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)

Amsacrine and demethylepipodophyllotoxins (etoposide and teniposide) are potent topoisomerase II inhibitors which have optimum activity in different cancers. To investigate whether these differences are due to different activity on cellular oncogenes, drug-induced topoisomerase II cleavage sites were mapped and sequenced in the human c-myc protooncogene. In the presence of purified murine L1210 topoisomerase II, amsacrine induces prominent cleavage in the P2 promoter (site 2499/2502). Footprinting experiments indicate that topoisomerase II binds to the entire promoter region (approximately 20 base pairs on the sides of the P2 site). In the case of teniposide or etoposide, cleavage is more diffuse and markedly less at the P2 site. Mapping of cleavage sites in human small cell lung carcinoma cells (NCI N417) also shows that cleavage in the P2 promoter region is induced preferentially by amsacrine but not by demethylepipodophyllotoxins. Thus, selective gene damage among topoisomerase II inhibitors may contribute to differential anticancer activity.
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PMID:Differential effects of amsacrine and epipodophyllotoxins on topoisomerase II cleavage in the human c-myc protooncogene. 131 59

The two-year survival rate of patients with small cell lung cancer is less than 10%. The major reason for this poor outcome is the development of drug resistance. Panels of small cell lung cancer cell lines have been established, providing models for the study of drug resistance in this tumour. One such model is the doxorubicin-selected H69AR cell line. H69AR displays the typical multidrug resistance phenotype in that it is cross-resistant to anthracyclines, Vinca alkaloids (e.g., vinblastine) and epipodophyllotoxins (e.g., VP-16). However, H69AR cells do not overexpress P-glycoprotein, the membrane drug efflux pump frequently found on multidrug resistant cells. Some alterations in glutathione levels and associated enzyme activities were found but the data do not support the notion that enhanced drug detoxication is involved in H69AR cell resistance. Fewer drug-induced DNA strand breaks, reduced levels of topoisomerase II, and reduced formation of drug-stabilized DNA/topoisomerase II complexes were observed in H69AR cells. These data implicate topoisomerase II in the resistance phenotype of H69AR cells, but cannot explain H69AR cell resistance to the Vinca alkaloids, which do not have topoisomerase II as a target. Monoclonal antibodies against antigens overexpressed on H69AR cells have been derived and four have been characterized. Immunoscreening of an H69AR cDNA expression library has allowed the identification of one of these antigens as p36 (annexin II), a Ca2+/phospholipid binding protein. Chemosensitizers and novel xenobiotics have been examined for their ability to circumvent the drug resistance of H69AR cells. The limited success of these investigations suggests that innovative approaches may be required. In conclusion, the data obtained with H69AR and other models of small cell lung cancer indicate that multiple mechanisms contribute to drug resistance in this disease.
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PMID:The 1991 Merck Frosst Award. Multidrug resistance in small cell lung cancer. 131 57

Drosophila melanogaster topoisomerase II is capable of joining phi X174 (+) strand DNA that it has cleaved to duplex oligonucleotide acceptor molecules by an intermolecular ligation reaction (Gale, K. C. and Osheroff, N. (1990) Biochemistry 29, 9538-9545). In order to investigate potential mechanisms for topoisomerase II-mediated DNA recombination, this intrinsic enzyme activity was further characterized. Intermolecular DNA ligation proceeded in a time-dependent fashion and was concentration-dependent with respect to oligonucleotide. The covalent linkage between phi X174 (+) strand DNA and acceptor molecules was confirmed by Southern analysis and alkaline gel electrophoresis. Topoisomerase II-mediated intermolecular DNA ligation required the oligonucleotide to contain a 3'-OH terminus. Moreover, the reaction was dependent on the presence of a divalent cation, was inhibited by salt, and was not affected by the presence of ATP. The enzyme was capable of ligating phi X174 (+) strand DNA to double-stranded oligonucleotides that contained 5'-overhang, 3'-overhand, or blunt ends. Single-stranded, nicked, or gapped oligonucleotides also could be used as acceptor molecules. These results demonstrate that the type II enzyme has an intrinsic ability to mediate illegitimate DNA recombination in vitro and suggests possible roles for topoisomerase II in nucleic acid recombination in vivo.
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PMID:Intrinsic intermolecular DNA ligation activity of eukaryotic topoisomerase II. Potential roles in recombination. 131 9

