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)

Poly(ADP-ribose) polymerase has been generally assumed to be involved in DNA repair. The level of the enzyme in various lung cancer cell lines was examined to determine if it is involved in drug resistance. Among nine cell lines of lung cancer tested, small-cell lung cancer lines, which showed higher sensitivity to cisplatin and etoposide, were unexpectedly found to contain significantly higher poly(ADP-ribose) polymerase activity than five non-small-cell lung cancer cell lines. This activity inversely correlated with IC50 values of lung cancer cell lines to etoposide, an inhibitor of topoisomerase II. The polymerase activity was also examined in several cisplatin-resistant variants of the cell lines. However, no difference was observed between parental and cisplatin-resistant cells. There was no significant relation between poly(ADP-ribose) polymerase activity and IC50 values for cisplatin and carboplatin. Although this enzyme was considered to play some role in the resistance to specific drugs, it might not be a critical factor in cisplatin-induced cytotoxicity.
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PMID:Participation of poly(ADP-ribose) polymerase in the drug sensitivity in human lung cancer cell lines. 131 78

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

Monoclonal antibodies directed against four different polypeptide epitopes on the Mr approximately 94,000 steroid-binding subunit of the rat liver cytosolic glucocorticoid receptor (GcR) were used to probe Western blots of epididymal spermatozoa from rats and mice. Two sperm polypeptides with apparent molecular weights of 94,000 (indistinguishable in size from the liver GcR subunit) and 150,000 reacted with these antibodies. Other polypeptides that are present in a wide variety of somatic cells [lamin-A, -B, and -C; topoisomerase-I; poly(ADP-ribose) polymerase; the 62-kilodalton internal nuclear matrix protein; the nucleolar protein B23; and histone H1] could not be detected in these preparations of spermatozoa, thus appearing to rule out contamination by somatic cells. Rat and mouse pachytene spermatocytes and round spermatids contained much lower amounts of the Mr approximately 94,000 and 150,000 polypeptides. These results suggested that the steroid-binding subunit of the GcR might be accumulated late in spermatogenesis. Consistent with this view, a 6-kilobase mRNA (identical in size to a mRNA detected in mouse somatic cell lines) was detected when Northern blots of mouse round spermatid RNA were probed with a cDNA to the steroid-binding GcR subunit. Although the results described above suggest the presence of GcR in rodent sperm, high affinity binding of glucocorticoids to epididymal sperm could not be detected in a whole cell binding assay. Further analysis revealed that the Mr approximately 90,000 heat shock protein (hsp90), a component reportedly required for high affinity ligand binding to the GcR, was present in early germ cells, but absent from rodent epididymal sperm. These results suggest that the Mr approximately 94,000 steroid-binding subunit of the GcR and an immunologically related Mr approximately 150,000 polypeptide are specifically accumulated during the later stages of rodent spermatogenesis, but are not assembled into receptor complexes capable of binding steroid. In addition, these results support the view that hsp90 is required for high affinity binding of glucocorticoids to the Mr approximately 94,000 GcR subunit in intact cells.
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PMID:Evidence that rodent epididymal sperm contain the Mr approximately 94,000 glucocorticoid receptor but lack the Mr approximately 90,000 heat shock protein. 157 14

MNNG-induced killing of V79 cells has been found to be enhanced on inhibition of topoisomerase II activity by nalidixic acid and poly(ADP-ribose) polymerase synthesis by benzamide. Using these 2 inhibitors in conjunction after MNNG treatment, some overlap in the functions of these 2 enzymes was observed. Nalidixic acid and benzamide were found to suppress the yields of mutations and SCEs induced by MNNG. Benzamide was more effective in suppressing the mutation yield whereas nalidixic acid was more effective in suppressing SCEs. A model based on the relative requirement of topoisomerase and poly(ADP-ribose) for the repair of different types of damage has been proposed to explain the results.
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PMID:Response of V79 cells to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatment: inhibition of poly(ADP-ribose) and topoisomerase activity. 164 62

