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

---

Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bisdioxopiperazines such as ICRF-159 and ICRF-193 have been shown to inhibit DNA topoisomerase II. To determine the molecular target of these compounds in vivo, we utilized a yeast genetic system in which the topoisomerase II activity can be modulated. To reduce topoisomerase II activity, we used top2-1 mutant yeast cells that have normal DNA topoisomerase II activity at 25 degrees C but greatly reduced enzyme activity at 30 degrees C, a temperature that is semipermissive for growth. At 25 degrees C top2-1 cells are as sensitive to the ICRF compounds as the wild-type strain; at 30 degrees C the cells became hypersensitive to these agents. In contrast, top2-1 strains become very resistant to the class of topoisomerase II inhibitors such as amsacrine and etoposide, which stabilize the covalent enzyme-DNA intermediate of the enzyme reaction. Overexpression of topoisomerase II from a plasmid-born TOP2 gene results in lower susceptibility to ICRF compounds and higher susceptibility to amsacrine than the parental strain exhibits. These results support the hypothesis that the main cellular target of ICRF compounds is DNA topoisomerase II, and that these compounds, unlike amsacrine and etoposide, inhibit topoisomerase II activity without stabilizing an enzyme-DNA covalent complex.
...
PMID:DNA topoisomerase II is the molecular target of bisdioxopiperazine derivatives ICRF-159 and ICRF-193 in Saccharomyces cerevisiae. 775 79

Sympathetic neurons depend on nerve growth factor (NGF) for their survival and die by apoptosis when NGF is withdrawn, despite their post-mitotic state. Martin et al. (1990, J. Neurosci. 10, 184-193) showed that cytosine arabinoside, but no other arabinofuranosyl nucleoside, could induce cell death in the presence of NGF and they suggested that it may block a critical step in the NGF-signalling pathway. We show that cytosine arabinoside is not the only nucleoside capable of inducing apoptosis in sympathetic neurons in the presence of NGF. In newly isolated neurons from P0 rat pups cultured in the presence of NGF, all the arabinose nucleosides (adenine, cytosine, guanine and thymine) induce apoptosis at 10 microM when combined with 5-fluorodeoxyuridine treatment. Because 1-beta-arabinofuranosylcytosine is associated with double-strand breaks and chromosomal abberrations, we examined whether topoisomerase II inhibitors, which also cause double-strand breaks by stabilising the enzyme-DNA 'cleavable complex', were capable of promoting apoptosis in these neurons. Although P0 rat neurons are strictly postmitotic, topoisomerase II inhibitors teniposide and mitoxantrone induced them to die by apoptosis in the presence of NGF with the same apparent time-course as arabinose treatment or NGF withdrawal. By contrast, ICRF 193, a catalytic inhibitor of topoisomerase II, reduced the extent of apoptosis induced by mitoxantrone or teniposide by 80% if added simultaneously with the latter but by 2 hours it had no rescue effect, suggesting that topoisomerase II is highly active in these neurons. ICRF 193 also partially reduced the induction of fluorodeoxyuridine-dependent apoptosis by the arabinose nucleosides.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Apoptosis is induced in post-mitotic rat sympathetic neurons by arabinosides and topoisomerase II inhibitors in the presence of NGF. 796 92

The enzyme DNA topoisomerase II, which removes the catenations formed between the DNA molecules of sister chromatids during replication and is a structural component of chromosome cores, is needed for chromosome condensation in yeast and in Xenopus extracts. Inhibitors of topoisomerase II arrest mammalian cells before mitosis in the G2 phase of the cell cycle, but also produce DNA damage, which causes arrest through established checkpoint controls. It is open to question whether cells need topoisomerase II to leave G2, or control late-cycle progression in response to its activity. Bisdioxopiperazines are topoisomerase II inhibitors that act without producing direct DNA damage; the most potent, ICRF-193, blocks mammalian entry into but not exit from mitosis. Here we show that checkpoint-evading agents such as caffeine override this block to produce abortively condensed chromosomes, indicating that topoisomerase II is needed for complete condensation. We find that exit from G2 is regulated by a catenation-sensitive checkpoint mechanism which is distinct from the G2-damage checkpoint.
...
PMID:A topoisomerase II-dependent G2 cycle checkpoint in mammalian cells/. 798 41

