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)

Cell lines deficient in poly(ADP-ribose) synthesis due to enzyme deficiency (ADPRT54 and ADPRT351) or substrate deficiency (N2, N3, and N4) are resistant to topoisomerase II-directed agents, including etoposide (VP-16), N-[4-(9-acridinylamino)-3-methoxyphenyl]methanesulfonamide, and Adriamycin, relative to the effect of these agents on parental V79 Chinese hamster cells. Resistance is stable in the ADPRT54 and ADPRT351 cell lines, whereas resistance in the N2, N3, and N4 cell lines occurs when the cells are grown in nicotinamide-deficient medium to produce a state of NAD deficiency. However, sensitivity to VP-16 reverts to normal when cellular NAD levels return to control levels during growth in nicotinamide-containing complete medium. Poly(ADP-ribose) polymerase-deficient cell lines show constitutively increased levels of a protein at M(r) 78,000 on Coomassie blue-stained, sodium dodecyl sulfate-polyacrylamide gels that was subsequently confirmed with monoclonal antibodies to be M(r) 78,000 glucose-regulated stress protein (GRP78). Similarly, N2, N3, and N4 cells show induction of GRP78 under nicotinamide-deficient conditions. Induction of GRP78 is associated with elevated levels of GRP78 mRNA and appears to be regulated at the transcriptional level. When N3 cells with deficiency of poly(ADP-ribose) synthesis due to NAD deficiency are shifted to complete, nicotinamide-containing medium, they restore their NAD content, undergo a decrease in GRP78 levels, and regain sensitivity to VP-16. When V79 cells are shifted to nicotinamide-deficient medium they undergo a reduction in NAD content, followed by a progressive elevation in GRP78 levels, and they subsequently become increasingly resistant to VP-16. These studies demonstrate a clear association between deficiency of the NAD-poly(ADP-ribose) synthesis system, induction of GRP78 synthesis, and resistance to VP-16.
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PMID:Induction of M(r) 78,000 glucose-regulated stress protein in poly(adenosine diphosphate-ribose) polymerase- and nicotinamide adenine dinucleotide-deficient V79 cell lines and its relation to resistance to the topoisomerase II inhibitor etoposide. 804 89

The Adriamycin-resistant small cell lung carcinoma cell line, GLC4/ADR, showed large differences in cross-resistance to drugs such as Adriamycin, etoposide (VP-16), teniposide (VM-26), 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA), and mitoxantrone, which stimulate the formation of topoisomerase (Topo) II-DNA complexes. GLC4/ADR cells demonstrated a reduced Topo II activity and no detectable levels of the P-glycoprotein compared to the parental GLC4 cells (S. De Jong et al., Cancer Res., 50: 304-309, 1990). In the present study, the resistance to VM-26 (59.5-fold) and to m-AMSA (4-fold) of GLC4/ADR after a 1-h incubation was further analyzed. Using the K(+)-sodium dodecyl sulfate precipitation assay, a reduction in VM-26- and m-AMSA-induced cleavable complex formation was found in GLC4/ADR cells compared to GLC4 cells that was related to the degree of resistance to each drug. Cellular accumulation of the VM-26 analogues VP-16 was 3- to 8-fold less and the accumulation of m-AMSA 1- to 2-fold less in GLC4/ADR cells than in the parental cells. Following the removal of VM-26, the cleavable complexes in GLC4/ADR cells disappeared at least 2-fold faster than in GLC4 cells, while the efflux of VP-16 was also enhanced in the resistant cells. On the contrary, no differences in cleavable complex disappearance or drug efflux between these cell lines were observed with m-AMSA. Efflux of both drugs, however, occurred at a much higher rate than cleavable complex disappearance. Using isolated nuclei, a reduction in cleavable complexes in GLC4/ADR was still observed with VM-26 as well as m-AMSA compared to GLC4. The resistant nuclei and nuclear extracts showed a 3-fold decrease in M(r) 170,000 Topo II by immunoblotting. No differences in cleavable complex formation were found between nuclear extracts of both cell lines, when the Topo II activities were equalized. These findings suggest that the cross-resistance to m-AMSA is due to a decreased amount of Topo II and decreased drug accumulation, while in addition to these mechanisms an increased rate of cleavable complex disappearance is involved in the cross-resistance to VM-26 of the GLC4/ADR cell line.
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PMID:Topoisomerase II as a target of VM-26 and 4'-(9-acridinylamino)methanesulfon-m-aniside in atypical multidrug resistant human small cell lung carcinoma cells. 838 51