The effects of selected DNA repair inhibitors on the frequency of human cytomegalovirus (HCMV)-induced chromosome aberrations were evaluated in human peripheral blood lymphocytes (PBLs). Treatment of HCMV-infected PBLs with camptothecin (0.05 to 0.3 micrograms/ml), an inhibitor of topoisomerase I, for 30 hr resulted in a significant (P less than 0.01) synergistic enhancement of the frequency of HCMV-induced chromosome damage. On the other hand, a significant increase in the frequency of chromosome damage was not noted for infected PBLs treated with either 3-aminobenzamide (3-AB; 3 to 30 micrograms/ml), an inhibitor of poly(ADP-ribose) polymerase, or novobiocin (3 to 30 micrograms/ml), an inhibitor of topoisomerase II or excision repair processes, for 30 hr. Chromatid-type breaks and exchanges were the predominant type of chromosome aberrations observed in the HCMV-infected cells treated with camptothecin, suggesting that HCMV infection is associated with the induction of single-strand DNA breaks. Furthermore, these findings suggest that HCMV infection does not inflict direct DNA damage which is repaired through 3-AB- or novobiocin-sensitive pathways.
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PMID:Modulation of the frequency of human cytomegalovirus-induced chromosome aberrations by camptothecin. 131 15

The effect of mammalian and bacterial topoisomerase II inhibitors on Leishmania promastigotes was studied in vitro. Parasites were incubated with drugs, and cytotoxicity was assessed on the basis of the loss of flagellar motility and cell lysis after 48 h. 9-Aminoacridines, which are structurally related to the known antileishmanial compounds quinacrine and chlorpromazine, showed activity against the parasite at concentrations in the range of 10 to 20 microM. Adriamycin showed far less activity, while etoposide and several quinolones were inactive at 100-microM concentrations. These results demonstrate that a particular structural class of compounds is cytotoxic to Leishmania species. The unique structure-activity relationship discovered suggests that leishmanial topoisomerase II could be a useful target for chemotherapy.
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PMID:Cytotoxicity of acridine compounds for Leishmania promastigotes in vitro. 131 84

In the past five years, several groups have reported acute myeloid leukemia (AML) often monoblastic, as a complication of chemotherapy regimens including the epipodophyllotoxins, etoposide and teniposide. This syndrome is distinct clinically, pathologically and cytogenetically from classical therapy-related myelodysplasia and AML. There is also evidence that other topoisomerase II inhibitors, such as the intercalating agents (including doxorubicin, mitoxantrone, and actinomycin D) may be leukemogenic. Furthermore, there may be further interactions from concomitant topoisomerase II inhibitors and alkylating agents. Topoisomerase II inhibitors induce DNA cleavage and other chromosomal aberrations, including sister chromatid exchanges. These clastogenic abnormalities are not fully understood, and may be specific for each cytotoxic agent. Work is in progress to clone breakpoints such as the t(9;11) and t(8;21) and the use of the resultant DNA probes will enhance our understanding of the leukemogenic process. Given the potential diversity in patients with secondary leukemia, cytogenetic studies should be mandatory for both enhancing our knowledge base and guiding treatment in individual patients. Clinicians must also be wary of the leukemogenic potential of 'dose-intense' regimens including agents such as etoposide and doxorubicin.
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PMID:Therapy-related acute myeloid leukemia secondary to inhibitors of topoisomerase II: from the bedside to the target genes. 128 Apr 61

Three camptothecin-resistant sublines (V79r, IRS-1r and IRS-2r) of V79 cells and their irradiation-sensitive mutants, IRS-1 and IRS-2, were developed by stepwise, continuous exposure to camptothecin (CPT). The degree of resistance varied among these cells. Based on the biochemical characterizations of these resistant cell lines, the mechanisms which could be responsible for the resistance to CPT were proposed to be: (a) a decrease in the intracellular accumulation of CPT with or without alteration of DNA topoisomerase I, (b) a decrease in the amount of DNA topoisomerase I, or (c) a decrease in the sensitivity of DNA topoisomerase I to CPT. The resistant cells which exhibited down-regulation of DNA topoisomerase I were collaterally sensitive to etoposide (VP-16) and its analogue, 4'-demethy-4 beta-(4"-fluoroanilino)-4-desoxypodophyllotoxin, despite the fact that there were equal amounts of DNA topoisomerase II in the parental and in the resistant cell lines. Alternating the usage of CPT and VP-16 for the treatment of cancer is indicated.
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PMID:Characterization of camptothecin-resistant Chinese hamster lung cells. 131 61