Mutant V79 Chinese hamster cell lines, deficient in poly(ADP-ribose) polymerase activity, were previously shown to be significantly resistant to etoposide, a topoisomerase II inhibitor, and hypersensitive to camptothecin, a topoisomerase I inhibitor (Chatterjee, S.; Trivedi, D.; Petzold, S.J.; Berler, N.A. Mechanism of epipophyllotoxin-induced cell death in poly(adenosine diphosphate-ribose) synthesis-deficient V79 Chinese hamster cell lines. Cancer Res. 50:2713-2718, 1990 and Chatterjee, S.; Cheng, M.F.; Trivedi, D.; Petzold, S.J.; Berger, N.A. Camptothecin hypersensitivity in poly(adenosine diphosphate-ribose) polymerase-deficient cell lines. Cancer Commun. 1:389-394; 1990). We have now demonstrated hypersensitivity of these mutant cell lines, designated ADPRT 54 and ADPRT 351, to a variety of antitumor agents including melphalan, BCNU, mitomycin, and bleomycin. They are also hypersensitive to UV- and x-irradiation. These mutants, however, are significantly resistant to the topoisomerase II-targeted DNA intercalators, Adriamycin and m-AMSA. Our results strongly suggest that inhibition of poly(ADP-ribose) polymerase could be useful to potentiate the cytotoxicity of a variety of currently available antitumor drugs.
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PMID:Hypersensitivity to clinically useful alkylating agents and radiation in poly(ADP-ribose) polymerase-deficient cell lines. 170 4

Starting with the V79 cell line, two poly(ADP-ribose) polymerase deficient mutants, designated ADPRT 54 and ADPRT 351, had been shown to be hypersensitive to x- and UV-irradiation and to topoisomerase I inhibitors but to be resistant to topoisomerase II inhibitors (Chatterjee, S.; Cheng, M. F.; Berger, N. A. Hypersensitivity to clinically useful alkylating agents and radiation in poly(ADP-ribose) polymerase-deficient cell lines. Cancer Commun. 2:401-407;1990). We now report that these mutants were hypersensitive to a series of different alkylating agents, including alkylsufonates, alkylnitrosoureas, and nitrosoguanidine. In addition, they were hypersensitive to the UV-mimetic agent 4-nitroquinoline-1-oxide. Our findings provide strong evidence that poly(ADP-ribose) polymerase was involved in the repair of alkylating agent induced DNA damage as well as in the damage induced by UV- and x-irradiation and radiomimetic agents. The poly(ADP-ribose) polymerase deficient cell lines showed a marked decrease in the shoulder region of their survival curves, suggesting that poly(ADP-ribose) polymerase was involved in the repair of alkylating agent induced sublethal damage.
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PMID:Alkylating agent hypersensitivity in poly(adenosine diphosphate-ribose) polymerase deficient cell lines. 190 Apr 26

The lamins, an intranuclear class of intermediate filament proteins, are major structural proteins of the nuclear envelope. In the present study, the three abundant mammalian lamins (lamins A, B, and C) were observed to be present in roughly equivalent amounts in the Calu-1, Calu-3, H157, and SK-MES-1 non-small cell lung cancer lines. In the small cell lung cancer lines OH-1, OH-3, NCI-H82, NCI-H209, and NCI-H249, levels of lamin B were similar to those observed in the non-small cell lines, but the levels of lamins A and C were diminished by greater than or equal to 80%. The relationship between lung cancer phenotype and lamin expression was explored further in the NCI-H249 small cell line. Introduction of the v-rasH oncogene into this line gives rise to a cell line (NCI-H249rasH) with many features of large cell carcinoma of the lung (Falco, J. P., Baylin, S. B., Lupu, R., et al. J. Clin. Invest., 85: 1740-1745, 1990). Concomitant with the v-rasH-induced change in phenotype, a greater than 10-fold increase in the amounts of lamins A and C was observed. Levels of the cytoplasmic intermediate filament protein vimentin also increased. In contrast, levels of a variety of nonlamin nuclear polypeptides including topoisomerase I, topoisomerase II, poly(ADP-ribose) polymerase, and the nucleolar protein B23/nucleophosmin did not change. Comparison of polyadenylated RNA from NCI-H249 and NCI-H249rasH cells on Northern blots revealed similar levels of the mRNA for lamin B but higher levels of the mRNAs for lamins A and C in the v-rasH-expressing cell line. These observations provide evidence for differences in nuclear envelope structure in histologically different neoplastic cells derived from the same epithelial cell system and suggest that differences in lamina structure result from phenotype-specific differences in lamin gene expression.
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PMID:Differential expression of nuclear envelope lamins A and C in human lung cancer cell lines. 198 76

