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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the tumor suppressor gene product p53 and the cyclin-dependent kinase inhibitor p21, which is transcriptionally activated by p53, was investigated and compared with patient survival in a retrospective longitudinal study of 202 cases of endometrial carcinoma. The median duration of follow-up was 4.3 years. P53 was observed immunohistochemically in 63 (31%) of the tumors and was found by univariate analysis to be related to reduced adjusted survival (p = 0.00028) and disease-free survival (p = 0.04). However, p53 expression was not found by multivariate analysis to be an independent prognostic factor when compared with FIGO stage, histologic grade, and proliferative activity, as determined by immunoreactivity for topoisomerase IIalpha with the antibody Ki-S1. Overexpression of p53 was related to histologic grade (p < 0.00001), proliferative activity (p = 0.0071), and inversely to progesterone receptor content (p = 0.042). Immunohistochemical identification of p21 was investigated in 95 cases and found to be positive in 19 (39%) of 49 tumors with p53 overexpression and in 13 (28%) of 46 tumors without p53 overexpression (p = 0.28). Expression of p21 is therefore not related to p53 expression, nor was it found to be related to proliferative activity. Strong expression of p21 was observed in tumors negative for progesterone receptors (p = 0.0028). P53 in endometrial carcinoma is not associated with induction of the cell cycle inhibitor p21, but is associated with an enhanced proliferative activity. The findings of multivariate analysis suggest that the prognostic significance of p53 is related mainly to cell proliferation.
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PMID:p53 protein in endometrial cancer is related to proliferative activity and prognosis but not to expression of p21 protein. 942 Oct 76

Few studies have analyzed the relationship among pathology, therapy-induced changes, proliferative activity, and outcome for rhabdomyosarcoma (RMS), despite the challenges of histopathologic interpretation of this tumor after treatment. Although cytodifferentiation and decreased mitotic activity after treatment were documented previously, the clinical consequences of these changes are uncertain because of the small number of cases analyzed. We analyzed 16 RMSs with pre- and post-treatment specimens for clinicopathologic features, outcome, and immunohistochemical data on formalin-fixed, paraffin-embedded tissue for vimentin, smooth muscle actin, muscle-specific actin, desmin, myoglobin, p53 protein, topoisomerase II-alpha, and MIB-1 proliferative activity. Four of eight alveolar (ARMS), five of five botryoid (BRMS), and two of three nonbotryoid embryonal (ERMS) RMSs displayed varying degrees of post-therapeutic histologic maturation and expressed one or more myoid markers. The remaining five RMSs had no cytodifferentiation. Myoid marker expression did not change significantly. In BRMS, MIB-1 and topoisomerase II-alpha proliferative activity decreased after therapy and correlated with cytodifferentiation and survival. This relationship was less clear for ERMS and ARMS. Five nonbotryoid RMSs without cytodifferentiation had either unchanged or increased proliferative activity, and four of these patients died of RMS. Six nonbotryoid RMSs with both cytodifferentiation and residual foci of undifferentiated cells had variable outcomes, including longer survival. We conclude that BRMS and ERMS exhibit therapy-induced cytodifferentiation more frequently than does ARMS. Cytodifferentiation and decreased proliferative activity are associated with favorable outcome in BRMS; unchanged or increased post-therapeutic proliferative activity suggests aggressive biologic potential in ERMS and ARMS. Combined patterns of cytodifferentiation and residual undifferentiated foci might be associated with increased, decreased, or unchanged proliferative activity and are difficult to interpret, but the presence of cytodifferentiation might presage an improved survival. Immunohistochemical analysis for proliferation markers might be useful for highlighting foci of less differentiated RMS or cytodifferentiated tumor cells in contrast to non-neoplastic, terminally differentiated muscle cells.
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PMID:Pathologic features of rhabdomyosarcoma before and after treatment: a clinicopathologic and immunohistochemical analysis. 943 61