Irinotecan (CPT-11) has been reported to be cytotoxic to tumor cells through its inhibitory activity on type I DNA topoisomerase. CPT-11 has also been shown to have several unique biological activities apart from direct cytotoxicity. We investigated the ability of CPT-11 to induce tumor necrosis factor (TNF) production. Human peripheral blood mononuclear cells (MNCs) were incubated with LPS, CPT-11, or with vinblastin sulfate as a control. The priming effect of CPT-11 on endogenous production of TNF was examined by injecting the drug intravenously into mice, followed 3 hours by the injection of OK432. At a dose of 200-400 micrograms/kg, CPT-11 showed a significant priming effect. A significant amount of TNF was released when MNCs were incubated with 100-300 microM of CPT-11 for more than 4 hours, but not with vinblastin sulfate, indicating a triggering effect of TNF production on MNCs in vitro. These effects may be advantageous in cancer therapy.
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PMID:Induction of tumor necrosis factor by a camptothecin derivative, irinotecan, in mice and human mononuclear cells. 891 43

Temperature-sensitive mutations (ts10, ts18, and ts39) of the vaccinia virus RNA helicase nucleoside triphosphate phosphohydrolase II (NPH-II) result in the production of noninfectious progeny virions at the restrictive temperature. The noninfectious mutant particles contain the wild-type complement of virion core and envelope polypeptides, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The results of Western blot (immunoblot) analysis indicate that these particles lack NPH-II, whereas other enzymatic components of the virus core are present. These components include the following: DNA-dependent RNA polymerase subunits rpo147, rpo132, rpo94, rpo35, rpo30, rpo22, and rpo18; early transcription initiation factor subunits A8 and D6; mRNA capping enzyme subunits D1 and D12; RNA cap 2'-O-methyltransferase; A18 DNA helicase; DNA-dependent ATPase NPH-I; and DNA topoisomerase. Although RNA polymerase is encapsidated by the mutant viruses, mRNA synthesis in vitro by permeabilized mutant virions is only 5 to 20% that of the wild-type virus, as judged by nucleoside monophosphate incorporation into acid-insoluble material. Moreover, the transcripts synthesized by the mutant particles are longer than normal and remain virion associated. Transcription initiation by mutant virions occurs accurately at an endogenous genomic promoter, albeit at reduced levels (1 to 7%) compared with that of wild-type virions. In contrast, extracts of the mutant virions catalyze the wild-type level of transcription from an exogenous template containing an early promoter. We conclude that NPH-II is required for early mRNA synthesis uniquely in the context of the virus particle. Possible roles in transcription termination and RNA transport are discussed.
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PMID:Vaccinia virions lacking the RNA helicase nucleoside triphosphate phosphohydrolase II are defective in early transcription. 897 Sep 79

New saintopin-type antibiotics (e.g., saintopin, saintopin E, UCE1022, UCE6) with a naphthacene-dione structure have been discovered through our mechanistically oriented screening using purified mammalian DNA topoisomerases. Saintopin is a dual inducer of topoisomerase I- and topoisomerase II-mediated DNA cleavages in a cell-free system using purified enzymes, whereas others induced topoisomerase I- but not topoisomerase II-mediated DNA cleavage. The order of topoisomerase I-mediated DNA cleavage activity at lower concentrations (<1 microM) was UCE6 > saintopin > saintopin E > UCE1022. The DNA cleavage-intensity patterns induced by these antibiotics with topoisomerase I were identical, indicating that saintopin-type antibiotics have a similar DNA sequence selectivity in stabilization of the cleavable complex with topoisomerase I. Increases in protein/DNA complexes were observed in saintopin-type antibiotic-treated HeLa S3 cells using the potassium/sodium dodecyl sulfate precipitation method. Brief heating of these drugs-treated cells at 65 degrees for 10 min resulted in a rapid reduction in the number of protein/DNA complexes. Immunoblot analysis using antibody against human topoisomerase I or II revealed that the protein linked to DNA in saintopin-type antibiotic-treated cells is most likely topoisomerase I. These results suggest that saintopin-type antibiotics interfere with topoisomerase I in cells by trapping reversible topoisomerase I/DNA cleavable complexes. The formation of topoisomerase I/DNA complexes by saintopin-type antibiotics correlates well with their growth-inhibitory activities, suggesting that topoisomerase I can be the principal target of these antibiotics.
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PMID:Correlation between the formation of cleavable complex with topoisomerase I and growth-inhibitory activity for saintopin-type antibiotics. 920 32

