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)

In the MCF-7 human breast [correction of beast] adenocarcinoma cell line, acute exposure to 1 muM doxorubicin inhibited cell proliferation by approximately 75%. Analysis of cell cycle distribution indicated that within 24 hr, the G(2)/M fraction increased more than 3-fold and the S-phase population declined by >50%. In addition to growth arrest, there was an approximately 40% reduction in the viable cell population after 72 hr. Gel electrophoretic resolution of low molecular weight DNA immediately after exposure of cells to doxorubicin failed to demonstrate "laddered" oligonucleosomal profiles associated with apoptosis. The absence of intracellular DNA fragments or release of fragmented DNA into the incubation medium was confirmed by spectrofluorophotometry over a 72 hr interval following exposure of cells to 1 muM doxorubicin. In addition, there was no evidence of the morphological features associated with apoptosis during this period. Acute exposure to 1 muM doxorubicin also produced a transient increase in c-myc message expression (within the first hour) followed by a decline to 70% of control levels within 2-4 hr. The reduction in c-myc mRNA levels was concentration dependent and corresponded closely with growth arrest (as well as with inhibition of DNA synthesis). These findings (as well as similar reports demonstrating a correspondence between reduced c-myc expression and growth inhibition by VM-26 and m-AMSA in MCF-7 cells) suggest that the down-regulation of c-myc expression may reflect perturbations in regulatory processes contributing to growth arrest in MCF-7 cells exposed to topoisomerase II inhibitors.
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PMID:Growth arrest and non-apoptotic cell death associated with the suppression of c-myc expression in MCF-7 breast tumor cells following acute exposure to doxorubicin. 865 43

The examination of topoisomerase II alpha content by Western blot analysis or topoisomerase II catalytic activity by decatenation of kDNA requires a large number of cells, but it is difficult to collect sufficient cells for these biochemical analyses from lung cancer patients by transbronchial brushing or aspiration. In this study, we explored the relationship between these biochemical analyses and topoisomerase II immunostaining in cytospin preparations of three lung adenocarcinoma cell lines. The levels of topoisomerase II alpha content were about 8.4 for A549, 2.9 for PC-3 and 1 for RERF-LC-MS, and the levels of topoisomerase II catalytic activity were about 4, 2, and 1, respectively. The percentages of strongly positive cells for topoisomerase II immunostaining were 60.9% for A549, 33.3% for PC-3, and 14.3% for RERF-LC-MS, and these were compatible with the levels of topoisomerase II alpha content or topoisomerase II catalytic activity. Our results indicate that topoisomerase II immunostaining can be utilized in place of biochemical analysis.
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PMID:Quantitative immunocytochemical assays of topoisomerase II in lung adenocarcinoma cell lines. Correlation to topoisomerase II alpha content and topoisomerase II catalytic activity. 869 54

A series of mitomycin C (MMC) analogues, namely cyclopentanthraquinone derivatives, were synthesized via Diels-Alder cyclization of naphthoquinone with 1-vinylcyclopent-1-enes. These new compounds are planar structures, like MMC, and bear an aziridine ring and a methyl carbamate side chain. After bioreduction, they are anticipated to be capable of intercalating into double-stranded DNA and bind covalently. Structure-activity relationships were studied. Of these compounds, 2,3-aziridino-4-[[(methylamino)carbonyl]methyl] cyclopent[alpha]anthracene-6,11-dione (4) was shown to have inhibitory activity against several leukemic and solid tumor cell lines. Mice (BDF1) bearing Lewis lung adenocarcinoma were treated with 4 and MMC (i.p., QD x 5). At a dose of 30.0 mg/kg, compound 4 was as effective as MMC (0.8 mg/kg). Compound 4 appears to be less toxic than MMC. DNA unwinding assay indicated that 4 is able to intercalate into DNA double strands and is also a topoisomerase II inhibitor.
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PMID:Cyclopent[a]anthraquinones as DNA intercalating agents with covalent bond formation potential: synthesis and biological activity. 870 11

