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)

Multidrug resistance (MDR) is a complex phenomenon that includes the expression of many different genes regulating drug transport or metabolism, cellular repair or detoxification mechanisms. The co-expression of several genes could be at the basis of the resistant phenotype in vivo. In order to test a possible prognostic role of the expression and co-expression of several MDR-related genes (MDR1, topoisomerase IIalpha, topoisomerase IIbeta, MRP, GSTpi, LRP), 35 patients affected by acute myeloid leukemia (AML) were tested by RT-PCR assays. In our series, topoisomerase IIbeta was significantly co-expressed with MRP (p = 0.05), GSTpi (p = 0.017) and LRP (p = 0.005). GSTpi was co-expressed with LRP (p = 0.03) and MRP (p = 0.007); on the other hand, 53.8% of patients were LRP and MRP-positive (p = 0.02). The PCR-positivity did not differ according to biological/clinical characteristics of patients, including age; this latter was the only parameter conditioning the response and overall survival. Neither the expression nor the co-expression of the tested genes was significantly correlated with the response to the induction treatment and long-term outcome.
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PMID:The clinical relevance of the expression of several multidrug-resistant-related genes in patients with primary acute myeloid leukemia. 1296 66

Chemoresistance is a major obstacle for successful treatment of cancer. To identify regions of the genome associated with acquired resistance to therapeutic drugs, we conducted molecular cytogenetic analyses of 23 cancer-cell lines, each resistant to either camptothecin, cisplatin, etoposide (VP-16), Adriamycin, or 1-beta-D-arabinofuranosylcytosine, although the parental tumor lines were not. Subtractive comparative genomic hybridization studies revealed regions of gain or loss in DNA-copy numbers that were characteristic of drug-resistant cell lines; i.e., differences from their drug-sensitive parental cell lines. Thirteen ATP-binding cassette (ABC) transporter genes [ABCA3, ABCB1 (MDR1), ABCB6, ABCB8, ABCB10, ABCB11, ABCC1 (MRP1), ABCC4, ABCC9, ABCD3, ABCD4, ABCE1, and ABCF2] were amplified among 19 of the resistant cell lines examined. Three genes encoding antiapoptotic BCL-2 proteins (BCL2L2, MCL1, and BCL2L10) were also amplified and consequently overexpressed in three of the derivative lines. Down-regulation of BCL2L2 with an antisense oligonucleotide sensitized a VP-16 resistant ovarian-cancer cell line (SKOV3/VP) to VP-16. A decrease in copy numbers of genes encoding deoxycytidine kinase, DNA topoisomerase I, and DNA topoisomerase II alpha reduced their expression levels in one cytosine arabinoside-resistant line, two of three camptothecin-resistant lines, and two of five VP-16-resistant cell lines, respectively. Our results indicated that changes in DNA-copy numbers of the genes mentioned can activate or down-regulate them in drug-resistant cell lines, and that such genomic alterations might be implicated in acquired chemoresistance.
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PMID:Alteration in copy numbers of genes as a mechanism for acquired drug resistance. 1497 57

XR11576 (MLN576) is a novel monophenazine with a mechanism of action that includes interaction with both topoisomerase (Topo) I and II. The aim of this study was to evaluate its cytotoxicity against fresh tumor cells taken from patients with a variety of solid tumors. Cells were obtained from 89 patients and exposed for 6 days to XR11576 alone, or in combination with doxorubicin, cisplatin, treosulfan, paclitaxel or vinorelbine. Cell survival was measured using the ATP-Tumor Chemosensitivity Assay (ATP-TCA). Immunohistochemical staining of Topo I, Topo IIalpha and MDR1 was performed on paraffin-embedded blocks in those tumors for which tissue was available (n = 49). Overall, the median IC90 and IC50 values of XR11576 in tumor-derived cells were 242 and 110 nM, respectively. In all samples XR11576 was more potent than the other cytotoxics tested. Breast and gynecological malignancies were most sensitive to XR11576, while the potency of this compound was slightly attenuated in gastrointestinal tumors, in which the median IC90 and IC50 values were 308 and 212 nM, respectively. Cases of synergism were identified when combining XR11576 with vinorelbine (nine of 30 samples) and doxorubicin (12 of 38 samples), while the addition of paclitaxel resulted in an antagonistic effect (CI50>1.2) in 38 of 42 tumors. A very modest correlation by linear regression analysis was found between the intensity of MDR1 staining and the IC50 of XR11576 (r = 0.311, p = 0.0312), but not with the IC90 (r = 0.247, NS). These data support the rapid introduction of XR11576 to clinical trials and suggest that it may be effective against a broad spectrum of tumor types.
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PMID:Ex vivo characterization of XR11576 (MLN576) against ovarian cancer and other solid tumors. 1545 25

