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: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.
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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

In the wake of recent progress in understanding the genetic pathways involved in the development of brain tumors, a major goal is to correlate molecular data with clinical outcome, survival, and response to treatment modalities. This is of particular importance among the pediatric population. Reliable prognostic factors could potentially permit a tailoring of therapy in that only patients with the most aggressive tumors would receive the most intense treatments. A survey of publications about prognosis-related molecular features among pediatric brain tumors revealed 74 series, of which 46 presented statistically significant outcome-associated parameters as defined by a p value <0.05. Most investigations revealing significant prognosis-related features were performed on medulloblastomas (34 publications), followed by astrocytic tumors (6 publications) and ependymomas (5 publications). Promising approaches and molecular markers include gene expression profiles, DNA ploidy, loss of heterozygosity and chromosomal aberrations as detected by CGH and FISH (1q, 17p, 17q), as well as oncogenes/ tumor suppressor genes and their proteins (TP53, PTEN, c-erbB2, N-myc, c-myc), growth factor and hormonal receptors (PDGFRA, VEGF, EGFR, HER2, HER4, ErbB-2, hTERT, TrkC), cell cycle genes (p27) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (multi-drug resistance, DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the predictive potential of molecular markers for clinical outcome and their influence on therapeutic decision-making among children with brain tumors.
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PMID:Prognosis-related molecular markers in pediatric central nervous system tumors. 1562 58

Brain tumors account for approximately 20% of all childhood cancers, and are the leading cause of cancer morbidity and mortality among children. Although numerous demographic, clinical and therapeutic parameters have been identified over the past few years that have significant prognostic bearing for some pediatric brain tumors, predicting the clinical course and outcome among children with central nervous system tumors is still difficult. A survey of publications on prognosis-related histopathological and immunohistochemical features among pediatric brain tumors revealed 172 series, of which 91 presented statistically significant outcome-associated parameters as defined by a P value of less than 0.05. Most investigations revealing significant prognosis-related markers were performed on medulloblastomas (30 publications), ependymomas (25) and astrocytic tumors (18). In total, 16 cohorts consisted of more than 100 cases (5 on ependymomas, 3 each on medulloblastomas and astrocytic tumors). On the other hand, there were also 13 series with fewer than 20 cases (5 on medulloblastomas). Potentially prognostic histopathological markers vary among different entities and consist of assessment of necroses, mitoses, differentiation, vascular proliferation, and growth pattern, whereas immunohistochemical features include proliferation markers (Ki-67, MIB-1), expression of oncogenes/tumor suppressor genes and their proteins (TP53, c-erbB2), growth factor and hormonal receptors (VEGF, EGFR, HER2, HER4, ErbB-2), cell cycle genes (p27, p14ARF) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the prognostic potential of histopathological and immunohistochemical markers that can be investigated by the practicing neuropathologist as part of the routine diagnostic workload, and scrutinizes their benefit for predicting therapy response and patient outcome among children with brain tumors.
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PMID:Prognosis-related histomorphological and immunohistochemical markers in central nervous system tumors of childhood and adolescence. 1564 46

Chemotherapy is often the only treatment possible for locally advanced or metastatic mesothelioma. This paper recalls which drugs might have therapeutic benefits in this condition and reviews recent studies of chemotherapy or targeted therapy. If the patient cannot be enrolled in a therapeutic trial the first line therapy in the absence of contraindications is a combination of cisplatin and pemetrexed, the latter having received a licence for this indication in September 2004. Among the alternatives reviewed are taxanes, liposomal anthracyclines, topoisomerase inhibitors, cisplatin derivatives, vinca alkaloids, and antimetabolites. Although the first three have show little or no benefit the vinca alkaloids (vinorelbine, vinflunine) and particularly the antimetabolites (gemcitabine, raltitrexed, pemetrexed) are very promising. Recent studies have looked most frequently at combinations of an anti-metabolite and a platinum salt, with data available from nearly 200 patients treated with gemcitabine. These studies have had fairly homogeneous results showing a one year survival of about 50%. Some preliminary data from studies of second line chemotherapy is also available. Finally studies of targeted therapies such as anti-EGFR, anti VEGF and anti PDGF are underway but have not as yet demonstrated major therapeutic benefit.
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PMID:[Mesothelioma: advances in chemotherapy]. 1634 Aug 36