Sobuzoxane (MST-16) is an analogue of ICRF-159 which was once evaluated on the clinical efficacies in England. Zenyaku Pharm. Ind. in Japan synthesized many derivatives of bis (2,6-dioxopiperazine) and sobuzoxane was selected from the antitumor efficacies, the results of the toxicity tests and pharmacological profiles from these derivative. The compound was a new type topoisomerase II inhibitor, and G2M phase of the cell cycle was most sensitive. The clinical phase studies proved that sobuzoxane was quite effective for the treatment of malignant lymphoma (overall response rate in phase II study 29.7%) and adult T cell leukemia (response rate for acute type: 46.2%). The dose-limiting factor was leukopenia.
...
PMID:[A novel antitumor agent, sobuzoxane (MST-16)]. 800 28

Internucleosomal DNA fragmentation and cell death were induced dose- and time-dependently by incubation of mouse thymocytes with bis(2,6-dioxopiperazine) derivatives, ICRF-154 and MST-16, inhibitors of topoisomerase II, which do not induce cleavable complex formation. The process was inhibited by actinomycin D and cycloheximide, indicating that the process was an active apoptotic process. Bis(2,6-dioxopiperazine) derivatives have been known to inhibit the etoposide-induced DNA cleavage, but ICRF-154 did not inhibit etoposide-induced apoptosis in thymocytes at 6 h incubation, suggesting that DNA cleavage is not essential for induction of apoptosis by topoisomerase II inhibitors. The alteration of DNA helicity induced by a subtle inhibition of topoisomerase II activity may have an important role in the induction of apoptosis in thymocytes, since topoisomerase II is a major component of the nuclear matrix that can regulate gene expression.
...
PMID:bis(2,6-dioxopiperaxine) derivatives, topoisomerase II inhibitors which do not form a DNA cleavable complex, induce thymocyte apoptosis. 801 76

High resolution gel electrophoresis was used to demonstrate an inverse relationship between catenation linking number and superhelicity in highly catenated simian virus 40 chromosomes caused by exposure to the topoisomerase II inhibitor ICRF-193. Since ICRF-193 does not unwind DNA, we conclude that the decreased superhelicity in catenated SV40 daughter chromosomes is a direct result of increased catenation. It is likely that catenation decreases superhelicity by interfering with the formation of nucleosomes. The absence of normal chromatin structure in regions of catenation may facilitate access to topoisomerase II under normal conditions. ICRF-193 does not prevent initiation of SV40 DNA replication.
...
PMID:Inverse relationship between catenation and superhelicity in newly replicated simian virus 40 daughter chromosomes. 802 97

ICRF-193, a novel noncleavable, complex-stabilizing type topoisomerase (topo) II inhibitor, has been shown to target topo II in mammalian cells (Ishida, R., T. Miki, T. Narita, R. Yui, S. Sato, K. R. Utsumi, K. Tanabe, and T. Andoh. 1991. Cancer Res. 51:4909-4916). With the aim of elucidating the roles of topo II in mammalian cells, we examined the effects of ICRF-193 on the transition through the S phase, when the genome is replicated, and through the M phase, when the replicated genome is condensed and segregated. Replication of the genome did not appear to be affected by the drug because the scheduled synthesis of DNA and activation of cdc2 kinase followed by increase in mitotic index occurred normally, while VP-16, a cleavable, complex-stabilizing type topo II inhibitor, inhibited all these processes. In the M phase, however, late stages of chromosome condensation and segregation were clearly blocked by ICRF-193. Inhibition at the stage of compaction of 300-nm diameter chromatin fibers to 600-nm diameter chromatids was demonstrated using the drug during premature chromosome condensation (PCC) induced in tsBN2 baby hamster kidney cells in early S and G2 phases. In spite of interference with M phase chromosome dynamics, other mitotic events such as activation of cdc2 kinase, spindle apparatus reorganization and disassembly and reassembly of nuclear envelopes occurred, and the cells traversed an unusual M phase termed "absence of chromosome segregation" (ACS)-M phase. Cells then continued through further cell cycle rounds, becoming polyploid and losing viability. This effect of ICRF-193 on the cell cycle was shown to parallel that of inactivation of topo II on the cell cycle of the ts top2 mutant yeast. The results strongly suggest that the essential roles of topo II are confined to the M phase, when the enzyme decatenates intertwined replicated chromosomes. In other phases of the cycle, including the S phase, topo II may thus play a complementary role with topo I in controlling the torsional strain accumulated in various genetic processes.
...
PMID:Inhibition of DNA topoisomerase II by ICRF-193 induces polyploidization by uncoupling chromosome dynamics from other cell cycle events. 808 69