Three parental neuroblastoma cell lines and nine derived lines resistant to Vincristin, Doxorubicin and Cisplatin, respectively, using CGH were studied. CGH profiles of all three parental cell lines were obtained using DNA from a healthy volunteer as reference DNA. Labeled DNA from each of the drug resistant daughter cell lines and labeled DNA from their parental sensitive cell lines were hybridized to obtain a comparison of gains and losses that accompanied the development of resistance for that particular drug. All three parental cell lines were characterized by typical findings for high risk neuroblastoma: N-myc amplification, gain of 17q, and loss of 1p36.2-36.3. Acquired drug resistance in the neuroblastoma cell lines appeared to be accompanied by a large array of DNA sequence copy number changes. The regions frequently affected in chemo-resistant cell lines included gains of 13q14.1-32, and 7q11.2-31.3, 4 q. Amplifications were seen at 7q 21.1 consistent with MDR1 amplification in UKF-NB-2 VCR, UKF-NB-3 DOXO, UKF-NB-4 VCR, and UKF-NB-4 DOXO, but not in any Cisplatin resistant line. All Cisplatin and Doxorubicin and two Vincristin resistant line (UKF-NB-2 VCR and UKF-NB-4 VCR) had a deletion of part of 19q or the whole 19 chromosome. All lines resistant to Vincristin or Doxorubicin and two Cisplatin resistant lines (UKF-NB-2 CDDP and UKF-NB-4 CDDP) had a deletion of at least part of 17q, UKF-NB-4 DOXO had deletion of the whole chromosome 17. The loss of 17q may cause chemoresistance by deletion of topoisomerase IIalpha gene. Deletion of 19 q in all but one chemo-resistant lines may influence of cytochromes P450 genes which are located on 19q13.2. Also gains of 15q 22, which were detected in UKF-NB-4 VCR, UKF-NB-2 DOXO and UKF-NB-4 DO X O, may affect other cytochromes P450 genes.
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PMID:Characterization of drug-resistant neuroblastoma cell lines by comparative genomic hybridization. 1615 87

Multidrug resistance (MDR) is a major obstacle to successful application of cancer chemotherapy and also a basic problem in cancer biology. Studies on the molecular basis of MDR have revealed that a number of proteins over express in multidrug resistant cells viz., multidrug resistant MDR1 gene product P-glycoprotein, the multidrug resistance-associated protein (MRP) and enzymes associated with the glutathione (GSH) metabolism. Decreased expression or altered activity of topoisomerase II has also been implicated in MDR. In the present investigation a number of changes in phase II detoxification parameters have been noticed in drug resistant cells but the novel aspect of the present report is the observation that the metal copper is involved in drug resistance. Although copper plays important roles in many human and other biological systems and even in the treatment of cancer but the relation of Cu and drug resistance has not so far been studied in detailed. The present report describes the novel findings that the level of copper increases with the development of drug resistance in Ehrlich ascites carcinoma and in Lewis lung carcinoma cells and also in serum of mice bearing drug resistant cancer cells compared to mice bearing drug sensitive cells; the work indicates the important aspect of treating drug resistant cancer patients by lowering Cu level in the cancerous cells and serum prior to treatment.
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PMID:The role of copper in development of drug resistance in murine carcinoma. 1678 40

Based on the topoisomerase IIalpha catalytic inhibitory activity of a previous hit compound, NSC35866, we screened 40 substituted purines or purine-like compounds from the National Cancer Institute repository for their ability to inhibit the ATPase activity of human topoisomerase IIalpha. Several compounds, including NSC348400, NSC348401 and NSC348402, were inhibitory at submicromolar concentrations. Three-dimensional quantitative structure-activity relationship models using comparative molecular field and comparative molecular similarity indices analyses were constructed using 24 of these compounds. The ability of 10 selected compounds to inhibit the complete DNA strand passage reaction of topoisomerase IIalpha correlated well with their potency as ATPase inhibitors. None of the 40 compounds significantly increased levels of the topoisomerase IIalpha-DNA covalent complex, suggesting that they functioned as catalytic topoisomerase II inhibitors and not as topoisomerase II poisons. Although some of these compounds could antagonize the effect of etoposide on the level of topoisomerase IIalpha-DNA covalent complex formation in vitro, in contrast to NSC35866, they were not capable of antagonizing etoposide-induced cytotoxicity and DNA strand breaks in cells. Two independently selected human SCLC cell lines with reduced topoisomerase IIalpha expression displayed cross-resistance to NSC348400, NBSC348401, and NSC348402, whereas an MDR1 line was fully sensitive. These results suggest that topoisomerase IIalpha is a functional cellular target for most of these substituted purine compounds and that these compounds do not display MDR1 liability.
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PMID:A three-dimensional quantitative structure-activity relationship study of the inhibition of the ATPase activity and the strand passing catalytic activity of topoisomerase IIalpha by substituted purine analogs. 1688 Feb 87