Melanoma cells often display a multidrug-resistant phenotype, but the mechanisms involved are largely unknown. In order to establish a reproducable model system for studying the exact mechanisms conferring chemoresistance, we selected drug-resistant sublines in vitro derived from one parental human melanoma (MeWo) cell line. Four commonly used chemotherapeutic drugs (vindesine, etoposide, fotemustine, cisplatin) with different modes of action were choosen and stable sublines exhibiting four different levels of resistance against each drug were selected by continuous exposure over two years. Analysis of the drug-resistant sublines regarding their pharmacological characteristics and cross-resistance pattern revealed an up to 26-fold increased relative resistance against the alkylating agent fotemustine (MeWoFOTE) and an up to 35.7-fold increased relative resistance against topoisomerase-II-inhibiting etoposide (MeWoETO). Cisplatin selection (MeWoCIS) resulted in a 6-fold higher resistance compared to parental MeWo cells, whereas vindesine exposure (MeWoVIND) increased relative resistance up to 10.2-fold. Sublines selected separately for resistance to the DNA-damaging agents fotemustine, cisplatin and etoposide demonstrated strong cross-resistance. In comparison to the parental cell line drug-resistant sublines showed altered expression patterns of proto-oncogenes. Levels of p53 mRNA decreased with increasing resistance to vindesine, etoposide and fotemustine. Expression of bcl-2 family members (bax, bcl-x) was modulated by fotemustine, etoposide and cisplatin. In addition the expression of members of the fos (c-fos) and jun (c-jun, jun-D) gene family encoding transcription factors of the AP-1 complex was altered in all drug-resistant sublines. The pattern of expression varied with the inducing stimulus and this was paralleled by changes in the transactivation potential of AP-1. Our results reinforce the central role of AP-l in drug resistance probably through its participation in a programmed cellular stress response.
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PMID:Human melanoma cell lines selected in vitro displaying various levels of drug resistance against cisplatin, fotemustine, vindesine or etoposide: modulation of proto-oncogene expression. 949 34

Teniposide (VM26) enhanced the anti-glioma activity of the cytotoxic cytokine, CD95 ligand. Synergy was observed at concentrations of teniposide that were insufficient for cleavable DNA topoisomerase II complex formation. CD95 ligand did not modulate the formation or removal of such complexes after teniposide treatment. These processes were also unaffected by ectopic expression of bcl-2. Teniposide enhanced CD95 expression in a glioma cell line with wild-type p53 (LN-229) but not in two p53 mutant cell lines (T98G, LN-308). Forced expression of a transdominant negative p53 mutant prevented the teniposide induced augmentation of CD95 expression in LN-229 cells but did not prevent the synergy of CD95 ligand and teniposide. Teniposide did not alter CD95 ligand expression, and forced expression of CD95 did not modulate sensitivity to VM26. Thus, teniposide-induced DNA lesions and alterations in CD95 or CD95 ligand are not necessary for teniposide-induced sensitization of human malignant glioma cells to CD95-mediated apoptosis.
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PMID:Synergy of CD95 ligand and teniposide: no role of cleavable complex formation and enhanced CD95 expression. 954 55

