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)

Over the past decade, DNA topoisomerase I and II appeared to be the targets of some antitumor agents: CPT-11 and Topotecan derived from Camptothecin which interact with topoisomerase I; Actinomycin D, Adriamycin and Daunorubicin, Elliptinium Acetate, Mitoxantrone, Etoposide and Teniposide, Amsacrine which interact with topoisomerase II. The multiple functions of these enzymes are important as they play a role during replication, transcription, recombination, repair and chromatine organisation. Particularly, they relax torsional constraints which appear when intertwined DNA strands are separated while replication fork or RNA polymerases are moving. To some extent, topoisomerase I and II are structurally and functionally different. Moreover, topoisomerase I is not indispensable for a living cell whereas topoisomerase II is. Drug-topoisomerase interaction which probably leads to antitumoral effect of the compounds studied in this review is not a trivial inhibition of the enzyme but rather a poisoning due to stabilization of cleavable complexes between the enzyme and DNA. These stabilized complexes are likely to induce apoptosis-like programmed cell death, which is characterised by DNA fragmentation. However, it appears that it is the collision of the replication fork with the drug-stabilized cleavable complex that is responsible for the cytotoxicity of the drug: poisoning of topoisomerases by antitumor agents leads to a new concept of "dynamic toxicity". Although they interact with a common target, topoisomerase II poisons have differential effects on macromolecules syntheses, cell cycle and chromosome fragmentation; a few compounds may produce free radicals. Because of these differential effects in addition to quantitative and qualitative variations of stabilized cleavable complexes, in particular DNA sequences on which topoisomerase II is stabilized, these antitumor agents do not resemble each other. Cellular resistance to topoisomerases poisons results of two principal types of alteration: target and/or drug transport modification. Decreased ability to form the cleavable complex in resistant cells may be the consequence of both decreased amount of topoisomerase or altered enzyme. On the other hand, overexpression of membrane P-glycoprotein, which pumps drugs out of the cell by an energy dependent process provokes a decreased accumulation of these drugs. Cross resistances to other drugs are mainly under control of these two different mechanisms of resistance. A complete knowledge of their individual effects and mechanisms of resistance would allow a better clinical use of topoisomerases poisons, especially when administered in combination chemotherapy.
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PMID:[Poisons of DNA topoisomerases I and II]. 808 Oct 34

DNA topoisomerase V is a novel prokaryotic enzyme related to eukaryotic topoisomerase I. The enzyme is a type I DNA topoisomerase and is recognized by polyclonal antibody against human topoisomerase I. We describe its purification from the hyperthermophilic methanogen Methanopyrus kandleri. The enzyme has high activity in crude extracts and is present in at least 1,500 copies/cell. Topoisomerase V migrates as a 110-kDa polypeptide in SDS-polyacrylamide gel electrophoresis and as a 142-kDa globular protein in gel filtration. It is active up to at least 100 degrees C on both positively and negatively supercoiled DNA and is not inhibited by single-stranded DNA. The enzyme works from 1 to 650 mM NaCl and up to 3.1 M potassium glutamate. It acts processively at low ionic strength and distributively at high NaCl or KCl concentration. Magnesium is not required and does not stimulate the enzymatic activity. Under DNA denaturing conditions, topoisomerase V catalyzes an unlinking reaction which results in substantial reduction in the linking number of closed circular DNA. The driving force for this process is DNA melting. Camptothecin is not nearly as good an inhibitor for topoisomerase V as it is for eukaryotic topoisomerase I. The unique occurrence of two major type I topoisomerases (reverse gyrase and topoisomerase V) in M. kandleri may shed new light on the evolution of this family of enzymes and supports the concept of a distant but significant relationship between some hyperthermophilic organisms and eukaryotes.
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PMID:Purification and characterization of DNA topoisomerase V. An enzyme from the hyperthermophilic prokaryote Methanopyrus kandleri that resembles eukaryotic topoisomerase I. 810 68

The mutants irs1, irs2 and irs3 were previously isolated from the Chinese hamster line V79-4 on the basis of their hypersensitivity (2-3-fold) to cell inactivation by X-rays. Here the cross-sensitivities of the irs mutants to an array of chemical mutagens and topoisomerase inhibitors was determined in a differential cytotoxicity assay. Irs2 showed moderate hypersensitivity (2-3-fold) to simple alkylating agents and oxidative mutagens but was most sensitive (8-fold) to the topisomerase I inhibitor camptothecin. In contrast irs2 showed little or no increased sensitivity to four topoisomerase II inhibitors. Irs3 proved to be particularly hypersensitive to DNA crosslinking agents (5-15-fold) such as 1,3-butadiene diepoxide and mitomycin C. Irs1 was hypersensitive (3-fold or greater) to simple alkylating agents, oxidative mutagens and topoisomerase I and II inhibitors and exhibited extreme sensitivity (20-100-fold) to DNA crosslinking agents. The cellular hypersensitivities of irs2 and irs3 were reflected at the level of the chromosome. Camptothecin induced chromosomal aberrations in irs2 consisted almost exclusively of chromatid deletions and exchanges, whilst in irs3 1,3 butadiene diepoxide induced a 50-fold increase in chromatid exchanges compared with V79-4. The nature of irs2's camptothecin hypersensitivity was investigated. Analysis of the protein associated DNA single strand breaks produced by camptothecin indicated that there was no difference between V79-4 and irs2 in either the number of breaks induced or in the rate of their reversal following drug removal. In addition, levels of topoisomerase I activity in V79-4 and irs2 were indistinguishable. The data presented suggest that irs3 is likely to be defective in some aspect of DNA cross-link removal and irs2, whilst showing no gross defect in DNA strand break repair may fail to correctly respond to or repair certain types of strand breaks, possibly those associated with replicating DNA. The phenotypes of irs2 and irs3 respectively show similarities to those of cultured cells from the syndromes ataxia telangiectasia and Fanconi's anaemia.
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PMID:Cellular and chromosomal hypersensitivity to DNA crosslinking agents and topoisomerase inhibitors in the radiosensitive Chinese hamster irs mutants: phenotypic similarities to ataxia telangiectasia and Fanconi's anaemia cells. 826 16