The results of multidrug resistance determinants expression analysis on leukemic cells of 56 acute myeloid leukemia (AML) patients by immunophenotyping are presented. Of these, there were 21 persons exposed to ionizing radiation due to the Chemobyl accident with radiation-associated AML and 35 patients with spontaneous leukemia. The aim of this study was to determine if transport proteins (P-glycoprotein, LRP, and MDR1), apoptosis-related proteins (Fas, Bcl-2, Bax, p53, and Bcl-X(L)), and topoisomerase IIalpha expression in AML patients with the history of radiation exposure differed from those in spontaneous AML cases. Leukemic cells in patients with radiation-associated diseases compared to spontaneous AML more often overexpressed antiapoptotic oncoprotein Bcl-2 (12/21 vs. 6/35, p < 0.005) and less often demonstrated expression of Fas receptor (12/21 vs. 30/35, p < 0.05). Moreover, leukemic cells were simultaneously Fas negative and Bcl-2 positive in 4 out of 21 patients exposed to ionizing radiation but none of spontaneous cases had similar phenotype (p < 0.05). Leukemic cells in patients with radiation-associated AML compared to spontaneous cases more often were P-glycoprotein positive (12/20 vs 9/31, p < 0.05). P-glycoprotein overexpression significantly correlated with resistant disease in patients with radiation-associated AML (r = 0.47, p < 0.05), but was not a prognostic variable for the treatment outcome in terms of overall survival. Defects in pathways of drug-induced apoptosis and function of pump, that actively effluxes drugs could contribute significantly to developing drug resistance in radiation-associated AML.
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PMID:[Multidrug resistance determinants in acute myeloid leukemia developed in persons exposed to ionizing radiation due to the Chernobyl accident]. 1713 22

We report a case with malignant meningioma in which new preliminary treatment trial was performed by chemotherapy using anti-cancer drugs selected on the basis of multidrug resistance gene mRNA expression, such as MDR1, MGMT, MRP1, MRP2, MXR1, and DNA topoisomerase II alpha, from RT-PCR assay. A 43-year-old female had been operated for parasagittal anaplastic meningioma three times because of recurrences. partial removal of tumor was performed at the 3rd operation. RT-PCR assay of this tissue revealed overexpression of MDR1, MRP1, MRP2 and MGMT mRNA, but no ABCG 2 expression was observed. The patient was given mitoxantrone and hydroxyurea following irradiation, after which the tumor did not recur for three years. Preliminary individual adjuvant chemotherapy based on mRNA expression of drug-resistance gene is available for the treatment of recurrent malignant meningioma.
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PMID:[A case of malignant meningioma treated by individual adjuvant chemotherapy based on the mRNA expression of drug-resistance gene]. 1730 41

The genomic profile of mantle cell lymphoma (MCL) has been reported to be significantly different from that of other indolent lymphoproliferative disorders, Topoisomerase IIalpha, glutathione-s-transferasepi (GSTpi) and ABCG2 (BCRP) chemoresistance genes being over-expressed in MCL. In our study, expression levels of the above mentioned genes plus MDR1 were tested on bone marrow samples from 20 patients treated with Rituximab plus hyper-CVAD regimen, in order to evaluate a possible impact of the chemoresistance phenomenon on this promising treatment regimen. All patients expressed ABCG2 and MDR1 genes; 85% of cases expressed GSTpi and topoisomerase IIalpha. Only ABCG2 were over-expressed in comparison both with marrow from healthy donors and tonsilar CD5+/CD20+ lymphocytes (adopted as normal counterpart of the neoplastic population). The overall response rate of the entire series was 87.5%, with 44% of complete responses. Fifty-seven percent of patients achieved the clearance of minimal residual disease. Levels of tested genes did not condition either quality of clinical response or PFS (76% at 24 months). Nevertheless, an ABCG2 higher expression appeared associated with a worse PFS and levels of this gene paralleled the status of minimal residual disease. A further evaluation of ABCG2 expression in larger series of MCL patients would be suitable.
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PMID:Evaluation of the MDR1, ABCG2, Topoisomerases IIalpha and GSTpi gene expression in patients affected by aggressive mantle cell lymphoma treated by the R-Hyper-CVAD regimen. 1770 72

A new series of 4 beta-anilino-podophyllotoxin analogs have been designed, synthesized and evaluated their bioactivities as novel DNA-topoisomerase II poisons as well as P-glycoprotein (P-gp)-dependent multidrug resistance (MDR) inhibitors. The new compounds show improved potency and efficacy with respect to the parent molecule etoposide (VP-16), one of the semisynthetic derivatives of podophyllotoxin. The treatment of 5k-n in KB/VCR cells caused G(2)/M phase arrest and finally induced apoptosis. Furthermore, molecular docking is applied to testify that 5k-n could not be the substrates of P-gp, which is consistent with the result of MDR1 and P-glycoprotein express tests. The most potent compound 5n is chosen for in vivo studies, the administration of 5n was effective in treatment of cancer with a lower dose than VP-16 in drug-sensitive xenograft model and drug-resistant xenograft model. Compound 5n is a potential drug candidate for anticancer chemotherapy.
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PMID:Novel 4 beta-anilino-podophyllotoxin derivatives: design synthesis and biological evaluation as potent DNA-topoisomerase II poisons and anti-MDR agents. 2009 61


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