We have established a cisplatin resistant subline, MKN/CDDP, from the MKN-45 human stomach adenocarcinoma cell line. MKN/CDDP was 10.7 fold more resistant to cisplatin, 5.4 fold resistant to carboplatin, 2.7 fold resistant to 5-fluorouracil and only 1.4 fold resistant to adriamycin. To investigate the mechanism of the cisplatin resistance in the MKN/CDDP subline, we performed the biochemical characterization of MKN-45 and MKN/CDDP. MKN/CDDP cells showed no induction in p-glycoprotein and topoisomerase II. The level of glutathione S-transferase-pi was higher in MKN/CDDP than the parent line, but a similar level of glutathione S-transferase-L isoform was observed. Superoxide dismutase activity was 1.67 fold higher in the MKN/CDDP subline than the parent line, but 60 kDa catalase was much lower in the MKN/CDDP subline. In addition to those changes. MKN/CDDP was not able to attach to the culture dish, which is probably due to the lack of fibronectin association on the cell surface. The MKN/CDDP subline revealed a variety of biochemical changes which are related to drug inactivation and to cell substratum adhesion. The significance of each modification in the development of the cisplatin resistance will be evaluated in future studies.
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PMID:Biochemical characterization of cisplatin-resistance in MKN-45 human stomach adenocarcinoma cell line. 891 23

Camptothecin (CPT), an alkaloid isolated from the stem wood and bark of Camptotheca acuminata native to China, was discovered in the early 60's after a systematic screening of natural products by the National Cancer Institute (NCI). This new anticancer agent displays an unique mechanism of action as it inhibits intranuclear enzyme topoisomerase 1, involved in DNA replication. CPT is poorly water soluble and causes severe and unpredictable toxicities such as haemorrhagic cystitis and diarrhea; for therefore reason, a number of analogues have been synthetized in a attempt to define the features of the molecule that are essential for cytotoxicity and to produce derivatives with increased solubility. Clinical trials of several soluble molecules are in progress in the different countries: irinotecan, topotecan, 9-AC. Encouraging results are observed against solid tumors. Irinotecan was recently commercialized in France. It is a prodrug; the active metabolite SN-38 showed a good activity in metastatic colorectal adenocarcinoma; the limiting toxicities are myelotoxicity and essentially late diarrhea. However, new studies are needed for state precisely the optimal schedule of administration and association with other chemotherapeutic agents.
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PMID:[Camptothecin and derivatives: a new class of antitumor agents]. 896 50

Aclarubicin and doxorubicin are DNA binding anthracycline antibiotics of related chemical structure but differing cytotoxic action. Although doxorubicin mediates its cytotoxicity by poisoning the enzyme topoisomerase II, aclarubicin has been hypothesized to inhibit the catalytic action of topoisomerase II. We show here that aclarubicin, in contrast to doxorubicin, is highly effective in inhibiting the action of topoisomerase I. Aclarubicin not only inhibits this enzyme in a cell-free assay but also markedly inhibits DNA-protein cross-linking in H460 human lung adenocarcinoma cells as measured by the K(+)-SDS precipitation technique. It also displaces topoisomerase I from DNA as measured by Western blotting. Aclarubicin reverses the cytotoxicity of both amsacrine and camptothecin in clonogenic survival assays, consistent with the hypothesis that it is a dual topoisomerase I/II inhibitor. We suggest that the self-inhibition of topoisomerase I in short-term assays may mask the underlying activity of aclarubicin as a topoisomerase I poison. In short-term (1-H) drug exposure assays, aclarubicin kills both exponential and plateau phase cells by a non-cell cycle-selective mechanism apparently not involving G2 phase arrest. This may be a consequence of simultaneous inhibition of topoisomerases I and II.
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PMID:Differential actions of aclarubicin and doxorubicin: the role of topoisomerase I. 950 31

The purpose of this study was to evaluate the ability of hexahydrocolupulone (HHC) to inhibit the growth of tumor cells in vitro and to investigate the potential mechanism(s) involved. HHC was demonstrated to have a wide spectrum of activity against a number of established human tumor cell lines, including some exhibiting drug resistance. Culturing human breast adenocarcinoma (MCF-7) cells in the presence of HHC for 18 hr resulted in a significant decrease in the incorporation of [3H]uridine and [3H]leucine into RNA and protein, respectively. MCF-7 cells cultured in the presence of 1.5 microM HHC for 48 hr demonstrated an increase in the amount of cells detected in G0/G1 and a decrease in the amount of cells detected in S phase. In contrast, treatment with 25 microM HHC decreased the amount of cells detected in G0/G1 and increased the amount of cells detected in S phase. HHC did not cause single-stranded or double-stranded DNA breaks, interfere with topoisomerase function, or generate free radicals. Mice injected intraperitoneally for 5 consecutive days with HHC to a final in vivo blood concentration of 200 microM survived and showed no obvious signs of toxicity. Mass spectroscopy analysis, crystal generation, and structure elucidation confirmed HHC purity. Consequently, all activity observed can be attributed to HHC, a metabolite, and/or a combination thereof. These data suggest that HHC inhibits tumor cell proliferation in vitro via a mechanism(s) that may involve effects on macromolecular synthesis, precursor metabolism/transport, and/or the cell cycle or cell cycle-dependent pathway(s).
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PMID:Hexahydrocolupulone and its antitumor cell proliferation activity in vitro. 951 86

