Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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 associated with poor prognosis in leukemia, and anthracyclines, which are used in the treatment of leukemia, are associated with the expression of P-glycoprotein and the development of MDR. We report here that idarubicin, a new anthracycline approved for use in the treatment of acute myelogenous leukemia (AML), did not induce P-glycoprotein expression in the K562 human leukemia cell line under conditions where daunorubicin, doxorubicin and epirubicin did induce expression of P-glycoprotein. The P-glycoprotein expressing, multidrug resistant sublines developed to daunorubicin (K/DNR), doxorubicin (K/DOX) and epirubicin (K/EPR) were cross-resistant to the other anthracyclines and to vinblastine, taxol, colchicine and actinomycin D, but were not resistant to idarubicin or etoposide. The idarubicin treated subline, K/IDA, was only resistant to taxol but was 12-fold sensitized to etoposide, suggesting that idarubicin had affected topoisomerase II in this subline.
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PMID:Development of drug resistance is reduced with idarubicin relative to other anthracyclines. 767 Jan 42

Six new bimetallic complexes of the type CuCu, CuCo, CuNi, CuZn and CuMn were prepared. The structures of these complexes and the ligand have been proposed on the basis of FAB mass, elemental analysis, UV-vis, IR, EPR and CV studies. All the complexes completely cleave pBS (SK-) DNA at a concentration of 10 microM; however, even at lower concentrations of 2 microM and 0.1 microM, the complexes (I and Ia) showed partial cleavage. The results of the fluorescence binding studies of the metal complexes with CT-DNA showed that the presence of aliphatic ligands added additional binding effects including electrostatic, hydrogen binding and vander Waals interactions. Complexes (I, Ia) showed 50% inhibition of COX-1 and COX-2 activities at as low a concentration as 12.5 microM, 13.5 microM, 14 microM and 14.5 microM. Inhibition assay of top I and top II by different complexes in mutant yeast strains (JN394, JN394 t(-1) and JN394 t(2-5)) with all the complexes showed significant inhibition of topoisomerase at 5 microM concentration. Complexes I and Ia exhibited good anti-microbial activities against all human pathogens tested except Klebsiella pneumoniae. The following studies showed that among the synthesized bimetallic complexes, complexes I and Ia seem to be promising candidates possessing DNA cleavage activities besides anti-microbial and anti-inflammatory properties to serve as chemical nucleases and chemotherapeutic agents.
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PMID:Synthesis, characterization and in vitro biological activity studies of Cu-M (M = Cu2+, Co2+, Ni2+, Mn2+, Zn2+) bimetallic complexes. 1701 70

A novel cyclolignanic quinone, 7-acetyl-3',4'-didemethoxy-3',4'-dioxopodophyllotoxin (CLQ), inhibits topoisomerase II (TOPO II) activity. The extent of this inhibition was greater than that produced by the etoposide quinone (EQ) or etoposide. Glutathione (GSH) reduces EQ and CLQ to their corresponding semiquinones under anaerobic conditions. The latter were detected by EPR spectroscopy in the presence of MgCl(2) but not in its absence. Semiquinone EPR spectra change with quinone/GSH mol ratio, suggesting covalent binding of GSH to the quinones. Quinone-GSH covalent adducts were isolated and identified by ESI-MS. These orthoquinones also react with nucleophilic groups from BSA to bind covalently under anaerobic conditions. BSA thiol consumption and covalent binding by these quinones are enhanced by MgCl(2). Complex formation between the parent quinones and Mg(+2) was also observed. Density functional calculations predict the observed blue-shifts in the absorption spectra peaks and large decreases in the partial negative charge of electrophilic carbons at the quinone ring when the quinones are complexed to Mg(+2). These observations suggest a possible role of Mg(+2) chelation by these quinones in increasing TOPO II thiol and/or amino/imino reactivity with these orthoquinones.
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PMID:Thiols oxidation and covalent binding of BSA by cyclolignanic quinones are enhanced by the magnesium cation. 1832 25

7-Ethyl-10-hydroxy-camptothecin (SN-38), an efficient topoisomerase inhibitor, is the biological metabolite of irinotecan used as the first-line chemotherapy drug for colon cancer. However, the hydrophobicity and instability of SN-38 limit its further clinical application. In this study, to improve water dispersity and the anti-tumor efficiency of SN-38, a prodrug, SN-38-BOC, that could efficiently transform to active SN-38 in the acidic tumor microenvironment was synthesized and encapsulated into MPEG-P(CL-ran-TMC) micelles (SN-38-BOC micelles). SN-38-BOC micelles could accumulate in tumors due to the EPR effect and exhibit a sustained release behavior, which was rapidly transformed to active SN-38 by the acidic environment of tumor tissues (pH 5.5-6.8), thus achieving efficient anti-tumor activity. Compared with the free SN-38-BOC group, enhanced cytotoxicity and apoptotic induction were obtained from the SN-38-BOC micelle-treated group in both HCT116 and CT26 cells. In addition, SN-38-BOC micelles showed more effective anti-angiogenesis than free SN-38-BOC in a transgenic zebrafish model. Furthermore, SN-38-BOC micelles exhibited stronger inhibition of tumor growth in both HCT116 and CT26 subcutaneous xenograft tumor models. Histological analysis revealed that SN-38-BOC micelles showed a more effective anti-tumor activity than the free drug by inducing more apoptosis, inhibiting angiogenesis, and suppressing proliferation. Thus, the pH-activatable SN-38-BOC micelle could serve as a promising candidate in colorectal tumor therapy.
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PMID:Biodegradable Polymeric Micelle-Mediated Delivery of a pH-Activatable Prodrug of 7-Ethyl-10-Hydroxy-Camptothecin (SN-38) to Enhance Anti-Angiogenesis and Anti-Tumor Activity. 3135 23