Mutant Chinese hamster V79 cells selected for alterations in poly(ADP-ribose) metabolism were shown to be resistant to epipodophyllotoxin (VP-16)-induced cytotoxicity. Cell lines ADPRT 54 and ADPRT 351 have reduced activity of poly(ADP-ribose) polymerase. N2, N3, and N4 cell lines grow in the absence of nicotinamide, with total NAD levels 1.5-3% of those found in parental V79 cells grown in complete medium. When grown in complete medium, the mutant cell lines are 2.3- to 9.6-fold resistant to VP-16-induced cytotoxicity. All of the cell lines respond to VP-16 treatment by formation of protein-cross-linked DNA strand breaks. Upon drug removal, all the cell lines reverse the DNA strand breaks at similar rates. Our studies show a clear dissociation between induction of DNA strand breaks and cytotoxicity. However, there is a good correlation between drug-induced sister chromatid exchanges and cytotoxicity. Thus, N3 cells, with low levels of VP-16-induced sister chromatid exchanges, show reduced levels of cytotoxicity relative to parental V79 cells, despite the fact that both cell lines show similar levels of VP-16-induced protein-cross-linked DNA strand breaks. Additional studies show that the time course of VP-16-induced cytotoxicity correlated better with the time course of sister chromatid exchange formation than with protein-cross-linked DNA strand break formation. These studies provide strong support for the proposal that VP-16-induced cytotoxicity involves the induction of sister chromatid exchanges. Thus, we suggest that drug-induced stabilization of topoisomerase II-DNA complexes stimulates induction of sister chromatid exchanges, which consequently lead to cell death.
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PMID:Mechanism of epipodophyllotoxin-induced cell death in poly(adenosine diphosphate-ribose) synthesis-deficient V79 Chinese hamster cell lines. 232 96

Treatment of human HL-60 or KG1A leukemia cells with the topoisomerase II inhibitor etoposide resulted in extensive DNA degradation. When DNA integrity was analyzed by agarose gel electrophoresis, a nucleosomal ladder became evident 1.5-2 h after addition of etoposide to cells, increased in intensity over 6 h, and persisted at 24 h. Six h after addition of the drug, 94 +/- 4% of the cells excluded trypan blue even though as much as 90% of the DNA had been degraded to oligosomal fragments. Exposure of cells to 10 micrograms/ml (17 microM) etoposide for as little as 45 min was sufficient to induce this DNA damage 4 h later. Preincubation with dinitrophenol abolished the effect of etoposide, suggesting that an energy-requiring step occurred prior to or during the endonucleolytic cleavage. In contrast, the effect of etoposide was not prevented by preincubation of HL-60 cells with the RNA synthesis inhibitor 5,6-dichloro-1-beta-ribofuranosylbenzimidazole or the protein synthesis inhibitors cycloheximide or puromycin. On the contrary, high concentrations of 5,6-dichloro-1-beta-ribofuranosylbenzimidazole, cycloheximide, or puromycin by themselves induced the same endonucleolytic cleavage, as did a variety of diverse cytotoxic agents, including camptothecin (0.1 microM), colcemid (0.1 microgram/ml), cis-platinum (20 microM), methotrexate (1 microM), and 1-beta-D-arabinofuranosylcytosine (3 microM). These results suggest that endonucleolytic DNA damage by a preexisting cellular enzyme occurs soon after treatment of HL-60 cells with any of a variety of cytotoxic agents. The observation that a variety of nuclear proteins [including poly(ADP-ribose) polymerase, lamin B, topoisomerase I, topoisomerase II, and histone H1] are degraded concomitant with the DNA fragmentation calls into question the selectivity of the degradative process for DNA. The implications of these results for (a) current theories which focus upon endonucleolytic damage of DNA as a critical early event during cell death, and (b) use of topoisomerase-directed drugs to map topoisomerase-binding sites in active chromatin are discussed.
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PMID:Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. 279 Aug

Poly(ADP-ribose) is synthesized in response to DNA strand breaks and covalently modifies numerous intracellular proteins. We have proposed that this modification regulates, i.e., inhibits, the activity of these enzymes, e.g., topoisomerases and proteases, which could otherwise cause additional DNA damage or alterations in chromatin structure. Inhibition of poly(ADP-ribose) polymerase by 3-amino-benzamide (3AB) in cells exposed to DNA-damaging agents would, according to this proposal, eliminate the regulatory role of ADP-ribosylation. When Chinese hamster ovary cells are cultured with methyl methanesulfonate (MMS) and 3AB, a synergistic increase in sister chromatid exchange frequency is observed. We investigated the regulatory role of poly(ADP-ribose) polymerase to see if topoisomerases or proteases are involved in this synergistic increase. Cells were exposed to MMS or the intercalating agent 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), 3AB, and either the topoisomerase inhibitor novobiocin or the protease inhibitor antipain. Neither novobiocin nor antipain affected the synergistic response of MMS and 3AB or the additive response of m-AMSA and 3AB. These results suggest that topoisomerases or proteases do not account for the effect of 3AB on sister chromatid exchange frequency after DNA damage.
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PMID:Potentiation of sister chromatid exchange by 3-aminobenzamide is not modulated by topoisomerases or proteases. 301 82


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