EGFR mutations are a major determinant of lung tumor response to gefitinib, an EGFR-specific tyrosine kinase inhibitor. Obtaining a response from lung tumors expressing wild-type EGFR is a major obstacle. The combination of gefitinib and cytotoxic drugs is one strategy against lung cancers expressing wild-type EGFR. The DNA topoisomerase inhibitor irinotecan sulfate (CPT-11) is active against lung cancer. We examined the sensitivity of lung cancers expressing wild- or mutant-type EGFR to the combination of gefitinib and CPT-11. The in vitro effect of gefitinib and SN-38 (the active metabolite of CPT-11) was examined in seven lung cancer cell lines using the dye formation assay with a combination index. When administered concurrently, gefitinib and SN-38 had a synergistic effect in five of the seven cell lines expressing wild-type EGFR, whereas the combination was antagonistic in PC-9 cells and a PC-9 subline resistant to gefitinib and expressing deletional mutant EGFR (PC-9/ZD). When administered sequentially, treatment with SN-38 followed by gefitinib had remarkable synergistic effects in the PC-9 and PC-9/ZD cells. In an in vivo tumor-bearing model, this combination had a schedule-dependent synergistic effect in the PC-9 and PC-9/ZD cells. An immunohistochemical analysis of the tumors in mice treated with CPT-11 and gefitinib demonstrated that the number of Ki-67 positive tumor cells induced by CPT-11 treatment was decreased when CPT-11 was administered in combination with gefitinib. In conclusion, the sequential combination of CPT-11 and gefitinib is considered to be active against lung cancer.
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PMID:Effects of different combinations of gefitinib and irinotecan in lung cancer cell lines expressing wild or deletional EGFR. 1671 12

Alteration of the epidermal growth factor (EGF) signaling pathway occurs frequently in human cancer cells and may subsequently affect the cell survival towards anti-cancer agents. To elucidate the effect of long-term EGF treatment on the chemo-sensitivity of human cancer cells, human squamous carcinoma A431 cells (AP) were incubated continuously with 50 ng/ml EGF for 30 weeks and these cells were designated as the AC cells. The long-term EGF treatment did not alter the EGFR level and the EGF-induced protein tyrosine phosphorylation pattern in the AC cells. By MTT assay, the AC cells were shown to be more resistant than the AP cells to doxorubicin, etoposide and amsacrine but not to cisplatin. Among the drug-resistant proteins, topoisomerase IIalpha (topoII) was downregulated in the AC cells while there was no apparent change in the levels of P-glycoprotein, MRP-1 or glutathione- S-transferase-pi as compared to the AP cells. Furthermore, knockdown of topoII by antisense topoII oligonucleotide transfection decreased the sensitivity to doxorubicin, etoposide and amsacrine in the A431 cells. Results from the present study support an idea that long-term treatment with EGF may induce drug resistance in cells through the downregulation of topoII.
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PMID:Epidermal growth factor induction of resistance to topoisomerase II toxins in human squamous carcinoma A431 cells. 1696 95

This years ASCO-meeting reinforced the trend of the recent years to get off from empirical treatment concepts to tailored and individualized diagnostics and therapy. However, the basis for an individual therapy is a specific molecular diagnostic which can be reflected in the analysis of hormonal receptor, HER-1, HER-2 and topoisomerase IIalpha in breast cancer. All these markers are not only able to prognosticate the course of disease but they also can predict the success of specific treatment approaches. Trastuzumab is standard therapy in HER-2 positive breast cancer both in the adjuvant and palliative setting. But new therapeutic agents, as e. g. lapatinib, are promising in the treatment of HER-2 positive breast cancer even if trastuzumab is failing. Otherwise it might possibly be an alternative option but adequate clinical results have to be awaited. The targeted inactivation of EGFR-related signal transduction pathways by e. g. gefitinib did not show a substantial improvement neither as a single agent nor in combination with endocrine treatment. However, the appropriate subgroup which might benefit from this therapy has to be defined even if molecular data suggest that patients with ER positive and PR negative breast cancer might be such a group. The increasing knowledge in terms of the biology of bone metastasis led to the development of new treatment options as e. g. denosumab, a humanized monoclonal antibody for RANK ligand. Two adjuvant cytotoxic treatment trials revealed that taxanes improve the prognosis of node positive breast cancer and should be administered sequentially. The advantage of switching to an aromatase inhibitor after two to three years of tamoxifen in endocrine treatment of postmenopausal patients is proved by two clinical trials (IES, ARNO) which could demonstrate a survival benefit. In conclusion it seems to be evident that new targeted therapy options are effective and will set new standards for the treatment of breast cancer patients in the near future. The presentation for the ovarian cancer focused on the addition of a third cytotoxic agent to carboplatin and paclitaxel as the standard therapy for the primary treatment of ovarian cancer. New data of Bevacizumab in the treatment of primary and recurrent ovarian cancer were presented. However, this is not yet a standard treatment for all patients and needs further investigations within large, multicentre, randomised trials. The lymphonodectomy as part of the primary therapy of the endometrial cancer seems to be a benefit at least in patients with advanced disease or high risk stage I tumours. The adjuvant therapy of uterine sarcomas is still not yet very well investigated and clear. A trial which recruited 12 years demonstrated a benefit in overall survival which has to be interpreted with caution. In this year again there have been registered an increasing number of interesting contributions from Germany, which also received international attention.
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PMID:[Molecular diagnostic and targeted therapy--"Barking dogs are going to bite": presentations from the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta 2006]. 1700 57