Five topoisomerase II inhibitors (amsacrine [m-AMSA], two epipodophyllotoxins, and two quinolones) and the alkaloid camptothecin (a topoisomerase I inhibitor) were evaluated to assess their activities against Pneumocystis carinii. In vitro, both etoposide (VP-16) and teniposide (VM-26) at 1 microgram/ml suppressed P. carinii growth. Amsacrine was toxic to P. carinii and to the feeder cells in vitro. Camptothecin suppressed the growth of P. carinii in vitro only at 100 micrograms/ml. Studies in immunosuppressed mice demonstrated the efficacy of teniposide against P. carinii pneumonia, but successful administration of teniposide was schedule dependent with significant toxicity at therapeutic dosages.
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PMID:Activity of topoisomerase inhibitors against Pneumocystis carinii in vitro and in an inoculated mouse model. 839 91

DNA strand breaks which occur in HL-60 cells as a result of activation of endonuclease during apoptosis induced by cell treatment with the DNA topoisomerase I inhibitor camptothecin and topoisomerase II inhibitors teniposide, 4'-(9-acridinylamino)-3-methanesulfon-m-anisidide, and fostriecin were labeled in situ, in individual fixed and permeabilized cells, with biotinylated dUTP (detected by fluoresceinated avidin), using the terminal deoxynucleotidyl transferase or nick translation assays. During the early stage of apoptosis, prior to nuclear fragmentation, the breaks were predominantly localized at the nuclear periphery, close to the nuclear envelope. In more advanced stages, all cellular DNA, then localized within the cell as dense, homogeneous granules of a variety of sizes, was strongly labeled, indicating extensive and more uniform distribution of breaks throughout genomic DNA. Bivariate analysis of the incorporated biotinylated dUTP and cellular DNA content by flow cytometry made it possible to estimate the kinetics of the labeling reaction and relate DNA breaks to cell position in the cycle. The kinetics of biotinylated dUTP incorporation was faster, and the distinction of cells with DNA breaks was more pronounced, using the terminal transferase rather than the nick translation assay. Camptothecin, teniposide, and 4'-(9-acridinylamino)-3-methanesulfon-m-anisidide induced DNA breaks preferentially in S-phase cells, having little effect on cells in the G1 phase of the cycle. In contrast, fostriecin affected cells indiscriminately, in all phases of the cell cycle. The method of detection of DNA strand breaks (3'-hydroxyl termini) in individual cells offers several advantages and can be applied to clinical material (tumor biopsies) to study the induction of apoptosis in tumors during treatment, as a possible prognostic marker. The protein-associated DNA breaks in the "cleavable" DNA-topoisomerase complexes, which are the primary lesions induced by the inhibitors and precede apoptosis, were not detectable by the present methods.
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PMID:Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays. 846 13

The type I DNA topoisomerase isolated from bovine liver mitochondria is demonstrated here to be inhibited by camptothecin, a plant alkaloid previously shown to target the nuclear type I topoisomerase in mammalian cells. The antitumor drug reduces the ability of the mitochondrial enzyme to relax positive as well as negative supercoils although the inhibition of the former process requires more than 60-fold more drug than the latter process. A similar response is seen with the nuclear topoisomerase I. Camptothecin also stimulates the mitochondrial topoisomerase-induced cleavage of pUC19 at numerous, discrete sites. The antitumor drug 4'-(9-acridinylamino)-methanesulfon-m-anisidide, which has been shown to target the nuclear topoisomerase II, inhibited the mitochondrial type I topoisomerase relaxation activity, but this effect was found to be the result of the drug intercalating into the negatively supercoiled DNA rather than from a specific interaction with the mitochondrial enzyme. VM-26, a nonintercalating topoisomerase II poison, showed no inhibitory effect up to a concentration of 50 microM.
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PMID:Response of purified mitochondrial DNA topoisomerase I from bovine liver to camptothecin and m-AMSA. 855 21