DACA [N-[2-(dimethylamino)ethyl]acridine-4-carboxamide], an acridine derivative that is highly active against solid tumours in mice, is currently in clinical trial. The ability of DACA to overcome "atypical" (topoisomerase II-mediated) multidrug resistance has been hypothesised to stem from its dual topoisomerase I/II specificity. We investigated the topoisomerase specificity of DACA and its 7-chloro derivative (C1-DACA) using camptothecin and amsacrine as control compounds. In cell-free assays employing supercoiled plasmid DNA, C1-DACA at 5 microM induced topoisomerase I-mediated DNA breakage, indicating cleavable complex formation (poisoning), and at 10 microM it inhibited relaxation of DNA, consistent with suppression (self-inhibition) of poisoning. In this assay, DACA provided no evidence of poisoning of this enzyme but inhibited its function at concentrations above 10 microM. In DNA cleavage assays utilising purified topoisomerase II, DACA induced breakage of supercoiled plasmid DNA at 5 microM whereas C1-DACA showed very weak poisoning at 1 microM and inhibition at 5 microM. Under conditions required for the assay of DNA relaxation, C1-DACA, but not DACA, inhibited topoisomerase II action at 5 microM. The actions of DACA and C1-DACA could also be distinguished by their ability to form DNA-protein cross-links in H460 human lung carcinoma cells as measured by precipitation of DNA-protein complexes with sodium dodecyl sulfate and potassium chloride. Both drugs stimulated the formation of complexes at low concentrations but inhibited formation at high concentrations. In survival assays with H460 cells, both drugs demonstrated biphasic responses with self-inhibition of cytotoxicity at intermediate drug concentrations. It was concluded that although both drugs have dual topoisomerase I/II specificity, DACA preferentially poisons topoisomerase II and C1-DACA preferentially poisons topoisomerase I. In addition, drug-induced inhibition of topoisomerase action at higher drug concentrations may mask poisoning in the cell-free assays as well as masking cytotoxicity in cultured cells. A model in which drug binding occludes topoisomerase-binding sites on the DNA can explain this self-inhibition of cytotoxic action.
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PMID:Mechanism of cytotoxicity of N-[2-(dimethylamino)ethyl] acridine-4-carboxamide and of its 7-chloro derivative: the roles of topoisomerases I and II. 1007 81

Increased levels of DNA-protein cross-links (DNAPC) have been observed in vitro and in vivo following treatment with a number of chemotherapeutic alkylating agents and topoisomerase II inhibitors, that is, agents that have also been associated with the development of bone marrow depression and acute myelogenous leukemia. The current studies were undertaken to examine the effect of benzene, a bone marrow toxin and human leukemogen, on DNAPC levels in mouse bone marrow cells. Using a K+/sodium dodecyl sulfate (SDS) precipitation assay for DNAPC determination, the results indicate increased DNA-protein cross-link levels in mouse bone marrow cells at 2 and 4 but not 8 h after a single ip injection of 440 mg/kg benzene. Following the administration of multiple hematotoxic benzene doses (440 or 880 mg/kg, 2x/d for 2 d), increases in DNA-protein cross-link levels were either slight or not present. These results suggest that DNAPC induced by benzene are neither cumulative nor persistent lesions. The toxicity of benzene is mediated by a number of number of ring-hydroxylated and ring-opened compounds; therefore the present studies also examined DNAPC levels in mice administered trans,trans-muconaldehyde (MUC), a ring-opened hematotoxic and genotoxic metabolite of benzene. No marked increases in DNAPC levels were observed in CD- mouse bone marrow cells 1-12 h following a single ip injection of 3 mg/kg muconaldehyde. It is possible that multiple doses of MUC are required to induce elevated DNAPC levels in bone marrow cells of mice, since multiple doses are required for MUC-induced hematotoxicity. Other reactive metabolites and/or an interaction of reactive intermediates may also be involved in DNAPC induced by benzene.
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PMID:DNA-protein cross-link levels in bone marrow cells of mice treated with benzene or trans,trans-muconaldehyde. 1009 61