Beta-lapachone (beta-lap) affects a number of enzymes in vitro, including type I topoisomerase (Topo I); however, its exact intracellular target(s) and mechanism of cell killing remain unknown. We compared the cytotoxic responses of MCF-7:WS8 (MCF-7) human breast cancer cells after 4-h pulses of beta-lap or camptothecin (CPT), a known Topo I poison. A direct correlation between loss of survival and apoptosis was seen after beta-lap treatment (LD50 = 2.5 microM). A concentration-dependent, transient sub-2 N preapoptotic cell population was observed at 4-8 h. Estrogen deprivation-induced synchronization and bromodeoxyuridine-labeling studies revealed an apoptotic exit point near the G1-S border. Apoptosis activated by beta-lap was closely correlated with cleavage of lamin B but not with increases in p53/p21 or decreases in bcl-2. Loss of hyperphosphorylated forms of the retinoblastoma protein was observed within 5 h, but cyclins A, B1, and E levels were unaltered for up to 72 h after 5 microM beta-lap. Topo I and Topo IIalpha levels decreased at > 24 h. Logarithmic-phase MCF-7 cells were not affected by < or = 1 microM beta-lap. In contrast, dramatic and irreversible G2-M arrest with no apoptosis was observed in MCF-7 cells treated with 1 microM CPT, monitored for 6-10 days posttreatment. MCF-7 cells treated with supralethal doses of CPT (5 microM) resulted in only approximately 20% apoptosis. No correlation between apoptosis and loss of survival was observed. MCF-7 cells exposed to > 5 microM CPT arrested at key cell cycle checkpoints (i.e., G1, S, and G2-M), with little or no movement for 6 days. Ten-fold increases in p53/p21 and 2-5-fold decreases in bcl-2, Topo I, Topo IIalpha, and cyclins A and B1, with no change in cyclin E, were observed. Temporal decreases in bcl-2 and cleavage of lamin B corresponded to the minimal apoptotic response observed. Beta-lap activated apoptosis without inducing p53/p21 or cell cycle arrest responses and killed MCF-7 cells solely by apoptosis. In contrast, concentration-dependent increases in nuclear p53/p21 and various cell cycle checkpoint arrests were seen in MCF-7 cells after CPT. Despite dramatic p53/p21 protein induction responses, CPT-treated MCF-7 cells showed low levels of apoptosis, possibly due to protective cell cycle checkpoints or the lack of specific CPT-activated apoptotic pathways in MCF-7 cells.
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PMID:Induction of apoptosis in MCF-7:WS8 breast cancer cells by beta-lapachone. 958 28

Segmental jumping translocations are chromosomal abnormalities in treatment-related leukemias characterized by multiple copies of the ABL and/or MLL oncogenes dispersed throughout the genome and extrachromosomally. Because gene amplification potential accompanies loss of wild-type p53, we examined the p53 gene in a case of treatment-related acute myeloid leukemia (t-AML) with MLL segmental jumping translocation. The child was diagnosed with ganglioneuroma and embryonal rhabdomyosarcoma (ERMS) at 2 years of age. Therapy for ERMS included alkylating agents, DNA topoisomerase I and DNA topoisomerase II inhibitors, and local radiation. t-AML was diagnosed at 4 years of age. The complex karyotype of the t-AML showed structural and numerical abnormalities. Fluorescence in situ hybridization analysis showed multiple copies of the MLL gene, consistent with segmental jumping translocation. A genomic region including CD3, MLL, and a segment of band 11q24 was unrearranged and amplified by Southern blot analysis. There was no family history of a cancer predisposing syndrome, but single-strand conformation polymorphism (SSCP) analysis detected identical band shifts in the leukemia, ganglioneuroma, ERMS, and normal tissues, consistent with a germline p53 mutation, and there was loss of heterozygosity in the ERMS and the t-AML. Sequencing showed a CGA-->TGA nonsense mutation at codon 306 in exon 8. The results of this analysis indicate that loss of wild-type p53 may be associated with genomic instability after DNA-damaging chemotherapy and radiation, manifest as a complex karyotype and gene amplification in some cases of t-AML.
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PMID:Association of germline p53 mutation with MLL segmental jumping translocation in treatment-related leukemia. 961 38

Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to the development of breast cancer, ovarian cancer, and other malignancies. Recent studies suggest that the BRCA1 and BRCA2 gene products may function in the sensing and/or repair of DNA damage. To investigate this possibility, we determined the effects of various DNA-damaging agents and other cytotoxic agents on the mRNA levels of BRCA1 and BRCA2 in the MCF-7 and other human breast cancer cell lines. We found that several agents, including adriamycin (a DNA intercalator and inhibitor of topoisomerase II), camptothecin (a topoisomerase I inhibitor), and ultraviolet radiation induced significant decreases in BRCA1 and BRCA2 mRNA levels. Decreased levels of BRCA1 and BRCA2 mRNAs were observed within 6-12 h after treatment with adriamycin and persisted for at least 72 h. Adriamycin also induced decreases in BRCA1 protein levels; but these decreases required several days. U.V. radiation induced dose-dependent down-regulation of BRCA1 and BRCA2 mRNAs, with significant decreases in both mRNAs at doses as low as 2.5 J/m2, a dose that yielded very little cytotoxicity. Adriamycin-induced down-regulation of BRCA1 and BRCA2 mRNAs was first observed at doses that yielded relatively little cytotoxicity and little or no apoptotic DNA fragmentation. Adriamycin and U.V. radiation induced distinct dose- and time-dependent alterations in the cell cycle distribution; but these alterations did not correlate well with corresponding changes in BRCA1 and BRCA2 mRNA levels. However, the adriamycin-induced reduction in BRCA1 and BRCA2 mRNA levels was correlated with p53 functional status. MCF-7 cells transfected with a dominant negative mutant p53 (143 val-->ala) required at least tenfold higher doses of adriamycin to down-regulate BRCA1 and BRCA2 mRNAs than did parental MCF-7 cells or control-transfected MCF-7 clones. These results suggest that BRCA1 and BRCA2 may play roles in the cellular response to DNA-damaging agents and that there may be a p53-sensitive component to the regulation of BRCA1 and BRCA2 mRNA expression.
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PMID:Regulation of BRCA1 and BRCA2 expression in human breast cancer cells by DNA-damaging agents. 961 32

The diagnosis of 'ALL with maturation' (ALLm) is proposed. One hundred and one patients with untreated ALL were entered into this study. The diagnosis of ALLm was made when more than 20% of all nucleated elements in the bone marrow showed maturation beyond prolymphocytes by light microscopic examination. The mature-appearing leukemic cells showed the same immunophenotype to remaining lymphoblasts. The number of ALLm cases was 19 (18.8%). The mean age at presentation of ALLm was 29 +/- 18, older than that of 18 +/- 16 of the remaining typical ALL (ALLt) (P = 0.015). Remission was induced with daunorubicin, vincristine, prednisone and L-asparaginase. Only two of 19 ALLm patients achieved CR after 4 weeks induction chemotherapy. In contrast, 57 of 82 (69.5%) ALLt patients achieved CR after the same induction chemotherapy. There was no significant difference in immunophenotype of ALLm compared with ALLt. Labeling index of DNA topoisomerase IIalpha (TopoLI) was studied by immunohistochemistry. Initial TopoLI of ALLm (221 +/- 147) was much lower than that of ALLt (609 +/- 262, P = 0.005). Furthermore, the remaining leukemic cells after chemotherapy were not labeled with anti-DNA topoisomerase IIalpha. The P53 protein was expressed in nine of 18 ALLm cases (50.0%) and P-glycoprotein was not expressed in ALLm cases. Twelve of 19 ALLm cases were studied for carrying bcr/abl fusion by karyotyping and/or fluorescent in situ hybridization. Only two cases revealed bcr/abl fusion. In conclusion, ALLm is a separate entity of ALL which has a very poor clinical course and is independent of other prognostic factors. The morphologically mature leukemic cells are in resting GO phase.
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PMID:Acute lymphoblastic leukemia with maturation--a new entity with clinical significance. 963 14

