levels of DNA damage in the growth arrested cells. Exposure of human osteosarcoma cells to either p16INK4a or p21WAF1 prior to and during etoposide therapy protected cells against etoposide-induced cell death. Infection of the cells by Ad-p16INK4a or Ad-p21WAF1 following exposure to etoposide resulted in loss of the protective effect with evidence of enhanced growth inhibition. The results suggest that the schedule of administration of DNA damaging etoposide chemotherapy and cell cycle inhibitory therapy is a major determinant of the resulting cytotoxicity.
...
PMID:The administration schedule of cyclin-dependent kinase inhibitor gene therapy and etoposide chemotherapy is a major determinant of cytotoxicity. 1040 29

The tumor suppressor gene product p53 can bind to and inhibit the helicase activity of the multisubunit transcription-repair factor TFIIH. We previously reported that p53-mediated apoptosis is attenuated in primary human fibroblasts from individuals with Xeroderma Pigmentosum (XP) that harbor mutations in the TFIIH DNA helicases XPD or XPB. In this study we show that apoptosis is reduced and delayed in three XPD lymphoblastoid cell lines (LCLs), but not in an XPD heterozygote LCL, after exposure to doxorubicin, a DNA-damaging agent and topoisomerase II inhibitor frequently used in cancer therapy. Apoptosis was assessed by quantitation of Annexin V binding to exposed phosphatidylserine residues and by caspase-mediated cleavage of Poly(ADP)Ribose Polymerase (PARP). Apoptosis induced by doxorubicin was suppressed in LCLs retrovirally transduced with the Human Papillomavirus 16 E6 oncoprotein, consistent with the hypothesis that this is a p53-dependent process. PARP cleavage was not delayed in XPD LCLs in response to anti-Fas (CD95) antibody-mediated apoptosis, thus, the defect in the apoptotic pathway in these cells lies upstream of caspase activation. Similar changes in the expression of apoptosis-effector genes, p53, and p53-responsive genes p21Cip1/WAF-1/Sid1 (p21), gadd45, bcl-2 and bax were observed in normal and XPD LCLs after treatment with doxorubicin, indicating that delayed apoptosis was not a consequence of defective transcription of these genes. Thus, our studies provide further support to the hypothesis that XPD and p53 can functionally interact in a p53-mediated apoptotic pathway.
...
PMID:Drug-induced apoptosis is delayed and reduced in XPD lymphoblastoid cell lines: possible role of TFIIH in p53-mediated apoptotic cell death. 1046 15

To evaluate the prognostic relevance of Ki-67 and topoisomerase IIalpha expression in relation to tumor stage, grade, and hormone receptor content, 942 ductal infiltrating carcinomas of the breast were examined by means of the monoclonal antibodies Ki-S11 (Ki-67) and Ki-S4 (topoisomerase IIalpha). pS2, c-erbB2, and p53 were additionally considered as prognostic variables. The median follow-up time was 149 months. Eight-hundred-and-sixty-three tumors reacted with Ki-S11 and Ki-S4; the labeling indices of the two antigens were closely associated (r = 0.93). Both correlated positively with the tumor size, c-erbB2, and p53 expression, and negatively with patient age, hormone receptor content, and pS2 immunostaining. In the univariate analysis, Ki-S11 and Ki-S4 scores, nodal status, tumor size, tumor grade, and progesterone receptor content strongly predicted both overall and metastasis-free survival (p < 0.00001). Estrogen receptor status, p53, and c-erbB2 were of minor significance. Concerning overall survival, multivariate Cox regression analysis selected a Ki-S4 score >25% (p < 0.00001) next to the nodal status, and before tumor size, progesterone receptor content, and patient age. Independent predictors of the occurrence of distant metastases were nodal status, Ki-S4, tumor size, grade 1, and progesterone receptor negativity, in that order. The Ki-S11 score was of independent prognostic significance only if examined as a continuous variable. We conclude that topoisomerase IIalpha expression as assessed by monoclonal antibody Ki-S4 may add valuable information to current prognostic models for breast cancer. Its predictive value appears to be essentially related to the proliferative activity of tumor cells.
...
PMID:Prognostic significance of Ki-67 and topoisomerase IIalpha expression in infiltrating ductal carcinoma of the breast. A multivariate analysis of 863 cases. 1047 80

Drug resistance is a major problem in patients with small cell lung cancer; in fact, most die of resistant disease, despite an initial response. Several markers of drug resistance have been described in preclinical models, but the mechanism of drug resistance in lung cancer patients remains unknown. The objective of this study was to evaluate the role of the expression of a number of markers of drug resistance, proliferation, and apoptosis in relation to response to chemotherapy and survival in patients with small cell lung cancer. Tumor samples were derived from 93 previously untreated patients who were randomized in a Phase III study to receive cyclophosphamide, epirubicine, and etoposide or cyclophosphamide, epirubicine and vincristine alternating with carboplatin and etoposide. Paraffin-embedded samples, derived from the primary tumor site prior to chemotherapy, were analyzed by immunohistochemistry for expression of markers implicated in drug resistance [topoisomerase (topo) IIalpha, topo IIbeta, and multidrug resistance-associated protein], apoptosis (p53, p21, and bcl-2), or proliferation (Ki67). Response prediction was analyzed by chi2 test and logistic regression analysis; overall and disease-free survival curves were compared by log-rank test and Cox regression analysis. Shorter survival was observed in patients with extensive disease (P = 0.037) and poorer performance status (P = 0.028) and in patients whose tumors expressed high topo IIalpha levels (P = 0.01) and high Ki67 (P = 0.024). By multivariate analysis, the following factors were found to be predictive for worse survival: high expression levels of topo IIalpha, Ki67, and bcl-2; male sex; and extensive disease. High topo IIbeta expression was found to be predictive for lower overall and complete response rate. No relationship between apoptotic pathway markers or MRP and response to chemotherapy was observed. In conclusion, high expression of topo IIalpha was predictive of worse survival, and high expression of topo IIbeta was predictive of lower response rates. Furthermore, lower survival probability was observed in patients with bcl-2-positive tumors. Immunohistochemical assessment of these markers in diagnostic biopsies may give important prognostic information and may help selecting patients in the worse prognostic categories for new therapeutic strategies.
...
PMID:Expression of DNA topoisomerase IIalpha and topoisomerase IIbeta genes predicts survival and response to chemotherapy in patients with small cell lung cancer. 1047 85


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

---