Camptothecin is an S-phase-specific anticancer agent that inhibits the activity of the enzyme DNA topoisomerase-I (topo-I). Irreversible DNA double-strand breaks are produced during DNA synthesis in the presence of camptothecin, suggesting that this agent should not be toxic to nondividing cells, such as neurons. Unexpectedly, camptothecin induced significant, dose-dependent cell death of postmitotic rat cortical neurons in vitro; astrocytes were more resistant. Aphidicolin, an inhibitor of DNA polymerase alpha, did not prevent camptothecin-induced neuronal death, while death was prevented by actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole as well as cycloheximide and anisomycin, inhibitors of RNA and protein synthesis, respectively. Camptothecin-induced neuronal death was apoptotic, as characterized by chromatin condensation, cytoplasmic shrinking, plasma membrane blebbing, and fragmentation of neurites. DNA fragmentation was also confirmed by the use of the in situ DNA end labeling assay. In addition, aurintricarboxylic acid, an inhibitor of the apoptotic endonuclease, partially protected against camptothecin-induced neuronal death. The toxicity of stereoisomers of a camptothecin analogue was stereospecific, demonstrating that toxicity was a result of inhibition of topo-I. The difference in sensitivity to camptothecin between neurons and astrocytes correlated with their transcriptional activity and level of topo-I protein expression. These data indicate important roles for topo-I in postmitotic neurons and suggest that topo-I inhibitors can induce apoptosis independent of DNA synthesis. We suggest a model based on transcriptionally mediated DNA damage, a novel mechanism of action of topo-I poisons.
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PMID:Induction of neuronal apoptosis by camptothecin, an inhibitor of DNA topoisomerase-I: evidence for cell cycle-independent toxicity. 870 53

Camptothecin (CPT) traps covalent DNA topoisomerase I-linked DNA single-strand breaks (cleavable complexes). To determine the differences in DNA damage signalling leading to differential sensitivity to CPT, two human colon cancer cell lines, SW620 and KM12, with nonfunctional p53 and the same level of topoisomerase I cleavable complex formation but differential sensitivity to CPT (Cancer Res. 56:4430-7; 1996) were studied. The levels of mRNA expression of DNA damage-inducible or death-related genes were measured at different times after CPT treatment. KM12 cells exhibited 3-fold higher basal levels of BCL-2 mRNA. Consistently, secondary DNA fragmentation, quantitated using a filter elution assay, was detected 24 h later and was 2-4-fold lower in KM12 cells than in SW620 cells. No induction of BAX was detected in either cell line. Consistent with the absence of functional p53, p21CIP1/WAF1 and GADD45 genes were not induced within the first 24 h. However, in SW620 cells, both mRNA levels were increased more than 10-fold at 48 h. The BCL-2-related gene MCL-1 and topoisomerase II mRNA were induced at 24 h, and topoisomerase I mRNA levels increased 3-fold at 48 h, only in SW620 cells. We conclude that cellular response to CPT-induced DNA damage can involve p53-independent pathways leading to the induction of p53-effector genes. Induction of these genes at the onset of apoptosis is associated with CPT sensitivity.
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PMID:Differential GADD45, p21CIP1/WAF1, MCL-1 and topoisomerase II gene induction and secondary DNA fragmentation after camptothecin-induced DNA damage in two mutant p53 human colon cancer cell lines. 893 95

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

The acridine derivative m-AMCA (methyl-N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), a carbamate analogue of the topoisomerase II poison amsacrine, is distinguished by its high cytotoxicity against non-cycling tumour cells. We compared the response of cultured Lewis lung carcinoma cells to m-AMCA, amsacrine and the topoisomerase I poison camptothecin. The DNA polymerase inhibitor aphidicolin reversed the cytotoxicity of camptothecin fully, that of amsacrine partially, and that of m-AMCA minimally. The ability of m-AMCA to induce the enzyme poly(ADP-ribose)polymerase (PARP) was markedly lower than that of camptothecin or amsacrine. Cell cycle responses to m-AMCA and amsacrine were similar, with slowing of progress through S-phase and arrest in G2-phase. These cell cycle changes were also observed when plateau phase cultures were exposed to drug for 1 h, washed free of drug and cultured in fresh medium, with m-AMCA having a more pronounced effect than amsacrine and camptothecin having no effect. We also examined the role of p53 protein in the response using cultured human H460 cells. Both m-AMCA and amsacrine induced p53 protein expression in proliferating but not in non-proliferating H460 cells, and induced p21WAF1 regardless of proliferation status. Both induced G1-phase cell cycle arrest. It is suggested that two cytotoxicity mechanisms can be distinguished using these drugs. The first is specific for S-phase cells, is reversed by aphidicolin and induces PARP activity. The second is cell cycle non-specific, does not induce PARP and is unaffected by aphidicolin. Camptothecin activates only the first, m-AMCA primarily the second and amsacrine activates both.
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PMID:Cellular responses to methyl-N-[4-9-acridinylamino)-2-methoxyphenyl] carbamate hydrochloride, an analogue of amsacrine active against non-proliferating cells. 938 32


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