The human lymphoblastoid cell lines TK6 (normal p53) and WI-L2-NS or WTK1 (mutant p53) differ in sensitivity to killing and induction of gene mutations and chromosome aberrations by ionizing radiation. This may be related to decreased apoptosis in the cells with mutated p53, such that more damaged cells survive. We compared the response of the two cell types to various chemicals. First, to ensure that the thymidine kinase deficiency does not increase the sensitivity of TK6 tk+/- cells to mutagens, we demonstrated that they were not hypersensitive to aberration induction by altered DNA precursor pools or DNA synthesis inhibition, by aphidicolin (APC), methotrexate, hydroxyurea (HU), cytosine arabinoside and thymidine. TK6 cells were then compared with WI-L2-NS or WTK1 cells. With APC, HU, methyl methanesulfonate (MMS), ethyl nitrosourea (ENU) and etoposide (etop), TK6 cells had more apoptosis in the first two days after treatment. Fewer aberrations were seen in normal p53 TK6 cells than the mutant p53 WI-L2-NS cells, ranging from very little difference between the two cell types with MMS to very large differences with ENU and etop. For MMS and ENU we followed cultures for several days, and found that WI-L2-NS cells underwent delayed apoptosis 3 to 5 days after treatment, in parallel with published observations with ionizing radiation. WI-L2-NS cells also had a delayed increase in aberrations (up to 5 days post-treatment) when no aberrations remained in TK6 cells. Colony forming efficiency was measured for APC, MMS and ENU, and was greater in the p53 mutant cells. Our results show that normal p53 function is required for rapid and efficient apoptosis in these lymphoblastoid cells with DNA synthesis inhibitors, alkylating agents and a topoisomerase II inhibitor, and support the hypothesis that induced levels of aberrations are higher in p53 mutant cells because of a failure to remove damaged cells by apoptosis.
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PMID:Fewer chromosome aberrations and earlier apoptosis induced by DNA synthesis inhibitors, a topoisomerase II inhibitor or alkylating agents in human cells with normal compared with mutant p53. 963 70

Although cytotoxic chemotherapy is widely used in advanced breast cancer, there are no powerful predictors for the therapy response. Because topoisomerase IIalpha (Topo IIalpha) is the molecular target for the anthracycline class of anti-cancer drugs, we compared the immunocytochemical assay of Topo IIalpha with other biomarkers in the prediction of clinical response to Topo II inhibitor chemotherapy. Fifty-five patients with advanced breast cancer were treated with a single cytotoxic drug, Topo II-inhibitor, epirubicin (30 mg m(-2) weekly up to 1000 mg m(-2)), as first line cytotoxic chemotherapy. Objective response to treatment was analysed according to UICC criteria. The predictive value of Topo IIalpha expression, c-erbB2 oncoprotein, p53 tumour-suppressor protein, oestrogen (ER) and progesterone receptor (PR), S-phase fraction and DNA ploidy were analysed from representative formalin-fixed paraffin-embedded primary tumour samples. The proportion of Topo IIalpha-positive cells (Topo IIalpha index) failed to predict response to epirubicin therapy. Mean Topo IIalpha scores in 29 responding patients were similar when compared with those with no change in disease progression (n = 13) and those with progressive disease (n = 13) (14.9% +/- 11.4% vs 15.5% +/- 7.6% vs 17.3% +/- 13.2%, not significant). Among the other biomarkers tested, overexpression of c-erbB2 oncoprotein and hormone receptor negativity were significantly associated with poor response. Response rate in patients with c-erbB2-overexpressing tumours was 32% compared with 65% in patients with no c-erbB2 overexpression (P = 0.0058). Accordingly, the response rate for ER-positive patients was 67% compared with 26% in ER-negative patients (P = 0.0021). Although both negative ER status and c-erbB2 overexpression are associated with high Topo IIalpha expression in breast cancer, step-wise logistic regression analysis showed that ER and c-erbB2 were associated with therapy response independent of Topo IIalpha expression. Histological grade, p53, DNA-ploidy, tumour proliferation rate (S-phase fraction), stage of the disease at diagnosis, age of the patient, previous anti-oestrogen therapy or site of metastasis did not predict the response to epirubicin therapy. In conclusion, despite extensive in vitro evidence, expression of Topo IIalpha is unlikely to predict the response to Topo II inhibitor chemotherapy in advanced breast cancer. Among the prognostic biomarkers, overexpression of c-erbB2 oncogene and negative ER may have predictive value in epirubicin therapy in patients with advanced breast cancer.
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PMID:Predictive value of topoisomerase IIalpha and other prognostic factors for epirubicin chemotherapy in advanced breast cancer. 964 44


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