A human stomach-adenocarcinoma cell line (MKN-45) was selected for resistance to Adriamycin by stepwise exposure to increasing concentrations of this agent. The resulting cell line (MKN/ADR) exhibited a high level of cross-resistance to topoisomerase II (topo II)-targeted drugs such as Adriamycin, mitoxantrone, and etoposide but showed no cross-resistance to other chemotherapeutic agents such as cisplatin, carboplatin, 5-fluorouracil, or mitomycin-C. P-glycoprotein encoded by the mdr-1 gene was not overexpressed in the MKN/ADR cell line. The doubling time of the MKN/ADR cell line (2.1 days) increased only slightly as compared with that of the MKN cell line (1.7 days). The patterns of cross-resistance to various chemotherapeutic agents led us to examine the cellular contents of topo II in both the drug-sensitive and the drug-resistant cells. Extractable topo II enzyme activity was 3-fold lower in MKN/ADR cells as compared with the parental MKN cells. Levels of topoisomerase I (topo I) catalytic activity were similar in both wild-type MKN and drug-resistant MKN/ADR cells. Southern-blot analysis of genomic DNA probed with topo IIalpha or IIbeta showed no sign of either gene rearrangement or hypermethylation. Northern-blot analysis revealed that both topo IIalpha and topo IIbeta mRNA transcripts were essentially identical in the MKN and MKN/ADR cells. In contrast, Western-blot analysis revealed an approximately 20-fold lower level of topo IIalpha in drug-resistant cells as compared with drug-sensitive cells, whereas topo IIbeta levels were similar in both lines. Moreover, the amount of in vivo topo IIalpha-DNA covalent complexes formed in the presence of etoposide was also approximately 20-fold lower in drug-resistant cells. No mutation was detected in the promoter region of the topo IIalpha gene in resistant cells as compared with sensitive cells. Thus, low levels of topo IIalpha polypeptide cannot be ascribed to changes in the mRNA levels. Collectively, the data suggest that a quantitative reduction in topo IIalpha may contribute to the resistance of MKN cells to Adriamycin and other topo II-targeted drugs.
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PMID:Reduced activity of topoisomerase II in an Adriamycin-resistant human stomach-adenocarcinoma cell line. 952 30

New members of the cytotoxic indolo[2,3-b]quinoline family, with a methyl groups at N-5, N-6 (their presence stabilizes the positive charge of the molecule), were prepared using a modified Graebe-Ullmann reaction. The derivatives obtained were well soluble in water in a non-pH-dependent manner. They displayed strong antimicrobial activity against Gram-positive bacteria and pathogenic fungi (the MIC values fall between 0.0025 and 0.12 mM) and highly selective cytotoxicity in vitro against different human cancer cell lines: colon adenocarcinoma SW 707, lung carcinoma A 549, transitional cell carcinoma Hu 1703, and oral epidermoid carcinoma KB, in the range of 0.01 to 3.0 microM. They also stimulated the formation of topoisomerase-II-mediated DNA cleavage at concentration from 0.04 to 0.5 microM. These observations correspond well with the ability of the tested compounds to increase the melting temperature of calf thymus DNA (delta Tm being between 13 degrees C and 22 degrees C).
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PMID:Methoxy- and methyl-, methoxy-5,6,11-trimethyl-6H-indolo [2,3-b]quinolinium derivatives as novel cytotoxic agents and DNA topoisomerase II inhibitors. 971 22

Two new series of antitumor agents, 4-aminomethylthioxanthenones (6-50) and 5-aminomethylbenzothiopyranoindazoles (51-61), are described and compared. Nearly all members of both series display excellent in vivo activity versus murine pancreatic adenocarcinoma 03 (Panc03) although there is little to distinguish the two series from each other. In both series there is no discernible relationship between structure and in vivo efficacy. Selected analogues were evaluated in vitro; all were observed to have moderate to strong DNA binding via intercalation. However, varying degrees of in vitro P388 cytotoxicity and topoisomerase II inhibition were seen. In general, those molecules which exhibited strong topoisomerase II inhibition were significantly more cytotoxic than those which did not. In both series, those derivatives (48-50, 60, and 61) having a phenolic hydroxy substitution exhibited the most potent P388 cytotoxicity and topoisomerase II inhibition.
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PMID:Synthesis and antitumor activity of 4-aminomethylthioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives. 973 89


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