The antitumor drug fostriecin (phosphotrienin, FST) has been reported to exert its cytostatic and cytotoxic effects via inhibition of DNA topoisomerase II. The sensitivity of human lymphocytic leukemic MOLT-4 and promyelocytic HL-60 leukemic cells to a wide range of FST concentrations was studied by analyzing the cell cycle-specific effects and changes in nuclear chromatin induced by this inhibitor. The latter was evaluated by assaying the sensitivity of DNA in situ to acid-induced denaturation cytofluorimetrically, with the use of the metachromatic fluorochrome acridine orange (AO), which differentially stains double-stranded and denatured DNA. The cytostatic effects were observed soon after addition of FST (at concentrations of 1-30 microM for MOLT-4 cultures and 1-5 microM for HL-60 cultures) as a perturbation of cell progression through S and G2 phases of the cell cycle. Cell progression through the cycle was halted at greater than 30 microM FST in MOLT-4 cultures and at greater than 5 microM in HL-60 cultures; the effect was instantaneous and affected all phases of the cycle, so that no changes in the cell cycle distribution were apparent with increasing length of exposure to the drug. Instead, at these high FST concentrations, immediate cytotoxic effects became evident, manifesting either as cell apoptosis or necrosis. Apoptosis was observed only in the case of HL-60 cells, at FST concentrations of 5-100 microM, and was characterized by markedly increased sensitivity of DNA to denaturation combined with a decrease in overall DNA stainability, either with the DNA-specific dye DAPI or with AO, indicative of the activation of endogenous nucleases. Necrotic cell death was observed at FST concentrations of 1 mM and at greater than 30 microM for HL-60 and MOLT-4 cells, respectively: in both cases the overall DNA stainability, with either DAPI or AO, was unchanged compared to the control, but their DNA was very sensitive to denaturation. Interestingly, DNA in G2 and late S phase MOLT-4 cells, which were undergoing necrotic death, was much more sensitive to denaturation than was DNA in G1 cells of this lineage. The data indicate that chromatin changes induced by DNA topoisomerase II inhibitors in cells that undergo apoptotic or necrotic death can be conveniently monitored by the assay of DNA in situ sensitivity to denaturation.
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PMID:Changes in nuclear chromatin related to apoptosis or necrosis induced by the DNA topoisomerase II inhibitor fostriecin in MOLT-4 and HL-60 cells are revealed by altered DNA sensitivity to denaturation. 131 46

Centrifugal elutriation was used to obtain synchronized cell populations in various cell cycle phases without prior growth-perturbing manipulation. Treatment of these subpopulations with novobiocin (NOVO), a putative inhibitor of the mammalian topoisomerase II enzyme, revealed a unique cell cycle phase-dependent cytotoxicity for this agent. At a concentration of 0.3 mM, NOVO was cytotoxic only to a specific cell subpopulation in the G1-S phase boundary. Cells in other cell cycle phases were completely unaffected. Additionally, S and G2M phase cells progressed through the cell cycle relatively unaffected by NOVO but were blocked at the G1-S boundary. NOVO treatment protected tumor cells from Adriamycin (ADR)-induced lethality but sensitized them to the toxic action of 4-hydroperoxycyclophosphamide, and alkylating agent. These opposing effects of NOVO were demonstrated in all of the four tumor cell lines investigated: A431 and HEp3 (derived from human squamous cell carcinomas); MLS, a human ovarian cancer cell line; and a Chinese hamster ovary cell line. The degree of protection against ADR was the greatest for S-phase cells, intermediate for cells in early G1 and M phases, and the least for late G1 cells. This cell cycle-dependent protection by NOVO, which is identical to the cell cycle-dependent cytotoxicity of ADR, was consistent with the idea that NOVO interfered directly with the cell-killing mechanism of ADR. In contrast, even though the cytotoxic activity of 4-hydroperoxycyclophosphamide exhibited significant cell cycle dependency, NOVO enhanced 4-hydroperoxycyclophosphamide lethality equally for all cell cycle phases.
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PMID:Modulation of the cell cycle-dependent cytotoxicity of adriamycin and 4-hydroperoxycyclophosphamide by novobiocin, an inhibitor of mammalian topoisomerase II. 131 22

The quinolone CP-115,953 (6,8-difluoro-7-(4-hydroxyphenyl)-1-cyclopropyl-4- quinolone-3-carboxylic acid) represents a novel mechanistic class of drugs with potent activity against eukaryotic topoisomerase II in vitro (Robinson, M. J., Martin, B. A., Gootz, T. D., McGuirk, P. R., Moynihan, M., Sutcliffe, J. A., and Osheroff, N. (1991) J. Biol. Chem. 266, 14585-14592). Although the quinolone is highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Therefore, yeast was used as a model system to determine whether topoisomerase II is the primary target responsible for the in vivo effects of CP-115,953. The quinolone was equipotent to etoposide at enhancing DNA breakage mediated by the Saccharomyces cerevisiae type II enzyme. Moreover, at concentrations as low as 5 microM, CP-115,953 was cytotoxic to yeast cells that carried wild type topoisomerase II (TOP2+). By utilizing a yeast strain that expressed the top2-1 temperature-sensitive mutant, the effect of topoisomerase II activity on quinolone cytotoxicity was determined. At the permissive temperature of 25 degrees C, cells were highly sensitive to CP-115,953. However, at the semipermissive temperature of 30 degrees C (where in vivo enzyme activity is present but is greatly diminished), cells displayed only marginal sensitivity to the quinolone at concentrations as high as 50 microM. These results strongly suggest that topoisomerase II is the primary physiological target responsible for quinolone cytotoxicity and that CP-115,953 kills cells by converting the type II enzyme into a cellular poison.
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PMID:Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast. 132 12


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