Pericosines A-E 1-5 have been isolated from a strain of Periconia byssoides originally separated from the sea hare Aplysia kurodai. Among them, pericosines C 3 and E 5 were separated as enantiomeric mixtures. Their stereostructures, except for compound 1, have been elucidated or identified on the basis of spectroscopic analyses, including 1D and 2D NMR techniques, and X-ray analysis. In addition, conformation for all the compounds has been discussed. Compounds 1-3 exhibited significant growth inhibition against tumour cell lines. Pericosine A 1 also showed significant in vivo tumour inhibitory activity. In addition, compound inhibited the protein kinase EGFR and topoisomerase II.
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PMID:Pericosines, antitumour metabolites from the sea hare-derived fungus Periconia byssoides. Structures and biological activities. 1804 3

Breast cancer is the most common female malignancy in many industrialized countries. Approximately one fourth of all women diagnosed with early breast cancer present with tumors that are characterized by erbB2 amplification. While the associated Her-2/neu receptor overexpression results in a high risk of relapse and poor prognosis, these tumors also represent a target for a selective monoclonal antibody therapy with trastuzumab (Herceptin). The combination of trastuzumab with chemotherapy has led to a considerable reduction of recurrences and to a significant reduction in breast cancer mortality both in the adjuvant and metastatic setting. Unfortunately, despite Her-2/neu overexpression, not all patients equally benefit from trastuzumab treatment, and almost all women with metastatic breast cancer eventually progress during antibody therapy. Moreover, trastuzumab is burdened with cardiotoxicity, thus increasing the risk of symptomatic congestive heart failure. In addition, the marginal costs for a 1 year therapy of trastuzumab-based therapy, which is currently considered to be the most effective treatment regimen in the adjuvant setting, may amount for up to US$ 40.000. Testing for erbB2 oncogene amplification by fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH), respectively, and staining for Her-2/neu receptor overexpression by immunohistochemistry (IHC) represent the current standard for determining patient eligibility for trastuzumab-based therapy. However, while the negative predictive value of these assays for predicting the absence of benefit from trastuzumab-based therapy is sufficiently high, their positive predictive value remains insufficient, i.e. only a proportion of patients selected by these tests substantially benefit from trastuzumab-containing regimen. Accordingly, over the last years a number of biomarkers have been evaluated in their potential to predict response to trastuzumab-based therapies. These include markers auf activation of Her-2/neu (e.g., tyrosine phosphorylated Her-2/neu in tissue and cleaved Her-2/neu extracellular domain in serum) and its dimerization partners (e.g., EGFR), respectively, but also components of Her-2/neu-induced downstream signaling pathways that are crucial for the growth inhibitory effects of trastuzumab (e.g., PTEN and PI3K). Other parameters, such as topoisomerase-II alpha and c-myc co-amplifications, have also been identified as potentially useful predictors of response to trastuzumab-based chemotherapy regimen. While the benefit of these predictive biomarkers in the metastatic setting is currently explored, their usefulness in the adjuvant setting is still largely unknown. It is, however, undisputable that, within the group of Her-2/neu overexpressing tumors, further response predictors are needed in order to minimize trastuzumab-associated side effects, and to reduce the considerable societal costs that are associated with trastuzumab-based treatment regimen.
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PMID:Predicting the efficacy of trastuzumab-based therapy in breast cancer: current standards and future strategies. 1837 8

Pure invasive micropapillary carcinoma (MPC) is a special histological type that accounts for 0.7-3% of all breast cancers. MPC has a distinctive growth pattern and a more aggressive clinical behaviour than invasive ductal carcinomas of no special type (IDC-NSTs). To define the molecular characteristics of MPCs, we profiled a series of 12 MPCs and 24 grade and oestrogen receptor (ER)-matched IDC-NSTs using high-resolution microarray comparative genomic hybridization (aCGH). In addition, we generated a tissue microarray containing a series of 24 MPCs and performed immunohistochemical analysis with ER, PR, Ki-67, HER2, CK5/6, CK14, CK17, EGFR, topoisomerase-IIalpha, cyclin D1, caveolin-1, E-cadherin, and beta-catenin antibodies. In situ hybridization probes were employed to evaluate the prevalence of amplification of HER2, TOP2A, EGFR, CCND1, MYC, ESR1, and FGFR1 genes. aCGH analysis demonstrated that MPCs significantly differed from IDC-NSTs at the genomic level. Gains of 1q, 2q, 4p, 6p, 6q23.2-q27, 7p, 7q, 8p, 8q, 9p, 10p, 11q, 12p, 12q, 16p, 17p, 17q, 19p, 20p, 20q, and 21q, and losses of 1p, 2p, 6q11.1-q16.3, 6q21-q22.1, 9p, 11p, 15q, and 19q were more prevalent in MPCs. High-level gains/amplifications of 8p12-p11, 8q12, 8q13, 8q21, 8q23, 8q24, 17q21, 17q23, and 20q13 were significantly associated with MPCs. A comparison between 24 MPCs and a series of 48 grade and ER-matched IDC-NSTs revealed that high cyclin D1 expression, high proliferation rates, and MYC (8q24) amplification were significantly associated with MPCs. Our results demonstrate that MPCs have distinct histological features and molecular genetic profiles supporting the contention that they constitute a distinct pathological entity.
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PMID:Genomic and immunophenotypical characterization of pure micropapillary carcinomas of the breast. 1848 83


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