Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of cyanomorpholinyldoxorubicin, morpholinyldoxorubicin, doxorubicin, and Actinomycin D were studied on purified mouse leukemia (L1210) DNA topoisomerases I and II. DNA unwinding and cross-linking were also studied. It was found that 1) morpholinyldoxorubicin, cyanomorpholinyldoxorubicin, and Actinomycin D (but not doxorubicin) stimulated DNA topoisomerase I-induced cleavage at specific DNA sites; 2) only doxorubicin and Actinomycin D stimulated DNA cleavage by DNA topoisomerase II; 3) at higher drug concentrations, DNA intercalators suppressed enzyme-mediated DNA cleavage induced by DNA topoisomerase I, as well as topoisomerase II; 4) only cyanomorpholinyldoxorubicin produced DNA-DNA cross-links; no DNA unwinding could be observed; and 5) DNA intercalation (unwinding) potency of morpholinyldoxorubicin was about 2-fold less than that of doxorubicin. The data indicate that some DNA intercalators are not only inhibitors of DNA topoisomerase II but act also on DNA topoisomerase I. The stabilization of cleavage intermediates by intercalators may have a common mechanism for DNA topoisomerase I and DNA topoisomerase II.
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PMID:Effects of morpholinyl doxorubicins, doxorubicin, and actinomycin D on mammalian DNA topoisomerases I and II. 216 30

The activity of the endogenous DNA topoisomerase type I (EC 5.99.1.2) can be quantified in situ by determining how efficiently the enzyme is trapped in a covalent complex with DNA upon lysis of nuclei with detergents. In this way, we can measure relative levels of topoisomerase binding to DNA at native sites in chromatin. Since the majority of topoisomerase I is localized in the nucleolus at rRNA genes, we have evaluated how low levels of actinomycin D, which terminate transcription of rRNA genes, affect the activity of topoisomerase I. In vivo, as well as in vitro with purified topoisomerase I, we have found that drug treatment extends the half-life of the covalent topoisomerase-DNA complex. Actinomycin D stabilizes the nicked intermediate in the cleavage and resealing reaction but otherwise does not significantly alter the strand-passing ability of topoisomerase I. Sequence-specific cleavages by topoisomerase I were stimulated by actinomycin D at identical sequences recognized by the enzyme in the absence of drug. The localization of topoisomerase I in the nucleolus, coupled with the observation that transcription in this organelle is highly sensitive to actinomycin D and camptothecin treatment, leads us to propose that topoisomerase I contributes to actinomycin D inhibition of transcription.
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PMID:Stabilization of type I topoisomerase-DNA covalent complexes by actinomycin D. 283 Jun 18

Recombinant human tumor necrosis factor (rTNF) is a macrophage secretory protein with antitumor activity. The murine bladder tumor cell line MBT-2 was used to evaluate the in vitro and in vivo antitumor effects of rTNF in combination with chemotherapeutic drugs targeted at DNA topoisomerase II. These drugs, such as adriamycin and etoposide (VP 16), are in widespread use in the treatment of human cancer. The rTNF significantly enhanced the cytotoxic efficacy of the topoisomerase-targeted drugs actinomycin D, adriamycin, etoposide (VP 16) and teniposide (VM 26) against MBT-2 cells in vitro. The rTNF alone had no effect upon the cells in the same assay. When examined in vivo using MBT-2 tumor-bearing C3H/HeJ mice, these same antitumor relationships were seen. The addition of rTNF to actinomycin D or VP 16 resulted in a significant reduction in tumor volume at 20 days compared to untreated animals. Actinomycin D, VP 16 or rTNF treatment alone had no significant effect on 20 day tumor volume. The data provide a reasonable basis for the addition of rTNF to experimental protocols for the treatment of human bladder cancer using topoisomerase-targeted drugs such as adriamycin both intravesically and systemically. These observations may also be relevant to other human cancers currently treated with these drugs.
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PMID:Tumor necrosis factor enhances the in vitro and in vivo efficacy of chemotherapeutic drugs targeted at DNA topoisomerase II in the treatment of murine bladder cancer. 303 27

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

Actinomycin D is a well-known antibiotic of the actinomycin group that exhibits high antibacterial and antitumor activity. Actinomycin D has been widely used in clinical practice since 1954 as an anticancer drug for treating many tumors and it is also a useful tool in biochemistry and molecular biology. According to the Internet bibliographic database -- MEDLINE, actinomycins, and mainly actinomycin D, have been the subject of about 3300 science papers so far, and this paper is a review of the information concerning the mechanisms of action of actinomycin D. There are several mechanisms of its action that are responsible for its cytotoxic and antitumor action, these being associated with DNA functionality, leading to RNA and, consequently, protein synthesis inhibition. The two main mechanisms are intercalation to DNA and the stabilization of cleavable complexes of topoisomerases I and II with DNA, in which a phenoxazone ring localizes between GpC base pair sequence in DNA and polypeptide lactones rings occupy a position in the minor groove of the DNA helix or the drug penetrates to a place in the DNA structure where topoisomerase binds with DNA, respectively. Moreover, the slow dissociation of actinomycin D from DNA complexes, its photodynamic activity and free radical formation, as well as other biochemical effects of activity of actinomycin D may be, as suggested, important factors that influence the biological activity of this drug. In the literature not enough convincing evidence has been proposed that could indicate one particular mechanism of action as responsible for the biological activity of actinomycin D.
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PMID:[Actinomycin D and its mechanisms of action]. 1599 96