ICRF-193, a bis-(2,6-dioxopiperazine) derivative and a non-cleavable-complex-forming-type topoisomerase II inhibitor, inhibited cell division but allowed cells to traverse the cell cycle, leading to the accumulation of polyploid cells with 8C complements or more of DNA. Analysis of the mechanism of how cell division is inhibited by ICRF-193 revealed that: (1) replication of DNA was inhibited only at terminal stages; (2) CDC2 kinase was activated and cells enter absence-of-chromosome-segregation ('ACS') M-phase, where chromosomes are not fully condensed and are not separated, but other mitotic events, such as nuclear-envelope breakdown and cytoskeletal reorganization forming the spindle apparatus, take place, i.e. chromosome dynamics could be uncoupled from the other mitotic events which are normally co-ordinated with the former in mitosis; (3) cells successfully exit from mitosis to the next G1-phase to continue the cell cycle; (4) progression through 'ACS' M-phase appears to be lethal to the cells. All of these observations could be accounted for by inactivation of topoisomerase II activity of the cells caused by the drug. ICRF-193 was thus shown to be a valuable agent in elucidation of the role of topoisomerase II in genetic processes in vivo.
...
PMID:Role of DNA topoisomerase II in chromosome dynamics in mammalian cells. 825 Nov 15

Certain bis(2,6-dioxopiperazine) derivatives, which include ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl]propane; ADR-529) and its racemic compound ICRF 159 (Razoxane), have been investigated as antineoplastic agents. In addition, ICRF-187 is currently under intense study as an agent to ameliorate the cardiac toxicity of anthracycline therapy. These agents have recently been identified as inhibitors of topoisomerase II. We studied the effects of ICRF-187 and ICRF-159 on the progression of cultured epithelial cells through M phase. Beginning approximately 1.5 h after drug addition, chromosome condensation was significantly inhibited. Cells entered and progressed through M phase at near normal rates, but the lack of complete chromosome separation during anaphase resulted in catastrophic effects on normal chromosome distribution. Immunolabeling with Crest autoimmune sera, which recognizes centromere proteins, and with MPM-2 monoclonal antibody, which recognizes mitotic phosphoproteins, indicated that the centromeres of the chromosomes assembled a normal metaphase array in the presence of ICRF-187 and ICRF-159. Centromere separation in anaphase was initiated normally but was not completed because the chromatid arms failed to disengage from each other. Massive chromosome bridges were formed, and the chromatin mass became trapped in the cleavage furrow leading to its unequal distribution to the daughter cells. In many cases, all the chromatin was pushed into one of the two dividing cells. It is likely that previous studies, based on flow cytometry, indicating that bis(2,6-dioxypiperazine) derivatives cause an accumulation of cells with a 4N DNA content, reflect the incomplete segregation of chromosomes in mitosis rather than a block in G2 of the cell cycle as had been proposed.
...
PMID:Cell cycle progression and chromosome segregation in mammalian cells cultured in the presence of the topoisomerase II inhibitors ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane; ADR-529] and ICRF-159 (Razoxane). 831 60

Yeast temperature-sensitive mutants of DNA topoisomerase II are incapable of chromosome condensation and anaphase chromatid segregation. In mammalian cells, topoisomerase II inhibitors such as etoposide (VP-16-123) have similar effects. Unfortunately, conclusions drawn from work with mammalian cells have been limited by the fact that the standard inhibitors of topoisomerase II also generate DNA strand breaks, which when produced by other agents (e.g. ionizing radiation) are known to affect progression into and through mitosis. Here we show that the anti-tumour agent ICRF-193, recently identified as a topoisomerase II inhibitor operating by a non-standard mechanism, generates neither covalent complexes between topoisomerase II and DNA, nor adjacent DNA strand breaks, in mitotic HeLa. However, the drug does prevent anaphase segregation in HeLa and PtK2 cells, with effects similar to those of etoposide. We therefore conclude that topoisomerase II function is required for anaphase chromosome segregation in mammalian cells, as it is in yeast.
...
PMID:Topoisomerase II inhibition prevents anaphase chromatid segregation in mammalian cells independently of the generation of DNA strand breaks. 840 85


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---