The purpose of these studies was to determine whether interferon-alpha (IFN-alpha) could enhance the sensitivity of human osteosarcoma cells to the cytotoxic actions of etoposide (VP-16). Cytostasis was determined using a [3H]thymidine incorporation assay, whereas cytotoxicity was quantified by a colony-formation assay. Low concentrations (0.1-5 U/ml) of IFN-alpha enhanced the cytostatic activity of VP-16 against MG-63, SAOS-2, and TE-85 osteosarcoma cells. The cytostatic activity of 1 microM VP-16 rose from 11% to 64%, 9% to 31%, and 10% to 71%, respectively, in the three cell lines when IFN-alpha was present. Survival fraction was also decreased when the osteosarcoma cells were treated with VP-16 + IFN-alpha as compared to either agent alone. The interaction between these two agents was determined to be synergistic rather than additive by interaction index analysis. Similar effects on cytostasis and cytotoxicity were observed when IFN-alpha was combined with Adriamycin but not cisplatin, actinomycin D, vinblastine, or amsacrine. VP-16 uptake was enhanced 12-fold in the presence of IFN-alpha, but this did not appear to translate into an increase in topoisomerase-II (topo-II)-DNA complex formation as quantified by the sodium dodecyl sulfate-KCl precipitation assay. We also could not detect alterations in topo-II expression, topo-II protein production, or cell cycle kinetics that have been shown to correlate with increased VP-16 cell sensitivity. Therefore, at this time the mechanism of enhanced cell sensitivity to the combination treatment remains unclear.
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PMID:Interferon-alpha enhances the sensitivity of human osteosarcoma cells to etoposide. 1043 62

We have previously purified an extracellular polysaccharide, D-galactan sulfate associated with L(+)-lactic acid, produced from a marine microalga Dinoflagellate Gymnodinium sp. A3 (GA3). The GA3 polysaccharide, irrespective of presence or absence of lactic acid, exhibited significant cytotoxicity, which is based on an induction of apoptotic cell death, toward human myeloid leukemia K562 cells. Furthermore, we found that the GA3 polysaccharide with or without lactic acid possesses an inhibitory effect on topoisomerase-I (topo-I). The potent cytotoxic effect of GA3 polysaccharide may result from its inhibitory effect on topo-I, because the topo-I inhibition is known to trigger apoptotic cell death.
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PMID:Induction of apoptosis and inhibition of DNA topoisomerase-I in K-562 cells by a marine microalgal polysaccharide. 1240 77

Topoisomerase IIalpha is a target for many chemotherapeutic agents in clinical use. To define mechanisms of resistance and regions crucial for the function of topoisomerase IIalpha, drug-resistant cell lines have been isolated following exposure to topoisomerase II poisons. Two resistant sublines, T47D-VP and MCF-7-VP, were isolated from human carcinoma cell lines following exposure to 300 or 500 ng / ml etoposide (VP-16). Cytotoxicity studies confirmed resistance to etoposide and other topoisomerase II poisons. KCl-sodium dodecyl sulfate (K-SDS) precipitation assays using intact cells showed reduced DNA-topoisomerase II complex formation following VP-16 or amsacrine (m-AMSA). RNAse protection analysis identified a deletion of 200 base pairs in the topoisomerase IIalpha cDNA of T47D-VP and rising dbl quote, left (low)AA insertion" in the topoisomerase IIalpha cDNA of MCF-7-VP. Reduced topoisomerase IIalpha mRNA and protein levels were observed in both cell lines. It was somewhat surprising to find that nuclear extracts from T47D-VP and MCF-7-VP cells had comparable topoisomerase II activity to that of parental cells. Analysis of the extent of phosphorylation demonstrated that topoisomerase IIalpha from the resistant cells was relatively hypophosphorylated compared to that of parental cells. In these cell lines, hypophosphorylation secondary to loss of a portion of the C-terminal domain of topoisomerase IIalpha mediated the restored activity, despite a fall in topoisomerase IIalpha mRNA and protein, and this resulted in cross resistance to topoisomerase II poisons.
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PMID:Hypophosphorylation of topoisomerase IIalpha in etoposide (VP-16)-resistant human carcinoma cell lines associated with carboxy-terminal truncation. 1147 32


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